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Xiao L, Li J, Liao J, Wu M, Lu X, Li J, Zeng Y. BCL2A1‑ and G0S2‑driven neutrophil extracellular traps: A protective mechanism linking preeclampsia to reduced breast cancer risk. Oncol Rep 2025; 53:64. [PMID: 40242964 PMCID: PMC12030921 DOI: 10.3892/or.2025.8897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 03/18/2025] [Indexed: 04/18/2025] Open
Abstract
Preeclampsia has been associated with a reduced risk of breast cancer (BC), but the mechanisms underlying this relationship remain unclear. It has been suggested that neutrophil extracellular traps (NETs), which are released upon neutrophil activation, play a key role in both preeclampsia and BC. To investigate this link, the single‑cell RNA sequencing dataset GSE173193 was analyzed and upregulated genes BCL2A1 and G0/G1 switch gene 2 (G0S2) were identified in neutrophils from preeclamptic placentas. These findings were validated using reverse transcription‑quantitative PCR and western blotting. Combined analyses of preeclampsia and BC tissues, from Gene Expression Omnibus (GSE24129) and The Cancer Genome Atlas databases respectively, identified 2,040 upregulated differentially expressed genes, including BCL2A1 and G0S2. Furthermore, these genes showed clinical relevance to BC, as demonstrated by Receiver Operating Characteristic curve, survival analyses and weighted gene co‑expression network analysis. Functional experiments revealed that overexpression of BCL2A1 and G0S2 increased NET release and inhibited BC cell proliferation, invasion and migration. The present study provides novel insights into the shared molecular pathways of preeclampsia and BC, emphasizing NETs as a potential protective mechanism as increased NET production in preeclampsia may contribute to a reduced BC risk by influencing tumor progression and offer avenues for further research into therapeutic interventions.
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Affiliation(s)
- Lu Xiao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jing Li
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jiahao Liao
- Department of Gastrointestinal Gland Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Min Wu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xiujing Lu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jiehua Li
- Department of Gastrointestinal Gland Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yachang Zeng
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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He A, Yang T, Lu S, Zou Y, Wan C, Chen Y, Zhao J, Liu N, Liu D, Li Y, Wang Y, Xu B, Hao J, Fu J, Zhang Q, Wang B, Li Y. Establishment and application of an RNA-seq-based predictive model for the hourly precision window of implantation (WOI) in patients with recurrent implantation failure. J Assist Reprod Genet 2025:10.1007/s10815-025-03468-8. [PMID: 40304883 DOI: 10.1007/s10815-025-03468-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 03/24/2025] [Indexed: 05/02/2025] Open
Abstract
PURPOSE This study aims to establish a single-time point RNA-sequencing-based endometrial receptivity test (rsERT) to provide hourly precision of endometrial WOI for patients with recurrent implantation failure (RIF). METHODS A two-phase study was conducted. In the first phase, a total of 70 patients with successful intrauterine pregnancy after personalized embryo transfer (pET) guided by three-time points rsERT were recruited for modified rsERT. Another 21 patients who underwent the prototype of single-time point rsERT were further included for optimization. In the second phase, another cohort of 574 patients with RIF that was recruited and assigned to the experimental group underwent pET guided by the modified rsERT (n = 261) or the control group underwent conventional ET (n = 313). The positive β-human chorionic gonadotropin (β-hCG), intrauterine pregnancy rate (IPR), implantation rate (IR), ongoing pregnancy rate, and live birth rate of the two groups were analyzed. RESULT The modified rsERT provided an hour-based predictive result of endometrial WOI with an average accuracy of 94.51% and sensitivity and specificity of 92.73% and 96.29%, respectively. The positive β-hCG, IPR, IR, ongoing pregnancy rate, and live birth rate of the experimental group were significantly different from those in the control group. After propensity score matching (PSM) control for the confounders, positive β-hCG, IR, and early spontaneous abortion rate showed significant differences. CONCLUSION The modified rsERT provided hourly precision WOI prediction using a single-time point endometrial biopsy and pregnancy outcomes were significantly improved, providing an enhanced endometrial receptivity test as an alternative requiring only a single-time point sampling for patients with RIF.
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Affiliation(s)
- Aihua He
- Reproductive Medicine Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, People's Republic of China
- Clinical Research Center for Women's Reproductive Health in Hunan Province, Changsha, 410008, Hunan, People's Republic of China
- Reproductive Medicine Center, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Tianli Yang
- Reproductive Medicine Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, People's Republic of China
- Clinical Research Center for Women's Reproductive Health in Hunan Province, Changsha, 410008, Hunan, People's Republic of China
| | - Sijia Lu
- Yikon Genomics Co., Ltd, Shanghai, 201499, People's Republic of China
| | - Yangyun Zou
- Yikon Genomics Co., Ltd, Shanghai, 201499, People's Republic of China
| | - Cheng Wan
- Yikon Genomics Co., Ltd, Shanghai, 201499, People's Republic of China
| | - Yulin Chen
- Yikon Genomics Co., Ltd, Shanghai, 201499, People's Republic of China
| | - Jing Zhao
- Reproductive Medicine Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, People's Republic of China
- Clinical Research Center for Women's Reproductive Health in Hunan Province, Changsha, 410008, Hunan, People's Republic of China
| | - Nenghui Liu
- Reproductive Medicine Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, People's Republic of China
- Clinical Research Center for Women's Reproductive Health in Hunan Province, Changsha, 410008, Hunan, People's Republic of China
| | - Donge Liu
- Reproductive Medicine Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, People's Republic of China
- Clinical Research Center for Women's Reproductive Health in Hunan Province, Changsha, 410008, Hunan, People's Republic of China
| | - Yumei Li
- Reproductive Medicine Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, People's Republic of China
- Clinical Research Center for Women's Reproductive Health in Hunan Province, Changsha, 410008, Hunan, People's Republic of China
| | - Yonggang Wang
- Reproductive Medicine Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, People's Republic of China
- Clinical Research Center for Women's Reproductive Health in Hunan Province, Changsha, 410008, Hunan, People's Republic of China
| | - Bin Xu
- Reproductive Medicine Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, People's Republic of China
- Clinical Research Center for Women's Reproductive Health in Hunan Province, Changsha, 410008, Hunan, People's Republic of China
| | - Jie Hao
- Reproductive Medicine Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, People's Republic of China
- Clinical Research Center for Women's Reproductive Health in Hunan Province, Changsha, 410008, Hunan, People's Republic of China
| | - Jing Fu
- Reproductive Medicine Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, People's Republic of China
- Clinical Research Center for Women's Reproductive Health in Hunan Province, Changsha, 410008, Hunan, People's Republic of China
| | - Qiong Zhang
- Reproductive Medicine Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, People's Republic of China
- Clinical Research Center for Women's Reproductive Health in Hunan Province, Changsha, 410008, Hunan, People's Republic of China
| | - Baisheng Wang
- Key Laboratory of Oral Health Research, Xiangya School of Stomatology, Central South University, Changsha, 410008, Hunan, People's Republic of China.
| | - Yanping Li
- Reproductive Medicine Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, People's Republic of China.
- Clinical Research Center for Women's Reproductive Health in Hunan Province, Changsha, 410008, Hunan, People's Republic of China.
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Yin Y, Pu L, Yang X, Zhu Y, Chen F, Wu C, Lei H, Wu W. G0S2 modulates normal vitreous-induced proliferation in endothelial cells. Commun Biol 2025; 8:560. [PMID: 40185884 PMCID: PMC11971441 DOI: 10.1038/s42003-025-07955-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 03/18/2025] [Indexed: 04/07/2025] Open
Abstract
Abnormal blood vessel growth in the eye is a leading cause of vision loss globally, particularly in diseases like diabetic retinopathy where the vitreous plays a crucial but poorly understood role in disease progression. While we know the vitreous can stimulate blood vessel growth, the specific molecular mechanisms remain unclear. Here we show that a protein called G0S2 (G0/G1 switch gene 2) serves as a key regulator of blood vessel growth in response to normal vitreous. Through comprehensive gene analysis, we discovered that G0S2 levels increase significantly when blood vessel cells are exposed to normal vitreous. The importance of G0S2 is highlighted by our finding that uveal melanoma patients with higher G0S2 levels had poorer survival rates. When we removed G0S2 from blood vessel cells, they no longer responded to vitreous stimulation, confirming its critical role. Notably, we identified an existing drug that can target G0S2, potentially offering a new therapeutic approach. This discovery of G0S2's role and its potential therapeutic targeting opens new avenues for treating eye diseases characterized by abnormal blood vessel growth, while also providing a valuable biomarker for predicting disease progression in eye cancer patients.
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Affiliation(s)
- Yiwei Yin
- Department of Ophthalmology, Hunan Key Laboratory of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
- Department of Pharmacy, Shenzhen Children's Hospital, Shenzhen, China
| | - Li Pu
- Department of Ophthalmology, Hunan Key Laboratory of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
- Department of Ophthalmology, Guiyang Aier Eye Hospital, Guiyang, China
| | - Xi Yang
- College of Computer Science and Technology, National University of Defense Technology, Changsha, Hunan, PR China
- National Key Laboratory of Parallel and Distributed Computing, National University of Defense Technology, Changsha, Hunan, PR China
| | - Ying Zhu
- Department of Ophthalmology, Hunan Key Laboratory of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Fang Chen
- Huan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China
| | - Chenkun Wu
- College of Computer Science and Technology, National University of Defense Technology, Changsha, Hunan, PR China
- State Key Laboratory of High-Performance Computing, National University of Defense Technology, Changsha, Hunan, PR China
| | - Hetian Lei
- Department of Ophthalmology The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Wenyi Wu
- Department of Ophthalmology, Hunan Key Laboratory of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China.
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Li Y, Wang B, Wang Z, Wen J, Zhou T, Tang J, Li Z. The Effect of G0S2 Gene Knockout on the Proliferation, Apoptosis, and Differentiation of Chicken Preadipocytes. Animals (Basel) 2025; 15:951. [PMID: 40218345 PMCID: PMC11988036 DOI: 10.3390/ani15070951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Revised: 03/24/2025] [Accepted: 03/24/2025] [Indexed: 04/14/2025] Open
Abstract
The G0/G1 switch gene 2 (G0S2) has been shown to be involved in cell proliferation, apoptosis, and differentiation in mammals. However, its function in poultry is not fully understood, especially in preadipocytes of chickens. This study aimed to establish a G0S2 knockout preadipocyte cell line in chickens through CRISPR/Cas9 technology and to thoroughly investigate the impact of G0S2 on chicken preadipocyte proliferation, apoptosis, and differentiation. To explore the involvement of G0S2 in chicken preadipocyte growth and development, transcriptome sequencing was performed. The results demonstrated that G0S2 was successfully deleted using the CRISPR/Cas9 system. G0S2 knockout significantly inhibited the differentiation of chicken preadipocytes while promoting their proliferation. Additionally, although G0S2 knockout exhibited a pro-apoptotic effect, it was relatively mild, primarily reflected in an increased proportion of early apoptotic cells. G0S2 deletion significantly affected the expression of important genes related to lipid metabolism, cell cycle control, and signaling pathways, based on transcriptomic analysis. In conclusion, our findings suggest that G0S2 performs a critical role in regulating chicken preadipocyte differentiation, proliferation, and apoptosis. This research offers valuable new insights into the molecular mechanisms and control of G0S2 in the growth and development of chicken preadipocytes.
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Affiliation(s)
- Yantao Li
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Y.L.); (B.W.); (Z.W.); (J.W.); (T.Z.); (J.T.)
- Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
| | - Boyu Wang
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Y.L.); (B.W.); (Z.W.); (J.W.); (T.Z.); (J.T.)
- Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
| | - Zhaochuan Wang
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Y.L.); (B.W.); (Z.W.); (J.W.); (T.Z.); (J.T.)
- Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
| | - Jintian Wen
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Y.L.); (B.W.); (Z.W.); (J.W.); (T.Z.); (J.T.)
- Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
| | - Tianle Zhou
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Y.L.); (B.W.); (Z.W.); (J.W.); (T.Z.); (J.T.)
- Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
| | - Jiahao Tang
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Y.L.); (B.W.); (Z.W.); (J.W.); (T.Z.); (J.T.)
- Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
| | - Zhenhui Li
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Y.L.); (B.W.); (Z.W.); (J.W.); (T.Z.); (J.T.)
- Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
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Wang X, Ye J, Wu Y, Zhang H, Li C, Liu B, Guan X, Tian X, Jia W, Liu Q, Li S, Sun R, Liu D, Xue G, Wang Z, Yan L, Lv A, Wu J, Qiu H, Hao C. Integrated lipidomics and RNA-seq reveal prognostic biomarkers in well-differentiated and dedifferentiated retroperitoneal liposarcoma. Cancer Cell Int 2024; 24:404. [PMID: 39696292 DOI: 10.1186/s12935-024-03585-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 11/26/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Retroperitoneal liposarcoma (RLPS) is a mesenchymal malignant tumor characterized by different degrees of adipocytic differentiation. Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are two of the most common subtypes of RLPS, exhibiting clear differences in biological behaviors and clinical prognosis. The metabolic features and genomic characteristics remain unclear. METHODS This study employed lipidomic and RNA-seq analyses of RLPS tissues from 19 WDLPS and 29 DDLPS patients. Western blot and immunohistochemistry staining were performed to verify the tumor tissue protein levels of TIMP1, FN1, MMP11, GPNMB, and ECM1. Enzyme-linked immunosorbent assay (ELISA) was performed to evaluate different serum protein levels in 128 blood samples from patients with RLPS. Multivariate analysis was performed to identify the most crucial variables associated with overall survival (OS) and recurrence-free survival (RFS) of the RLPS patients. RESULTS Lipidomic analysis revealed a significant difference in lipid metabolism, particularly in phosphatidylcholines and triacylglycerides metabolism. RNA sequencing analysis revealed that 1,630 differentially expressed genes (DEGs) were significantly enriched in lipid metabolism, developmental process, and extracellular matrix (ECM) pathways. Integrated lipidomic and transcriptomic analysis identified 29 genes as potential biomarkers between WDLPS and DDLPS. Among the 29 DEGs, we found that TIMP1, FN1, MMP11, GPNMB, and ECM1 were increased in DDLPS tumor tissues than in WDLPS tumor tissues. The receiver operating characteristic (ROC) curve showed high specificity and sensitivity in diagnosing patients using a five-gene combination (AUC = 0.904). ELISA revealed a significant increase in the serum levels of ECM1 and GPNMB in patients with DDLPS compared to patients with WDLPS. ECM1 increased progressively across different FNCLCC Grades, correlating negatively with RFS (P = 0.043). GPNMB levels showed a negative correlation with OS (P = 0.019). CONCLUSIONS Our study reveals different lipid metabolism, several transcriptional pathways between WDLPS and DDLPS, and examines several serum markers associated with the prognosis of RLPS. These findings provide a vital basis for future endeavors in diagnosing and predicting the prognosis of retroperitoneal liposarcoma with different differentiations.
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Affiliation(s)
- Xiaopeng Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Jingjing Ye
- Trauma Treatment Center, Peking University People's Hospital; Key Laboratory of Trauma Treatment and Neural Regeneration (Peking University), National Center for Trauma Medicine, Beijing, 100044, P. R. China
| | - Yan Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Hongtao Zhang
- Guowen (Changchun) International Hospital, Changchun, 130000, P. R. China
| | - Chengpeng Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Bonan Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Xiaoya Guan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Xiuyun Tian
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Weiwei Jia
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Qiao Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Shuquan Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Rongze Sun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Daoning Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Guoqiang Xue
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Zhen Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Liang Yan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Ang Lv
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Jianhui Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Hui Qiu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China.
| | - Chunyi Hao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China.
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Akula S, Alvarado-Vazquez A, Haide Mendez Enriquez E, Bal G, Franke K, Wernersson S, Hallgren J, Pejler G, Babina M, Hellman L. Characterization of Freshly Isolated Human Peripheral Blood B Cells, Monocytes, CD4+ and CD8+ T Cells, and Skin Mast Cells by Quantitative Transcriptomics. Int J Mol Sci 2024; 25:13050. [PMID: 39684762 DOI: 10.3390/ijms252313050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 11/25/2024] [Accepted: 12/01/2024] [Indexed: 12/18/2024] Open
Abstract
Quantitative transcriptomics offers a new way to obtain a detailed picture of freshly isolated cells. By direct isolation, the cells are unaffected by in vitro culture, and the isolation at cold temperatures maintains the cells relatively unaltered in phenotype by avoiding activation through receptor cross-linking or plastic adherence. Simultaneous analysis of several cell types provides the opportunity to obtain detailed pictures of transcriptomic differences between them. Here, we present such an analysis focusing on four human blood cell populations and compare those to isolated human skin mast cells. Pure CD19+ peripheral blood B cells, CD14+ monocytes, and CD4+ and CD8+ T cells were obtained by fluorescence-activated cell sorting, and KIT+ human connective tissue mast cells (MCs) were purified by MACS sorting from healthy skin. Detailed information concerning expression levels of the different granule proteases, protease inhibitors, Fc receptors, other receptors, transcription factors, cell signaling components, cytoskeletal proteins, and many other protein families relevant to the functions of these cells were obtained and comprehensively discussed. The MC granule proteases were found exclusively in the MC samples, and the T-cell granzymes in the T cells, of which several were present in both CD4+ and CD8+ T cells. High levels of CD4 were also observed in MCs and monocytes. We found a large variation between the different cell populations in the expression of Fc receptors, as well as for lipid mediators, proteoglycan synthesis enzymes, cytokines, cytokine receptors, and transcription factors. This detailed quantitative comparative analysis of more than 780 proteins of importance for the function of these populations can now serve as a good reference material for research into how these entities shape the role of these cells in immunity and tissue homeostasis.
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Affiliation(s)
- Srinivas Akula
- Department of Cell and Molecular Biology, Uppsala University, The Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden
- Department of Animal Biosciences, Swedish University of Agricultural Sciences, Box 7023, SE-75007 Uppsala, Sweden
| | - Abigail Alvarado-Vazquez
- Department of Medical Biochemistry and Microbiology, The Biomedical Center, Box 582, SE-75123 Uppsala, Sweden
| | - Erika Haide Mendez Enriquez
- Department of Medical Biochemistry and Microbiology, The Biomedical Center, Box 582, SE-75123 Uppsala, Sweden
| | - Gürkan Bal
- Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Kristin Franke
- Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Sara Wernersson
- Department of Animal Biosciences, Swedish University of Agricultural Sciences, Box 7023, SE-75007 Uppsala, Sweden
| | - Jenny Hallgren
- Department of Medical Biochemistry and Microbiology, The Biomedical Center, Box 582, SE-75123 Uppsala, Sweden
| | - Gunnar Pejler
- Department of Medical Biochemistry and Microbiology, The Biomedical Center, Box 582, SE-75123 Uppsala, Sweden
| | - Magda Babina
- Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Lars Hellman
- Department of Cell and Molecular Biology, Uppsala University, The Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden
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Takii R, Fujimoto M, Pandey A, Jaiswal K, Shearwin-Whyatt L, Grutzner F, Nakai A. HSF1 is required for cellular adaptation to daily temperature fluctuations. Sci Rep 2024; 14:21361. [PMID: 39266731 PMCID: PMC11393418 DOI: 10.1038/s41598-024-72415-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 09/06/2024] [Indexed: 09/14/2024] Open
Abstract
The heat shock response (HSR) is a universal mechanism of cellular adaptation to elevated temperatures and is regulated by heat shock transcription factor 1 (HSF1) or HSF3 in vertebrate endotherms, such as humans, mice, and chickens. We here showed that HSF1 and HSF3 from egg-laying mammals (monotremes), with a low homeothermic capacity, equally possess a potential to maximally induce the HSR, whereas either HSF1 or HSF3 from birds have this potential. Therefore, we focused on cellular adaptation to daily temperature fluctuations and found that HSF1 was required for the proliferation and survival of human cells under daily temperature fluctuations. The ectopic expression of vertebrate HSF1 proteins, but not HSF3 proteins, restored the resistance in HSF1-null cells, regardless of the induction of heat shock proteins. This function was associated with the up-regulation of specific HSF1-target genes. These results indicate the distinct role of HSF1 in adaptation to thermally fluctuating environments and suggest association of homeothermic capacity with functional diversification of vertebrate HSF genes.
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Affiliation(s)
- Ryosuke Takii
- Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Minami-Kogushi 1-1-1, Ube, 755-8505, Japan
| | - Mitsuaki Fujimoto
- Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Minami-Kogushi 1-1-1, Ube, 755-8505, Japan
| | - Akanksha Pandey
- Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Minami-Kogushi 1-1-1, Ube, 755-8505, Japan
| | - Kritika Jaiswal
- Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Minami-Kogushi 1-1-1, Ube, 755-8505, Japan
| | - Linda Shearwin-Whyatt
- School of Biological Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia
| | - Frank Grutzner
- School of Biological Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia
| | - Akira Nakai
- Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Minami-Kogushi 1-1-1, Ube, 755-8505, Japan.
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8
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Shen NX, Luo MY, Gu WM, Gong M, Lei HM, Bi L, Wang C, Zhang MC, Zhuang G, Xu L, Zhu L, Chen HZ, Shen Y. GSTO1 aggravates EGFR-TKIs resistance and tumor metastasis via deglutathionylation of NPM1 in lung adenocarcinoma. Oncogene 2024; 43:2504-2516. [PMID: 38969770 DOI: 10.1038/s41388-024-03096-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 06/20/2024] [Accepted: 06/27/2024] [Indexed: 07/07/2024]
Abstract
Despite significantly improved clinical outcomes in EGFR-mutant lung adenocarcinoma, all patients develop acquired resistance and malignancy on the treatment of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Understanding the resistance mechanisms is crucial to uncover novel therapeutic targets to improve the efficacy of EGFR-TKI treatment. Here, integrated analysis using RNA-Seq and shRNAs metabolic screening reveals glutathione S-transferase omega 1 (GSTO1) as one of the key metabolic enzymes that is required for EGFR-TKIs resistance in lung adenocarcinoma cells. Aberrant upregulation of GSTO1 confers EGFR-TKIs resistance and tumor metastasis in vitro and in vivo dependent on its active-site cysteine 32 (C32). Pharmacological inhibition or knockdown of GSTO1 restores sensitivity to EGFR-TKIs and synergistically enhances tumoricidal effects. Importantly, nucleophosmin 1 (NPM1) cysteine 104 is deglutathionylated by GSTO1 through its active C32 site, which leads to activation of the AKT/NF-κB signaling pathway. In addition, clinical data illustrates that GSTO1 level is positively correlated with NPM1 level, NF-κB-mediated transcriptions and progression of human lung adenocarcinoma. Overall, our study highlights a novel mechanism of GSTO1 mediating EGFR-TKIs resistance and malignant progression via protein deglutathionylation, and GSTO1/NPM1/AKT/NF-κB axis as a potential therapeutic vulnerability in lung adenocarcinoma.
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Affiliation(s)
- Ning-Xiang Shen
- Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Collaborative Innovation Center for Clinical and Translational Science by Chinese Ministry of Education & Shanghai, Shanghai, 200025, China
| | - Ming-Yu Luo
- Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Collaborative Innovation Center for Clinical and Translational Science by Chinese Ministry of Education & Shanghai, Shanghai, 200025, China
| | - Wei-Ming Gu
- Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Collaborative Innovation Center for Clinical and Translational Science by Chinese Ministry of Education & Shanghai, Shanghai, 200025, China
| | - Miaomiao Gong
- Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Collaborative Innovation Center for Clinical and Translational Science by Chinese Ministry of Education & Shanghai, Shanghai, 200025, China
| | - Hui-Min Lei
- Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Collaborative Innovation Center for Clinical and Translational Science by Chinese Ministry of Education & Shanghai, Shanghai, 200025, China
| | - Ling Bi
- Department of Medical Oncology & Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Cheng Wang
- Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Collaborative Innovation Center for Clinical and Translational Science by Chinese Ministry of Education & Shanghai, Shanghai, 200025, China
| | - Mo-Cong Zhang
- Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Collaborative Innovation Center for Clinical and Translational Science by Chinese Ministry of Education & Shanghai, Shanghai, 200025, China
| | - Guanglei Zhuang
- State Key Laboratory of Oncogenes and Related Genes, Department of Thoracic Surgery, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Lu Xu
- Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Collaborative Innovation Center for Clinical and Translational Science by Chinese Ministry of Education & Shanghai, Shanghai, 200025, China
| | - Liang Zhu
- Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Collaborative Innovation Center for Clinical and Translational Science by Chinese Ministry of Education & Shanghai, Shanghai, 200025, China
| | - Hong-Zhuan Chen
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ying Shen
- Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Collaborative Innovation Center for Clinical and Translational Science by Chinese Ministry of Education & Shanghai, Shanghai, 200025, China.
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9
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Shantaram D, Hoyd R, Blaszczak AM, Antwi L, Jalilvand A, Wright VP, Liu J, Smith AJ, Bradley D, Lafuse W, Liu Y, Williams NF, Snyder O, Wheeler C, Needleman B, Brethauer S, Noria S, Renton D, Perry KA, Nagareddy P, Wozniak D, Mahajan S, Rana PSJB, Pietrzak M, Schlesinger LS, Spakowicz DJ, Hsueh WA. Obesity-associated microbiomes instigate visceral adipose tissue inflammation by recruitment of distinct neutrophils. Nat Commun 2024; 15:5434. [PMID: 38937454 PMCID: PMC11211470 DOI: 10.1038/s41467-024-48935-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 05/17/2024] [Indexed: 06/29/2024] Open
Abstract
Neutrophils are increasingly implicated in chronic inflammation and metabolic disorders. Here, we show that visceral adipose tissue (VAT) from individuals with obesity contains more neutrophils than in those without obesity and is associated with a distinct bacterial community. Exploring the mechanism, we gavaged microbiome-depleted mice with stool from patients with and without obesity during high-fat or normal diet administration. Only mice receiving high-fat diet and stool from subjects with obesity show enrichment of VAT neutrophils, suggesting donor microbiome and recipient diet determine VAT neutrophilia. A rise in pro-inflammatory CD4+ Th1 cells and a drop in immunoregulatory T cells in VAT only follows if there is a transient spike in neutrophils. Human VAT neutrophils exhibit a distinct gene expression pattern that is found in different human tissues, including tumors. VAT neutrophils and bacteria may be a novel therapeutic target for treating inflammatory-driven complications of obesity, including insulin resistance and colon cancer.
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Affiliation(s)
- Dharti Shantaram
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH, 43210, USA
| | - Rebecca Hoyd
- Pelotonia Institute for Immuno-Oncology at The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, 43210, USA
| | - Alecia M Blaszczak
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH, 43210, USA
| | - Linda Antwi
- Pelotonia Institute for Immuno-Oncology at The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, 43210, USA
| | - Anahita Jalilvand
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH, 43210, USA
| | - Valerie P Wright
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH, 43210, USA
| | - Joey Liu
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH, 43210, USA
| | - Alan J Smith
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH, 43210, USA
| | - David Bradley
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH, 43210, USA
| | - William Lafuse
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, 43210, USA
| | - YunZhou Liu
- Pelotonia Institute for Immuno-Oncology at The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, 43210, USA
| | - Nyelia F Williams
- Pelotonia Institute for Immuno-Oncology at The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, 43210, USA
| | - Owen Snyder
- Pelotonia Institute for Immuno-Oncology at The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, 43210, USA
| | - Caroline Wheeler
- Pelotonia Institute for Immuno-Oncology at The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, 43210, USA
| | - Bradley Needleman
- Center for Minimally Invasive Surgery, Department of General Surgery, The Ohio State University, Columbus, OH, 43210, USA
| | - Stacy Brethauer
- Center for Minimally Invasive Surgery, Department of General Surgery, The Ohio State University, Columbus, OH, 43210, USA
| | - Sabrena Noria
- Center for Minimally Invasive Surgery, Department of General Surgery, The Ohio State University, Columbus, OH, 43210, USA
| | - David Renton
- Center for Minimally Invasive Surgery, Department of General Surgery, The Ohio State University, Columbus, OH, 43210, USA
| | - Kyle A Perry
- Center for Minimally Invasive Surgery, Department of General Surgery, The Ohio State University, Columbus, OH, 43210, USA
| | - Prabha Nagareddy
- Department of Internal Medicine, Cardiovascular Section University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK, 73117, USA
| | - Daniel Wozniak
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, 43210, USA
| | - Sahil Mahajan
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, 43210, USA
| | - Pranav S J B Rana
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, 43210, USA
| | - Maciej Pietrzak
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA
| | - Larry S Schlesinger
- Host Pathogen Interactions Program, Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
| | - Daniel J Spakowicz
- Pelotonia Institute for Immuno-Oncology at The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, 43210, USA.
| | - Willa A Hsueh
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH, 43210, USA.
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10
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Zhao X, Chen K, Wang J, Qiu Y. Analysis of Prospective Genetic Indicators for Prenatal Exposure to Arsenic in Newborn Cord Blood of Using Machine Learning. Biol Trace Elem Res 2024; 202:2466-2473. [PMID: 37740142 DOI: 10.1007/s12011-023-03863-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 09/12/2023] [Indexed: 09/24/2023]
Abstract
Using a machine learning methods, we aim to find biological effect biomarkers of prenatal arsenic exposure in newborn cord blood. From the Gene Expression Omnibus (GEO) database, two datasets (GSE48354 and GSE7967) pertaining to cord blood sequencing while exposed to arsenic were retrieved and merged for additional study. Using the "limma" package in the R, differentially expressed genes (DEGs) were eliminated. Machine learning techniques of the LASSO regression algorithm and SVM-RFE algorithm were used to find potential biological effect biomarkers for cord blood sequencing in pregnant women exposed to arsenic. To evaluate the efficacy of biomarkers, a receiver operating characteristic (ROC) curve was used. Furthermore, we investigated the proportion of invading immune cells in each sample using CIBERSORT, and we investigated the relationship between biomarkers and immune cells using the Spearman approach. Using LASSO regression and the SVM-RFE technique, 28 DEGs were discovered, and the main biomarkers of cord blood exposed to arsenic were discovered to be DENND2D, OLIG1, RGS18, CXCL16, DDIT4, FOS, G0S2, GPR183, JMJD6, and SOCS3. According to an immune infiltration analysis and correlation analysis, key biomarkers were substantially associated with the invading immune cells. Ten genes are important biomarkers of cord blood exposed to arsenic connected with infiltrating immune cells, and infiltrating immune cells may play important roles in cord blood exposed to arsenic, according to the study's findings.
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Affiliation(s)
- Xiaotian Zhao
- Department of Toxicology, School of Public Health, Shanxi Medical University, 56 Xinjian Nan Road, Taiyuan, CN 030001, China
| | - Kun Chen
- Department of Toxicology, School of Public Health, Shanxi Medical University, 56 Xinjian Nan Road, Taiyuan, CN 030001, China
| | - Jing Wang
- Department of Toxicology, School of Public Health, Shanxi Medical University, 56 Xinjian Nan Road, Taiyuan, CN 030001, China
| | - Yulan Qiu
- Department of Toxicology, School of Public Health, Shanxi Medical University, 56 Xinjian Nan Road, Taiyuan, CN 030001, China.
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11
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Pereira F, Fernández-Barral A, Larriba MJ, Barbáchano A, González-Sancho JM. From molecular basis to clinical insights: a challenging future for the vitamin D endocrine system in colorectal cancer. FEBS J 2024; 291:2485-2518. [PMID: 37699548 DOI: 10.1111/febs.16955] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 08/03/2023] [Accepted: 09/11/2023] [Indexed: 09/14/2023]
Abstract
Colorectal cancer (CRC) is one of the most life-threatening neoplasias in terms of incidence and mortality worldwide. Vitamin D deficiency has been associated with an increased risk of CRC. 1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the most active vitamin D metabolite, is a pleiotropic hormone that, through its binding to a transcription factor of the nuclear receptor superfamily, is a major regulator of the human genome. 1,25(OH)2D3 acts on colon carcinoma and stromal cells and displays tumor protective actions. Here, we review the variety of molecular mechanisms underlying the effects of 1,25(OH)2D3 in CRC, which affect multiple processes that are dysregulated during tumor initiation and progression. Additionally, we discuss the epidemiological data that associate vitamin D deficiency and CRC, and the most relevant randomized controlled trials of vitamin D3 supplementation conducted in both healthy individuals and CRC patients.
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Affiliation(s)
- Fábio Pereira
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Servicio de Oncología Radioterápica, Complejo Hospitalario Universitario de Ourense, Spain
| | - Asunción Fernández-Barral
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
| | - María Jesús Larriba
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
| | - Antonio Barbáchano
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
| | - José Manuel González-Sancho
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
- Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain
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12
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Lin S, Ma L, Mo J, Zhao R, Li J, Yu M, Jiang M, Peng L. Immune cell senescence and exhaustion promote the occurrence of liver metastasis in colorectal cancer by regulating epithelial-mesenchymal transition. Aging (Albany NY) 2024; 16:7704-7732. [PMID: 38683136 PMCID: PMC11132022 DOI: 10.18632/aging.205778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 04/03/2024] [Indexed: 05/01/2024]
Abstract
BACKGROUND Liver metastasis (LM) stands as a primary cause of mortality in metastatic colorectal cancer (mCRC), posing a significant impediment to long-term survival benefits from targeted therapy and immunotherapy. However, there is currently a lack of comprehensive investigation into how senescent and exhausted immune cells contribute to LM. METHODS We gathered single-cell sequencing data from primary colorectal cancer (pCRC) and their corresponding matched LM tissues from 16 mCRC patients. In this study, we identified senescent and exhausted immune cells, performed enrichment analysis, cell communication, cell trajectory, and cell-based in vitro experiments to validate the results of single-cell multi-omics. This process allowed us to construct a regulatory network explaining the occurrence of LM. Finally, we utilized weighted gene co-expression network analysis (WGCNA) and 12 machine learning algorithms to create prognostic risk model. RESULTS We identified senescent-like myeloid cells (SMCs) and exhausted T cells (TEXs) as the primary senescent and exhausted immune cells. Our findings indicate that SMCs and TEXs can potentially activate transcription factors downstream via ANGPTL4-SDC1/SDC4, this activation plays a role in regulating the epithelial-mesenchymal transition (EMT) program and facilitates the development of LM, the results of cell-based in vitro experiments have provided confirmation of this conclusion. We also developed and validated a prognostic risk model composed of 12 machine learning algorithms. CONCLUSION This study elucidates the potential molecular mechanisms underlying the occurrence of LM from various angles through single-cell multi-omics analysis in CRC. It also constructs a network illustrating the role of senescent or exhausted immune cells in regulating EMT.
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Affiliation(s)
- Sen Lin
- The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lanyue Ma
- The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiaxin Mo
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ruiqi Zhao
- The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jinghao Li
- Department of Traditional Chinese Medicine, The Sixth Affiliated Hospital, South China University of Technology, Foshan, China
| | - Mengjiao Yu
- The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Mei Jiang
- Department of Oncology, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lisheng Peng
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
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13
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Ferrer-Mayorga G, Muñoz A, González-Sancho JM. Vitamin D and colorectal cancer. FELDMAN AND PIKE'S VITAMIN D 2024:859-899. [DOI: 10.1016/b978-0-323-91338-6.00039-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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14
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Engin AB, Engin A. The Checkpoints of Intestinal Fat Absorption in Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:73-95. [PMID: 39287849 DOI: 10.1007/978-3-031-63657-8_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
In this chapter, intestinal lipid transport, which plays a central role in fat homeostasis and the development of obesity in addition to the mechanisms of fatty acids and monoacylglycerol absorption in the intestinal lumen and reassembly of these within the enterocyte was described. A part of the resynthesized triglycerides (triacylglycerols; TAG) is repackaged in the intestine to form the hydrophobic core of chylomicrons (CMs). These are delivered as metabolic fuels, essential fatty acids, and other lipid-soluble nutrients, from enterocytes to the peripheral tissues following detachment from the endoplasmic reticulum membrane. Moreover, the attitudes of multiple receptor functions in dietary lipid uptake, synthesis, and transport are highlighted. Additionally, intestinal fatty acid binding proteins (FABPs), which increase the cytosolic flux of fatty acids via intermembrane transfer in enterocytes, and the functions of checkpoints for receptor-mediated fatty acid signaling are debated. The importance of the balance between storage and secretion of dietary fat by enterocytes in determining the physiological fate of dietary fat, including regulation of blood lipid concentrations and energy balance, is mentioned. Consequently, promising checkpoints regarding how intestinal fat processing affects lipid homeostatic mechanisms and lipid stores in the body and the prevention of obesity-lipotoxicity due to excessive intestinal lipid absorption are evaluated. In this context, dietary TAG digestion, pharmacological inhibition of TAG hydrolysis, the regulation of long-chain fatty acid uptake traffic into adipocytes, intracellular TAG resynthesis, the enlargement of cytoplasmic lipid droplets in enterocytes and constitutional alteration of their proteome, CD36-mediated conversion of diet-derived fatty acid into cellular lipid messengers and their functions are discussed.
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
| | - Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey
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15
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Kulminskaya N, Rodriguez Gamez CF, Hofer P, Cerk IK, Dubey N, Viertlmayr R, Sagmeister T, Pavkov-Keller T, Zechner R, Oberer M. Unmasking crucial residues in adipose triglyceride lipase for coactivation with comparative gene identification-58. J Lipid Res 2024; 65:100491. [PMID: 38135254 PMCID: PMC10828586 DOI: 10.1016/j.jlr.2023.100491] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 12/04/2023] [Accepted: 12/08/2023] [Indexed: 12/24/2023] Open
Abstract
Lipolysis is an essential metabolic process that releases unesterified fatty acids from neutral lipid stores to maintain energy homeostasis in living organisms. Adipose triglyceride lipase (ATGL) plays a key role in intracellular lipolysis and can be coactivated upon interaction with the protein comparative gene identification-58 (CGI-58). The underlying molecular mechanism of ATGL stimulation by CGI-58 is incompletely understood. Based on analysis of evolutionary conservation, we used site directed mutagenesis to study a C-terminally truncated variant and full-length mouse ATGL providing insights in the protein coactivation on a per-residue level. We identified the region from residues N209-N215 in ATGL as essential for coactivation by CGI-58. ATGL variants with amino acids exchanges in this region were still able to hydrolyze triacylglycerol at the basal level and to interact with CGI-58, yet could not be activated by CGI-58. Our studies also demonstrate that full-length mouse ATGL showed higher tolerance to specific single amino acid exchanges in the N209-N215 region upon CGI-58 coactivation compared to C-terminally truncated ATGL variants. The region is either directly involved in protein-protein interaction or essential for conformational changes required in the coactivation process. Three-dimensional models of the ATGL/CGI-58 complex with the artificial intelligence software AlphaFold demonstrated that a large surface area is involved in the protein-protein interaction. Mapping important amino acids for coactivation of both proteins, ATGL and CGI-58, onto the 3D model of the complex locates these essential amino acids at the predicted ATGL/CGI-58 interface thus strongly corroborating the significance of these residues in CGI-58-mediated coactivation of ATGL.
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Affiliation(s)
| | | | - Peter Hofer
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Ines Kathrin Cerk
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Noopur Dubey
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Roland Viertlmayr
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Theo Sagmeister
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Tea Pavkov-Keller
- Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria
| | - Rudolf Zechner
- Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria
| | - Monika Oberer
- Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria.
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16
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Liang Y, Lai S, Huang L, Li Y, Zeng S, Zhang S, Chen J, Deng W, Liu Y, Liang J, Xu P, Liu M, Xiong Z, Chen D, Tu Z, Du L. JAZF1 safeguards human endometrial stromal cells survival and decidualization by repressing the transcription of G0S2. Commun Biol 2023; 6:568. [PMID: 37244968 DOI: 10.1038/s42003-023-04931-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 05/12/2023] [Indexed: 05/29/2023] Open
Abstract
Decidualization of human endometrial stromal cells (hESCs) is essential for the maintenance of pregnancy, which depends on the fine-tuned regulation of hESCs survival, and its perturbation contributes to pregnancy loss. However, the underlying mechanisms responsible for functional deficits in decidua from recurrent spontaneous abortion (RSA) patients have not been elucidated. Here, we observed that JAZF1 was significantly downregulated in stromal cells from RSA decidua. JAZF1 depletion in hESCs resulted in defective decidualization and cell death through apoptosis. Further experiments uncovered G0S2 as a important driver of hESCs apoptosis and decidualization, whose transcription was repressed by JAZF1 via interaction with G0S2 activator Purβ. Moreover, the pattern of low JAZF1, high G0S2 and excessive apoptosis in decidua were consistently observed in RSA patients. Collectively, our findings demonstrate that JAZF1 governs hESCs survival and decidualization by repressing G0S2 transcription via restricting the activity of Purβ, and highlight the clinical implications of these mechanisms in the pathology of RSA.
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Affiliation(s)
- Yingyu Liang
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Siying Lai
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Lijun Huang
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Yulian Li
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Shanshan Zeng
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Shuang Zhang
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Jingsi Chen
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Wenbo Deng
- Department of Obstetrics and Gynecology, Fujian Provincial Key Laboratory of Reproductive Health Research, The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, 361102, China
| | - Yu Liu
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Jingying Liang
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Pei Xu
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Mingxing Liu
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Zhongtang Xiong
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Dunjin Chen
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
| | - Zhaowei Tu
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
| | - Lili Du
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
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17
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Corbet AK, Bikorimana E, Boyd RI, Shokry D, Kries K, Gupta A, Paton A, Sun Z, Fazal Z, Freemantle SJ, Nelson ER, Spinella MJ, Singh R. G0S2 promotes antiestrogenic and pro-migratory responses in ER+ and ER- breast cancer cells. Transl Oncol 2023; 33:101676. [PMID: 37086619 DOI: 10.1016/j.tranon.2023.101676] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/12/2023] [Accepted: 04/14/2023] [Indexed: 04/24/2023] Open
Abstract
G0/G1 switch gene 2 (G0S2) is known to inhibit lipolysis by inhibiting adipose triglyceride lipase (ATGL). In this report, we dissect the role of G0S2 in ER+ versus ER- breast cancer. Overexpression of G0S2 in ER- cells increased cell proliferation, while G0S2 overexpression in ER+ cells decreased cell proliferation. Transcriptome analysis revealed that G0S2 mediated distinct but overlapping transcriptional responses in ER- and ER+ cells. G0S2 reduced genes associated with an epithelial phenotype, especially in ER- cells, including CDH1, ELF3, STEAP4 and TACSTD2, suggesting promotion of the epithelial-mesenchymal transition (EMT). G0S2 also repressed estrogen signaling and estrogen receptor target gene signatures, especially in ER+ cells, including TFF1 and TFF3. In addition, G0S2 overexpression increased cell migration in ER- cells and increased estrogen deprivation sensitivity in ER+ cells. Interestingly, two genes downstream of ATGL in fat utilization and very important in steroid hormone biosynthesis, HMGCS1 and HMGCS2, were downregulated in G0S2 overexpressing ER+ cells. In addition, HSD17B11, a gene that converts estradiol to its less estrogenic derivative, estrone, was highly upregulated in G0S2 overexpressing ER+ cells, suggesting G0S2 overexpression has a negative effect on estradiol production and maintenance. High expression of G0S2 and HSD17B11 was associated with improved relapse-free survival in breast cancer patients while high expression of HMGSC1 was associated with poor survival. Finally, we deleted G0S2 in breast cancer-prone MMTV-PyMT mice. Our data indicates a complex role for G0S2 in breast cancer, dependent on ER status, that may be partially mediated by suppression of the estrogen signaling pathway.
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Affiliation(s)
- Andrea K Corbet
- Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Emmanuel Bikorimana
- Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Raya I Boyd
- Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Doha Shokry
- Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Kelly Kries
- Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Ayush Gupta
- Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Anneliese Paton
- Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Zhengyang Sun
- Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Zeeshan Fazal
- Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Sarah J Freemantle
- Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Erik R Nelson
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA; Carle Illinois College of Medicine University of Illinois Urbana-Champaign, Urbana IL 61801, USA; Carl R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People Theme, University of Illinois Urbana-Champaign, Urbana IL 61801, USA; Cancer Center of Illinois, University of Illinois Urbana-Champaign, Urbana IL 61801, USA
| | - Michael J Spinella
- Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA; Carle Illinois College of Medicine University of Illinois Urbana-Champaign, Urbana IL 61801, USA; Carl R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People Theme, University of Illinois Urbana-Champaign, Urbana IL 61801, USA; Cancer Center of Illinois, University of Illinois Urbana-Champaign, Urbana IL 61801, USA.
| | - Ratnakar Singh
- Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA.
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18
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Neill G, Masson GR. A stay of execution: ATF4 regulation and potential outcomes for the integrated stress response. Front Mol Neurosci 2023; 16:1112253. [PMID: 36825279 PMCID: PMC9941348 DOI: 10.3389/fnmol.2023.1112253] [Citation(s) in RCA: 78] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/19/2023] [Indexed: 02/10/2023] Open
Abstract
ATF4 is a cellular stress induced bZIP transcription factor that is a hallmark effector of the integrated stress response. The integrated stress response is triggered by phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 complex that can be carried out by the cellular stress responsive kinases; GCN2, PERK, PKR, and HRI. eIF2α phosphorylation downregulates mRNA translation initiation en masse, however ATF4 translation is upregulated. The integrated stress response can output two contradicting outcomes in cells; pro-survival or apoptosis. The mechanism for choice between these outcomes is unknown, however combinations of ATF4 heterodimerisation partners and post-translational modifications have been linked to this regulation. This semi-systematic review article covers ATF4 target genes, heterodimerisation partners and post-translational modifications. Together, this review aims to be a useful resource to elucidate the mechanisms controlling the effects of the integrated stress response. Additional putative roles of the ATF4 protein in cell division and synaptic plasticity are outlined.
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Affiliation(s)
- Graham Neill
- Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, United Kingdom
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19
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Rider SD, Damewood FJ, Gadgil RY, Hitch DC, Alhawach V, Shrestha R, Shanahan M, Zavada N, Leffak M. Suppressors of Break-Induced Replication in Human Cells. Genes (Basel) 2023; 14:genes14020398. [PMID: 36833325 PMCID: PMC9956954 DOI: 10.3390/genes14020398] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/23/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
Short tandem DNA repeats are drivers of genome instability. To identify suppressors of break-induced mutagenesis human cells, unbiased genetic screens were conducted using a lentiviral shRNA library. The recipient cells possessed fragile non-B DNA that could induce DNA double-strand breaks (DSBs), integrated at an ectopic chromosomal site adjacent to a thymidine kinase marker gene. Mutagenesis of the thymidine kinase gene rendered cells resistant to the nucleoside analog ganciclovir (GCV). The screen identified genes that have established roles in DNA replication and repair, chromatin modification, responses to ionizing radiation, and genes encoding proteins enriched at replication forks. Novel loci implicated in BIR included olfactory receptors, the G0S2 oncogene/tumor suppressor axis, the EIF3H-METTL3 translational regulator, and the SUDS3 subunit of the Sin3A corepressor. Consistent with a role in suppressing BIR, siRNA knockdown of selected candidates increased the frequency of the GCVr phenotype and increased DNA rearrangements near the ectopic non-B DNA. Inverse PCR and DNA sequence analyses showed that hits identified in the screen increased genome instability. Further analysis quantitated repeat-induced hypermutagenesis at the ectopic site and showed that knockdown of a primary hit, COPS2, induced mutagenic hotspots, remodeled the replication fork, and increased nonallelic chromosome template switches.
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20
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Justynski O, Bridges K, Krause W, Forni MF, Phan Q, Sandoval-Schaefer T, Driskell R, Miller-Jensen K, Horsley V. Apoptosis recognition receptors regulate skin tissue repair in mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.17.523241. [PMID: 36711968 PMCID: PMC9882102 DOI: 10.1101/2023.01.17.523241] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Apoptosis and clearance of apoptotic cells via efferocytosis are evolutionarily conserved processes that drive tissue repair. However, the mechanisms by which recognition and clearance of apoptotic cells regulate repair are not fully understood. Here, we use single-cell RNA sequencing to provide a map of the cellular dynamics during early inflammation in mouse skin wounds. We find that apoptotic pathways and efferocytosis receptors are elevated in fibroblasts and immune cells, including resident Lyve1 + macrophages, during inflammation. Interestingly, human diabetic foot wounds upregulate mRNAs for apoptotic genes and display increased and altered efferocytosis signaling via the receptor Axl. During early inflammation in mouse wounds, we detect upregulation of Axl in dendritic cells and fibroblasts via TLR3-independent mechanisms. Inhibition studies in vivo in mice reveal that Axl signaling is required for wound repair but is dispensable for efferocytosis. By contrast, inhibition of another efferocytosis receptor, Timd4, in mouse wounds decreases efferocytosis and abrogates wound repair. These data highlight the distinct mechanisms by which apoptotic cell detection coordinates tissue repair and provides potential therapeutic targets for chronic wounds in diabetic patients.
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21
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Broeders M, van Rooij J, Oussoren E, van Gestel T, Smith C, Kimber S, Verdijk R, Wagenmakers M, van den Hout J, van der Ploeg A, Narcisi R, Pijnappel W. Modeling cartilage pathology in mucopolysaccharidosis VI using iPSCs reveals early dysregulation of chondrogenic and metabolic gene expression. Front Bioeng Biotechnol 2022; 10:949063. [PMID: 36561048 PMCID: PMC9763729 DOI: 10.3389/fbioe.2022.949063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 11/09/2022] [Indexed: 12/12/2022] Open
Abstract
Mucopolysaccharidosis type VI (MPS VI) is a metabolic disorder caused by disease-associated variants in the Arylsulfatase B (ARSB) gene, resulting in ARSB enzyme deficiency, lysosomal glycosaminoglycan accumulation, and cartilage and bone pathology. The molecular response to MPS VI that results in cartilage pathology in human patients is largely unknown. Here, we generated a disease model to study the early stages of cartilage pathology in MPS VI. We generated iPSCs from four patients and isogenic controls by inserting the ARSB cDNA in the AAVS1 safe harbor locus using CRISPR/Cas9. Using an optimized chondrogenic differentiation protocol, we found Periodic acid-Schiff positive inclusions in hiPSC-derived chondrogenic cells with MPS VI. Genome-wide mRNA expression analysis showed that hiPSC-derived chondrogenic cells with MPS VI downregulated expression of genes involved in TGF-β/BMP signalling, and upregulated expression of inhibitors of the Wnt/β-catenin signalling pathway. Expression of genes involved in apoptosis and growth was upregulated, while expression of genes involved in glycosaminoglycan metabolism was dysregulated in hiPSC-derived chondrogenic cells with MPS VI. These results suggest that human ARSB deficiency in MPS VI causes changes in the transcriptional program underlying the early stages of chondrogenic differentiation and metabolism.
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Affiliation(s)
- M. Broeders
- Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam, Netherlands
- Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands
- Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | - Jgj van Rooij
- Department of Internal Medicine, Erasmus MC Medical Center, Rotterdam, Netherlands
| | - E. Oussoren
- Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam, Netherlands
- Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | - Tjm van Gestel
- Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam, Netherlands
- Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands
- Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | - Ca Smith
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Sj Kimber
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Rm Verdijk
- Department of Pathology, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | - Maem Wagenmakers
- Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands
- Department of Internal Medicine, Erasmus MC Medical Center, Rotterdam, Netherlands
| | - Jmp van den Hout
- Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam, Netherlands
- Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | - At van der Ploeg
- Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam, Netherlands
- Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | - R. Narcisi
- Department of Orthopaedics and Sports Medicine, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | - Wwmp Pijnappel
- Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam, Netherlands
- Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands
- Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands
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22
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Gonzalez MA, Olivas IM, Bencomo‐Alvarez AE, Rubio AJ, Barreto‐Vargas C, Lopez JL, Dang SK, Solecki JP, McCall E, Astudillo G, Velazquez VV, Schenkel K, Reffell K, Perkins M, Nguyen N, Apaflo JN, Alvidrez E, Young JE, Lara JJ, Yan D, Senina A, Ahmann J, Varley KE, Mason CC, Eide CA, Druker BJ, Nurunnabi M, Padilla O, Bajpeyi S, Eiring AM. Loss of G0/G1 switch gene 2 (G0S2) promotes disease progression and drug resistance in chronic myeloid leukaemia (CML) by disrupting glycerophospholipid metabolism. Clin Transl Med 2022; 12:e1146. [PMID: 36536477 PMCID: PMC9763536 DOI: 10.1002/ctm2.1146] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 11/23/2022] [Accepted: 11/28/2022] [Indexed: 12/24/2022] Open
Abstract
Tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 have turned chronic myeloid leukaemia (CML) from a fatal disease into a manageable condition for most patients. Despite improved survival, targeting drug-resistant leukaemia stem cells (LSCs) remains a challenge for curative CML therapy. Aberrant lipid metabolism can have a large impact on membrane dynamics, cell survival and therapeutic responses in cancer. While ceramide and sphingolipid levels were previously correlated with TKI response in CML, the role of lipid metabolism in TKI resistance is not well understood. We have identified downregulation of a critical regulator of lipid metabolism, G0/G1 switch gene 2 (G0S2), in multiple scenarios of TKI resistance, including (1) BCR::ABL1 kinase-independent TKI resistance, (2) progression of CML from the chronic to the blast phase of the disease, and (3) in CML versus normal myeloid progenitors. Accordingly, CML patients with low G0S2 expression levels had a worse overall survival. G0S2 downregulation in CML was not a result of promoter hypermethylation or BCR::ABL1 kinase activity, but was rather due to transcriptional repression by MYC. Using CML cell lines, patient samples and G0s2 knockout (G0s2-/- ) mice, we demonstrate a tumour suppressor role for G0S2 in CML and TKI resistance. Our data suggest that reduced G0S2 protein expression in CML disrupts glycerophospholipid metabolism, correlating with a block of differentiation that renders CML cells resistant to therapy. Altogether, our data unravel a new role for G0S2 in regulating myeloid differentiation and TKI response in CML, and suggest that restoring G0S2 may have clinical utility.
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Affiliation(s)
- Mayra A. Gonzalez
- Department of Molecular and Translational MedicineCenter of Emphasis in CancerTexas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | - Idaly M. Olivas
- Department of Molecular and Translational MedicineCenter of Emphasis in CancerTexas Tech University Health Sciences Center El PasoEl PasoTexasUSA
- L. Frederick Francis Graduate School of Biomedical SciencesTexas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | - Alfonso E. Bencomo‐Alvarez
- Department of Molecular and Translational MedicineCenter of Emphasis in CancerTexas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | - Andres J. Rubio
- Department of Molecular and Translational MedicineCenter of Emphasis in CancerTexas Tech University Health Sciences Center El PasoEl PasoTexasUSA
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | | | - Jose L. Lopez
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | - Sara K. Dang
- L. Frederick Francis Graduate School of Biomedical SciencesTexas Tech University Health Sciences Center El PasoEl PasoTexasUSA
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | - Jonathan P. Solecki
- L. Frederick Francis Graduate School of Biomedical SciencesTexas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | - Emily McCall
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | - Gonzalo Astudillo
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | - Vanessa V. Velazquez
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | - Katherine Schenkel
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | - Kelaiah Reffell
- L. Frederick Francis Graduate School of Biomedical SciencesTexas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | - Mariah Perkins
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | - Nhu Nguyen
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | - Jehu N. Apaflo
- Metabolic, Nutrition and Exercise Research (MiNER) Laboratory, Department of KinesiologyUniversity of Texas at El PasoEl PasoTexasUSA
| | - Efren Alvidrez
- Department of Pharmaceutical SciencesSchool of PharmacyUniversity of Texas at El PasoEl PasoTexasUSA
| | - James E. Young
- L. Frederick Francis Graduate School of Biomedical SciencesTexas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | - Joshua J. Lara
- L. Frederick Francis Graduate School of Biomedical SciencesTexas Tech University Health Sciences Center El PasoEl PasoTexasUSA
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | - Dongqing Yan
- Huntsman Cancer InstituteThe University of UtahSalt Lake CityUtahUSA
| | - Anna Senina
- Huntsman Cancer InstituteThe University of UtahSalt Lake CityUtahUSA
| | - Jonathan Ahmann
- Huntsman Cancer InstituteThe University of UtahSalt Lake CityUtahUSA
| | | | - Clinton C. Mason
- Huntsman Cancer InstituteThe University of UtahSalt Lake CityUtahUSA
| | - Christopher A. Eide
- Knight Cancer InstituteDivision of Hematology/Medical OncologyOregon Health & Science UniversityPortlandOregonUSA
| | - Brian J. Druker
- Knight Cancer InstituteDivision of Hematology/Medical OncologyOregon Health & Science UniversityPortlandOregonUSA
| | - Md Nurunnabi
- Department of Pharmaceutical SciencesSchool of PharmacyUniversity of Texas at El PasoEl PasoTexasUSA
| | - Osvaldo Padilla
- Department of PathologyTexas Tech University Health Sciences Center El PasoEl PasoTexasUSA
| | - Sudip Bajpeyi
- Metabolic, Nutrition and Exercise Research (MiNER) Laboratory, Department of KinesiologyUniversity of Texas at El PasoEl PasoTexasUSA
| | - Anna M. Eiring
- Department of Molecular and Translational MedicineCenter of Emphasis in CancerTexas Tech University Health Sciences Center El PasoEl PasoTexasUSA
- L. Frederick Francis Graduate School of Biomedical SciencesTexas Tech University Health Sciences Center El PasoEl PasoTexasUSA
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El PasoEl PasoTexasUSA
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23
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Zhang L, Sang X, Han Y, Abulitibu A, Elken M, Mao Z, Kang S, Yang W, Lu C. The expression of apoptosis related genes in HK-2 cells overexpressing PPM1K was determined by RNA-seq analysis. Front Genet 2022; 13:1004610. [PMID: 36386814 PMCID: PMC9663473 DOI: 10.3389/fgene.2022.1004610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 10/18/2022] [Indexed: 01/24/2023] Open
Abstract
Chronic kidney disease (CKD) is a serious disease that endangers human health. It is reported that inhibiting renal cell apoptosis can delay the progress of CKD. Our previous study found that the mice with protein phosphatase Mg2+/Mn2+ dependent 1K (PPM1K) gene deletion had obvious symptoms of glomerular vascular and interstitial vascular dilatation, congestion and hemorrhage, glomerular hemorrhage and necrosis, interstitial fibrous tissue proliferation, decreased urinary creatinine clearance, and increased urinary protein level. In addition, studies have found that PPM1K is essential for cell survival, apoptosis and metabolism. However, no study has confirmed that PPM1K can inhibit renal cell apoptosis. In this study, PPM1K was overexpressed in human kidney-2 cells (HK-2), and the biological process of differentially expressed genes and its effect on apoptosis were comprehensively screened by RNA sequencing (RNA-seq). Through sequencing analysis, we found that there were 796 differentially expressed genes in human renal tubular epithelial cells transfected with PPM1K gene, of which 553 were down-regulated and 243 were up-regulated. Enrichment analysis found that differentially expressed genes may play an important role in amino acid metabolism and biosynthesis. In the GO analysis functional pathway list, we also found that multiple genes can be enriched in apoptosis related pathways, such as G0S2, GADD45A, TRIB3, VEGFA, NUPR1 and other up-regulated genes, and IL-6, MAGED1, CCL2, TP53INP1 and other down-regulated genes. Then we verified these differentially expressed genes by RT-PCR, and found that only the RT-PCR results of G0S2, VEGFA and NUPR1 were consistent with the transcriptome sequencing results. We believe that G0S2, VEGFA, NUPR1 and other genes may participate in the apoptosis process of HK-2 cells induced by PPM1K.In conclusion, these findings provide some data support for the study of HK-2 cell apoptosis mechanism, and also provide a scientific theoretical basis for further study of the effect of PPM1K on kidney disease.
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Affiliation(s)
- Li Zhang
- Nephrology Center of the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China,Xinjiang Clinical Research Center of Renal Replacement Therapy, Urumqi, China,Xinjiang Branch of National Clinical Research Center for Kidney Disease, Urumqi, China,Xinjiang Blood Purification Medical Quality Control Center, Urumqi, China,Institute of Nephrology of Xinjiang, Urumqi, China
| | - Xiaohong Sang
- Nephrology Center of the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China,Xinjiang Clinical Research Center of Renal Replacement Therapy, Urumqi, China,Xinjiang Branch of National Clinical Research Center for Kidney Disease, Urumqi, China,Xinjiang Blood Purification Medical Quality Control Center, Urumqi, China,Institute of Nephrology of Xinjiang, Urumqi, China
| | - Yuanyuan Han
- Nephrology Center of the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China,Xinjiang Clinical Research Center of Renal Replacement Therapy, Urumqi, China,Xinjiang Branch of National Clinical Research Center for Kidney Disease, Urumqi, China,Xinjiang Blood Purification Medical Quality Control Center, Urumqi, China,Institute of Nephrology of Xinjiang, Urumqi, China
| | - Alpati Abulitibu
- Nephrology Center of the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China,Xinjiang Clinical Research Center of Renal Replacement Therapy, Urumqi, China,Xinjiang Branch of National Clinical Research Center for Kidney Disease, Urumqi, China,Xinjiang Blood Purification Medical Quality Control Center, Urumqi, China,Institute of Nephrology of Xinjiang, Urumqi, China
| | - Mufunayi Elken
- Nephrology Center of the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China,Xinjiang Clinical Research Center of Renal Replacement Therapy, Urumqi, China,Xinjiang Branch of National Clinical Research Center for Kidney Disease, Urumqi, China,Xinjiang Blood Purification Medical Quality Control Center, Urumqi, China,Institute of Nephrology of Xinjiang, Urumqi, China
| | - Zhijie Mao
- Nephrology Center of the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China,Xinjiang Clinical Research Center of Renal Replacement Therapy, Urumqi, China,Xinjiang Branch of National Clinical Research Center for Kidney Disease, Urumqi, China,Xinjiang Blood Purification Medical Quality Control Center, Urumqi, China,Institute of Nephrology of Xinjiang, Urumqi, China
| | - Shaotao Kang
- Nephrology Center of the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China,Xinjiang Clinical Research Center of Renal Replacement Therapy, Urumqi, China,Xinjiang Branch of National Clinical Research Center for Kidney Disease, Urumqi, China,Xinjiang Blood Purification Medical Quality Control Center, Urumqi, China,Institute of Nephrology of Xinjiang, Urumqi, China
| | - Wenjun Yang
- Nephrology Center of the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China,Xinjiang Clinical Research Center of Renal Replacement Therapy, Urumqi, China,Xinjiang Branch of National Clinical Research Center for Kidney Disease, Urumqi, China,Xinjiang Blood Purification Medical Quality Control Center, Urumqi, China,Institute of Nephrology of Xinjiang, Urumqi, China,*Correspondence: Wenjun Yang, ; Chen Lu,
| | - Chen Lu
- Nephrology Center of the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China,Xinjiang Clinical Research Center of Renal Replacement Therapy, Urumqi, China,Xinjiang Branch of National Clinical Research Center for Kidney Disease, Urumqi, China,Xinjiang Blood Purification Medical Quality Control Center, Urumqi, China,Institute of Nephrology of Xinjiang, Urumqi, China,*Correspondence: Wenjun Yang, ; Chen Lu,
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Hao X, Fan H, Yang J, Tang J, Zhou J, Zhao Y, Huang L, Xia Y. Network Pharmacology Research and Dual-omic Analyses Reveal the Molecular Mechanism of Natural Product Nodosin Inhibiting Muscle-Invasive Bladder Cancer in Vitro and in Vivo. JOURNAL OF NATURAL PRODUCTS 2022; 85:2006-2017. [PMID: 35976233 DOI: 10.1021/acs.jnatprod.2c00400] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Bladder cancer, specifically, muscle-invasive bladder cancer (MIBC), is among the most common malignant tumors. Patients with MIBC who cannot tolerate standard drugs require novel treatments. Targeting apoptosis may help treat cancer, which may be achieved with the use of some natural products. Nodosin, found in Isodon serra (Maxim.) Kudo (known as Xihuangcao), may inhibit bladder cancer cells. Transcriptomics and proteomics dual-omic analyses revealed the network pharmacological mechanism: (1) blocking the S phase by up-regulating RPA2, CLSPN, MDC1, PDCD2L, and E2F6 gene expressions, suppressing cancer cell proliferation; (2) inducing apoptosis and autophagy and restraining ferroptosis by up-regulating HMOX1, G0S2, SQSTM1, FTL, SLC7A11, and AIFM2 gene expressions; (3) preventing cancer cell migration by down-regulating NEXN, LIMA1, CFL2, PALLD, and ITGA3 gene expressions. In vivo, nodosin inhibited bladder cancer cell growth in a model of xenograft tumor in nude mice. This study is the first to report basic research findings on the network pharmacological mechanism of cytotoxicity of bladder cancer cells by nodosin, providing novel evidence for the application of nodosin in the field of oncology; however, other mechanisms may be involved in the effects of nodosin for further research. These findings provide a foundation for the development of novel MIBC drugs.
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Affiliation(s)
- Xiaopeng Hao
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, Henan 450008, China
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining, Shandong 272067, China
| | - Huixia Fan
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining, Shandong 272067, China
| | - Jian Yang
- State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Jinfu Tang
- State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Junhui Zhou
- State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yuyang Zhao
- State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Luqi Huang
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, Henan 450008, China
- State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yong Xia
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining, Shandong 272067, China
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25
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Xiong T, Lv XS, Wu GJ, Guo YX, Liu C, Hou FX, Wang JK, Fu YF, Liu FQ. Single-Cell Sequencing Analysis and Multiple Machine Learning Methods Identified G0S2 and HPSE as Novel Biomarkers for Abdominal Aortic Aneurysm. Front Immunol 2022; 13:907309. [PMID: 35769488 PMCID: PMC9234288 DOI: 10.3389/fimmu.2022.907309] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/06/2022] [Indexed: 11/20/2022] Open
Abstract
Identifying biomarkers for abdominal aortic aneurysms (AAA) is key to understanding their pathogenesis, developing novel targeted therapeutics, and possibly improving patients outcomes and risk of rupture. Here, we identified AAA biomarkers from public databases using single-cell RNA-sequencing, weighted co-expression network (WGCNA), and differential expression analyses. Additionally, we used the multiple machine learning methods to identify biomarkers that differentiated large AAA from small AAA. Biomarkers were validated using GEO datasets. CIBERSORT was used to assess immune cell infiltration into AAA tissues and investigate the relationship between biomarkers and infiltrating immune cells. Therefore, 288 differentially expressed genes (DEGs) were screened for AAA and normal samples. The identified DEGs were mostly related to inflammatory responses, lipids, and atherosclerosis. For the large and small AAA samples, 17 DEGs, mostly related to necroptosis, were screened. As biomarkers for AAA, G0/G1 switch 2 (G0S2) (Area under the curve [AUC] = 0.861, 0.875, and 0.911, in GSE57691, GSE47472, and GSE7284, respectively) and for large AAA, heparinase (HPSE) (AUC = 0.669 and 0.754, in GSE57691 and GSE98278, respectively) were identified and further verified by qRT-PCR. Immune cell infiltration analysis revealed that the AAA process may be mediated by T follicular helper (Tfh) cells and the large AAA process may also be mediated by Tfh cells, M1, and M2 macrophages. Additionally, G0S2 expression was associated with neutrophils, activated and resting mast cells, M0 and M1 macrophages, regulatory T cells (Tregs), resting dendritic cells, and resting CD4 memory T cells. Moreover, HPSE expression was associated with M0 and M1 macrophages, activated and resting mast cells, Tregs, and resting CD4 memory T cells. Additional, G0S2 may be an effective diagnostic biomarker for AAA, whereas HPSE may be used to confer risk of rupture in large AAAs. Immune cells play a role in the onset and progression of AAA, which may improve its diagnosis and treatment.
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Affiliation(s)
- Tao Xiong
- Department of Cardiovascular, Shaanxi Provincial People’s Hospital, Xi’an, China
- Department of Cardiovascular Surgery, Yan'an Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xiao-Shuo Lv
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Gu-Jie Wu
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Yao-Xing Guo
- Department of Pathology, College of Basic Medical Sciences China Medical University, Shenyang, China
| | - Chang Liu
- Department of Cardiovascular Surgery, Yan'an Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Fang-Xia Hou
- Department of Cardiovascular, Shaanxi Provincial People’s Hospital, Xi’an, China
| | - Jun-Kui Wang
- Department of Cardiovascular, Shaanxi Provincial People’s Hospital, Xi’an, China
| | - Yi-Fan Fu
- School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Fu-Qiang Liu
- Department of Cardiovascular, Shaanxi Provincial People’s Hospital, Xi’an, China
- *Correspondence: Fu-Qiang Liu,
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26
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Cui H, Duan R, Niu H, Yu T, Huang K, Chen C, Hao K, Yang T, Wang C. Integrated analysis of mRNA and long noncoding RNA profiles in peripheral blood mononuclear cells of patients with bronchial asthma. BMC Pulm Med 2022; 22:174. [PMID: 35501805 PMCID: PMC9059365 DOI: 10.1186/s12890-022-01945-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 04/11/2022] [Indexed: 12/02/2022] Open
Abstract
Background Bronchial asthma is a heterogeneous disease with distinct disease phenotypes and underlying pathophysiological mechanisms. Long non-coding RNAs (lncRNAs) are involved in numerous functionally different biological and physiological processes. The aim of this study was to identify differentially expressed lncRNAs and mRNAs in patients with asthma and further explore the functions and interactions between lncRNAs and mRNAs. Methods Ten patients with asthma and 9 healthy controls were enrolled in this study. RNA was isolated from peripheral blood mononuclear cells. We performed microarray analysis to evaluate lncRNA and mRNA expression. The functions of the differentially expressed mRNAs were analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. A global signal transduction network was constructed to identify the core mRNAs. An lncRNA–mRNA network was constructed. Five mRNAs showing the greatest differences in expression levels or high degrees in the gene–gene functional interaction network, with their correlated lncRNAs, were validated by real-time quantitative polymerase chain reaction. Results We identified 2229 differentially expressed mRNAs and 1397 lncRNAs between the asthma and control groups. Kyoto Encyclopedia of Genes and Genomes pathway analysis identified many pathways associated with inflammation and cell survival. The gene–gene functional interaction network suggested that some core mRNAs are involved in the pathogenesis of bronchial asthma. The lncRNA–mRNA co-expression network revealed correlated lncRNAs. CXCL8, FOXO3, JUN, PIK3CA, and G0S2 and their related lncRNAs NONHSAT115963, AC019050.1, MTCYBP3, KB-67B5.12, and HNRNPA1P12 were identified according to their differential expression levels and high degrees in the gene–gene network. Conclusions We identified the core mRNAs and their related lncRNAs and predicted the biological processes and signaling pathways involved in asthma. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-022-01945-9.
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Affiliation(s)
- Han Cui
- Department of Pathophysiology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.,Department of Geriatric, Beijing Hospital, Beijing, China
| | - Ruirui Duan
- Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Hongtao Niu
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Tao Yu
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Ke Huang
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Chen Chen
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Ke Hao
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ting Yang
- Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China. .,Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China. .,Institute of Respiratory Medicine, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.
| | - Chen Wang
- Department of Pathophysiology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. .,Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China. .,Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China. .,Institute of Respiratory Medicine, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.
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27
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Riegler-Berket L, Wechselberger L, Cerk IK, Padmanabha Das KM, Viertlmayr R, Kulminskaya N, Rodriguez Gamez CF, Schweiger M, Zechner R, Zimmermann R, Oberer M. Residues of the minimal sequence of G0S2 collectively contribute to ATGL inhibition while C-and N-terminal extensions promote binding to ATGL. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159105. [PMID: 35026402 DOI: 10.1016/j.bbalip.2021.159105] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 11/29/2021] [Accepted: 12/17/2021] [Indexed: 11/25/2022]
Abstract
The protein encoded by the G0/G1 switch gene 2 (G0S2) is a potent inhibitor of adipose triglyceride lipase (ATGL) and thus an important regulator of intracellular lipolysis. Since dysfunction of lipolysis is associated with metabolic diseases including diabetes and obesity, inhibition of ATGL is considered a therapeutic strategy. G0S2 interacts with ATGL's patatin-domain to mediate non-competitive inhibition, however atomic details of the inhibition mechanism are incompletely understood. Sequences of G0S2 from higher organisms show a highly conserved N-terminal part, including a hydrophobic region covering amino acids 27 to 42. We show that predicted G0S2 orthologs from platypus, chicken and Japanese rice-fish are able to inhibit human and mouse ATGL, emphasizing the contribution of conserved amino acid to ATGL inhibition. Our site directed mutagenesis and truncation studies give insights in the protein-protein interaction on a per-residue level. We determine that the minimal sequence required for ATGL inhibition ranges from amino acids 20 to 44. Residues Y27, V28, G30, A34 G37, V39 or L42 within this sequence play a substantial role in ATGL inhibition. Furthermore, we show that unspecific interactions of the N-terminal part (amino acids 20-27) of the minimal sequence facilitate the interaction to ATGL. Our studies also demonstrate that full-length G0S2 shows higher tolerance to specific single amino acid exchanges in the hydrophobic region due to the stronger contributions of unspecific interactions. However, exchanges of more than one amino-acid in the hydrophobic region also result in the loss of function as ATGL inhibitor even in the full-length protein.
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Affiliation(s)
- L Riegler-Berket
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
| | - L Wechselberger
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
| | - I K Cerk
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
| | - K M Padmanabha Das
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - R Viertlmayr
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
| | - N Kulminskaya
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
| | | | - M Schweiger
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; BioTechMed Graz, 8010 Graz, Austria
| | - R Zechner
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; BioTechMed Graz, 8010 Graz, Austria; BioHealth Field of Excellence, University of Graz, 8010 Graz, Austria
| | - R Zimmermann
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; BioTechMed Graz, 8010 Graz, Austria; BioHealth Field of Excellence, University of Graz, 8010 Graz, Austria
| | - M Oberer
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; BioTechMed Graz, 8010 Graz, Austria; BioHealth Field of Excellence, University of Graz, 8010 Graz, Austria.
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28
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Zhang QY, Ye XP, Zhou Z, Zhu CF, Li R, Fang Y, Zhang RJ, Li L, Liu W, Wang Z, Song SY, Lu SY, Zhao SX, Lin JN, Song HD. Lymphocyte infiltration and thyrocyte destruction are driven by stromal and immune cell components in Hashimoto's thyroiditis. Nat Commun 2022; 13:775. [PMID: 35140214 PMCID: PMC8828859 DOI: 10.1038/s41467-022-28120-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 01/07/2022] [Indexed: 11/09/2022] Open
Abstract
Hashimoto's thyroiditis (HT) is the most common autoimmune disease characterized by lymphocytic infiltration and thyrocyte destruction. Dissection of the interaction between the thyroidal stromal microenvironment and the infiltrating immune cells might lead to a better understanding of HT pathogenesis. Here we show, using single-cell RNA-sequencing, that three thyroidal stromal cell subsets, ACKR1+ endothelial cells and CCL21+ myofibroblasts and CCL21+ fibroblasts, contribute to the thyroidal tissue microenvironment in HT. These cell types occupy distinct histological locations within the thyroid gland. Our experiments suggest that they might facilitate lymphocyte trafficking from the blood to thyroid tissues, and T cell zone CCL21+ fibroblasts may also promote the formation of tertiary lymphoid organs characteristic to HT. Our study also demonstrates the presence of inflammatory macrophages and dendritic cells expressing high levels of IL-1β in the thyroid, which may contribute to thyrocyte destruction in HT patients. Our findings thus provide a deeper insight into the cellular interactions that might prompt the pathogenesis of HT.
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Affiliation(s)
- Qian-Yue Zhang
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Xiao-Ping Ye
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
| | - Zheng Zhou
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.,Department of geriatric endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Chen-Fang Zhu
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Discipline Construction Research Center of China Hospital Development Institute, Shanghai Jiao Tong University, Shanghai, 200011, China
| | - Rui Li
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Ya Fang
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Rui-Jia Zhang
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Lu Li
- Department of Endocrinology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Wei Liu
- Department of Endocrinology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Zheng Wang
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Shi-Yang Song
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Sang-Yu Lu
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Shuang-Xia Zhao
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Jian-Nan Lin
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
| | - Huai-Dong Song
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. .,Department of Endocrinology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
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Ziemann M, Lim SC, Kang Y, Samuel S, Sanchez IL, Gantier M, Stojanovski D, McKenzie M. MicroRNA-101-3p Modulates Mitochondrial Metabolism via the Regulation of Complex II Assembly. J Mol Biol 2021; 434:167361. [PMID: 34808225 DOI: 10.1016/j.jmb.2021.167361] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/17/2021] [Accepted: 11/11/2021] [Indexed: 12/27/2022]
Abstract
MicroRNA-101-3p (miR-101-3p) is a tumour suppressor that regulates cancer proliferation and apoptotic signalling. Loss of miR-101-3p increases the expression of the Polycomb Repressive Complex 2 (PRC2) subunit enhancer of zeste homolog 2 (EZH2), resulting in alterations to the epigenome and enhanced tumorigenesis. MiR-101-3p has also been shown to modulate various aspects of cellular metabolism, however little is known about the mechanisms involved. To investigate the metabolic pathways that are regulated by miR-101-3p, we performed transcriptome and functional analyses of osteosarcoma cells transfected with miR-101-3p. We found that miR-101-3p downregulates multiple mitochondrial processes, including oxidative phosphorylation, pyruvate metabolism, the citric acid cycle and phospholipid metabolism. We also found that miR-101-3p transfection disrupts the transcription of mitochondrial DNA (mtDNA) via the downregulation of the mitochondrial transcription initiation complex proteins TFB2M and Mic60. These alterations in transcript expression disrupt mitochondrial function, with significant decreases in both basal (54%) and maximal (67%) mitochondrial respiration rates. Native gel electrophoresis revealed that this diminished respiratory capacity was associated with reduced steady-state levels of mature succinate dehydrogenase (complex II), with a corresponding reduction of complex II enzymatic activity. Furthermore, miR-101-3p transfection reduced the expression of the SDHB subunit, with a concomitant disruption of the assembly of the SDHC subunit into mature complex II. Overall, we describe a new role for miR-101-3p as a modulator of mitochondrial metabolism via its regulation of multiple mitochondrial processes, including mtDNA transcription and complex II biogenesis.
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Affiliation(s)
- Mark Ziemann
- School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 3216 Geelong, Australia. https://twitter.com/@mdziemann
| | - Sze Chern Lim
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 3168 Melbourne, Australia
| | - Yilin Kang
- Department of Biochemistry and Pharmacology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 3052 Melbourne, Australia
| | - Sona Samuel
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria 3002, Australia
| | - Isabel Lopez Sanchez
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria 3002, Australia; Ophthalmology, University of Melbourne, Department of Surgery Melbourne, Victoria 3000, Australia. https://twitter.com/@DrIsabelLopez
| | - Michael Gantier
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 3168 Melbourne, Australia; Department of Molecular and Translational Science, Monash University, 3168 Melbourne, Australia. https://twitter.com/@GantierLab
| | - Diana Stojanovski
- Department of Biochemistry and Pharmacology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 3052 Melbourne, Australia
| | - Matthew McKenzie
- School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 3216 Geelong, Australia; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 3168 Melbourne, Australia; Department of Molecular and Translational Science, Monash University, 3168 Melbourne, Australia.
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Han Y, Kang L, Liu X, Zhuang Y, Chen X, Li X. Establishment and validation of a logistic regression model for prediction of septic shock severity in children. Hereditas 2021; 158:45. [PMID: 34772470 PMCID: PMC8588704 DOI: 10.1186/s41065-021-00206-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 10/14/2021] [Indexed: 11/10/2022] Open
Abstract
Background Septic shock is the most severe complication of sepsis, and is a major cause of childhood mortality, constituting a heavy public health burden. Methods We analyzed the gene expression profiles of septic shock and control samples from the Gene Expression Omnibus (GEO). Four differentially expressed genes (DEGs) from survivor and control groups, non-survivor and control groups, and survivor and non-survivor groups were selected. We used data about these genes to establish a logistic regression model for predicting the survival of septic shock patients. Results Leave-one-out cross validation and receiver operating characteristic (ROC) analysis indicated that this model had good accuracy. Differential expression and Gene Set Enrichment Analysis (GSEA) between septic shock patients stratified by prediction score indicated that the systemic lupus erythematosus pathway was activated, while the limonene and pinene degradation pathways were inactivated in the high score group. Conclusions Our study provides a novel approach for the prediction of the severity of pathology in septic shock patients, which are significant for personalized treatment as well as prognostic assessment. Supplementary Information The online version contains supplementary material available at 10.1186/s41065-021-00206-9.
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Affiliation(s)
- Yujie Han
- Department of Neonatal, Qilu Children's Hospital of Shandong University, No. 23976, Huaiyin District, Jinan City, 250022, Shandong, People's Republic of China
| | - Lili Kang
- Department of Neonatal, Qilu Children's Hospital of Shandong University, No. 23976, Huaiyin District, Jinan City, 250022, Shandong, People's Republic of China
| | - Xianghong Liu
- Department of Neonatal, Qilu Children's Hospital of Shandong University, No. 23976, Huaiyin District, Jinan City, 250022, Shandong, People's Republic of China
| | - Yuanhua Zhuang
- Department of Neonatal, Qilu Children's Hospital of Shandong University, No. 23976, Huaiyin District, Jinan City, 250022, Shandong, People's Republic of China
| | - Xiao Chen
- Department of Neonatal, Qilu Children's Hospital of Shandong University, No. 23976, Huaiyin District, Jinan City, 250022, Shandong, People's Republic of China
| | - Xiaoying Li
- Department of Neonatal, Qilu Children's Hospital of Shandong University, No. 23976, Huaiyin District, Jinan City, 250022, Shandong, People's Republic of China.
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Qian Y, Zhang L, Sun Z, Zang G, Li Y, Wang Z, Li L. Biomarkers of Blood from Patients with Atherosclerosis Based on Bioinformatics Analysis. Evol Bioinform Online 2021; 17:11769343211046020. [PMID: 34594098 PMCID: PMC8477683 DOI: 10.1177/11769343211046020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 08/24/2021] [Indexed: 12/17/2022] Open
Abstract
Atherosclerosis is a multifaceted disease characterized by the formation and accumulation of plaques that attach to arteries and cause cardiovascular disease and vascular embolism. A range of diagnostic techniques, including selective coronary angiography, stress tests, computerized tomography, and nuclear scans, assess cardiovascular disease risk and treatment targets. However, there is currently no simple blood biochemical index or biological target for the diagnosis of atherosclerosis. Therefore, it is of interest to find a biochemical blood marker for atherosclerosis. Three datasets from the Gene Expression Omnibus (GEO) database were analyzed to obtain differentially expressed genes (DEG) and the results were integrated using the Robustrankaggreg algorithm. The genes considered more critical by the Robustrankaggreg algorithm were put into their own data set and the data set system with cell classification information for verification. Twenty-one possible genes were screened out. Interestingly, we found a good correlation between RPS4Y1, EIF1AY, and XIST. In addition, we know the general expression of these genes in different cell types and whole blood cells. In this study, we identified BTNL8 and BLNK as having good clinical significance. These results will contribute to the analysis of the underlying genes involved in the progression of atherosclerosis and provide insights for the discovery of new diagnostic and evaluation methods.
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Affiliation(s)
- Yongjiang Qian
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lili Zhang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhen Sun
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Guangyao Zang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Yalan Li
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhongqun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lihua Li
- Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
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Liu JB, Chen K, Liu TB, Wang ZY, Wang L. Global transcriptome profiling reveals antagonizing response of head kidney of juvenile common carp exposed to glyphosate. CHEMOSPHERE 2021; 280:130823. [PMID: 34162096 DOI: 10.1016/j.chemosphere.2021.130823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/23/2021] [Accepted: 05/05/2021] [Indexed: 06/13/2023]
Abstract
Glyphosate (GLY) frequently detected in various water bodies has imposed a serious risk on fish. Head kidney of fish is an important defense organ, playing a vital part in antagonizing exogenous hazardous matter. The objective of this study was to characterize toxic mechanisms of GLY in head kidney of common carp based on transcriptome profiling. After 45-days exposure of GLY at environmentally relevant concentrations, juvenile common carp were used as experimental subjects to analyze how the head kidney responded to GLY. The transcriptome profiling identified 1381 different expressed genes (DEGs) between the control and exposure groups (5 and 50 mg/L). Functional analysis of DEGs substantiated over-representative pathways mainly involving cellular stress responses, cell proliferation and turnover, apoptosis, lipid metabolism, and innate immune processes in both treated groups compared with the control group. Predicted network of gene regulation indicated that GLY-induced tp53 played a vital role in linking a battery of signals. Furthermore, the expression of 10 candidate genes by qRT-PCR aligned with transcriptional profiling. In addition, western blotting analysis confirmed that GLY-induced apoptosis and cellular proliferation were closely involved in activating MAKP signaling pathway and lipid metabolism pathway in both treated groups. Collectively, these data demonstrate that head kidney of juvenile common carp mainly leverages upregulation of genes related to cell proliferation and turnover, apoptosis, and lipid metabolism to combat sub-chronic exposure of GLY. This study casts new understanding into the risk of GLY in aquatic animals.
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Affiliation(s)
- Jing-Bo Liu
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China
| | - Kai Chen
- New Drug Evaluation Center of Shandong Academy of Pharmaceutical Sciences, Shandong Academy of Pharmaceutical Sciences, 989 Xinluo Street, Ji'nan City, Shandong Province, 250101, China
| | - Tian-Bin Liu
- New Drug Evaluation Center of Shandong Academy of Pharmaceutical Sciences, Shandong Academy of Pharmaceutical Sciences, 989 Xinluo Street, Ji'nan City, Shandong Province, 250101, China
| | - Zhen-Yong Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China
| | - Lin Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China.
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Hu X, Luo H, Dou C, Chen X, Huang Y, Wang L, Xue S, Sun Z, Chen S, Xu Q, Geng T, Zhao X, Cui H. Metformin Triggers Apoptosis and Induction of the G0/G1 Switch 2 Gene in Macrophages. Genes (Basel) 2021; 12:1437. [PMID: 34573418 PMCID: PMC8468785 DOI: 10.3390/genes12091437] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/14/2021] [Accepted: 09/16/2021] [Indexed: 12/13/2022] Open
Abstract
Metformin is a widely used antidiabetic drug for the treatment of type 2 diabetes and has been recently demonstrated to possess anti-inflammatory properties via AMPK-mediated modulation of M2 macrophage activation. However, the anti-inflammatory mechanisms of metformin on inflammatory macrophages are still not fully elucidated. In this study, we found that metformin induced apoptosis in macrophages. In particular, metformin induced apoptosis of M1 macrophages, based on M1 marker genes in apoptotic macrophages. Next, we comprehensively screened metformin-responsive genes in macrophages by RNA-seq and focused on the extrinsic apoptotic signaling pathway. The G0/G1 switch 2 gene (G0S2) was robustly up-regulated by metformin in macrophages. Overexpression of G0S2 significantly induced apoptosis of macrophages in a dose-dependent manner and blunted the function of the crucial anti-apoptotic gene Bcl-2, which was significantly reduced by metformin. These findings show that metformin promoted apoptosis of macrophages, especially M1 macrophages, via G0S2 induction and provides a novel anti-inflammatory mechanism of metformin through induction of macrophage apoptosis.
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Affiliation(s)
- Xuming Hu
- Institute of Epigenetics and Epigenomics, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (X.H.); (H.L.); (C.D.); (X.C.); (L.W.); (S.X.); (Z.S.); (S.C.); (T.G.)
- Department of Animal Science, McGill University, Montréal, QC H3A 0G4, Canada;
| | - Huan Luo
- Institute of Epigenetics and Epigenomics, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (X.H.); (H.L.); (C.D.); (X.C.); (L.W.); (S.X.); (Z.S.); (S.C.); (T.G.)
| | - Chunfeng Dou
- Institute of Epigenetics and Epigenomics, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (X.H.); (H.L.); (C.D.); (X.C.); (L.W.); (S.X.); (Z.S.); (S.C.); (T.G.)
| | - Xujing Chen
- Institute of Epigenetics and Epigenomics, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (X.H.); (H.L.); (C.D.); (X.C.); (L.W.); (S.X.); (Z.S.); (S.C.); (T.G.)
| | - Yi Huang
- Department of Pharmacy, Suzhou Vocational Health College, Suzhou 215009, China;
| | - Liping Wang
- Institute of Epigenetics and Epigenomics, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (X.H.); (H.L.); (C.D.); (X.C.); (L.W.); (S.X.); (Z.S.); (S.C.); (T.G.)
| | - Songlei Xue
- Institute of Epigenetics and Epigenomics, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (X.H.); (H.L.); (C.D.); (X.C.); (L.W.); (S.X.); (Z.S.); (S.C.); (T.G.)
| | - Zhen Sun
- Institute of Epigenetics and Epigenomics, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (X.H.); (H.L.); (C.D.); (X.C.); (L.W.); (S.X.); (Z.S.); (S.C.); (T.G.)
| | - Shihao Chen
- Institute of Epigenetics and Epigenomics, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (X.H.); (H.L.); (C.D.); (X.C.); (L.W.); (S.X.); (Z.S.); (S.C.); (T.G.)
| | - Qi Xu
- Department of Animal Science, McGill University, Montréal, QC H3A 0G4, Canada;
| | - Tuoyu Geng
- Institute of Epigenetics and Epigenomics, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (X.H.); (H.L.); (C.D.); (X.C.); (L.W.); (S.X.); (Z.S.); (S.C.); (T.G.)
| | - Xin Zhao
- Department of Animal Science, McGill University, Montréal, QC H3A 0G4, Canada;
| | - Hengmi Cui
- Institute of Epigenetics and Epigenomics, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (X.H.); (H.L.); (C.D.); (X.C.); (L.W.); (S.X.); (Z.S.); (S.C.); (T.G.)
- Joint International Research Laboratory of Agricultural & Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention & Control of Important Animal Infectious Diseases & Zoonoses, Yangzhou 225009, China
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Moran MW, Ramirez EP, Zook JD, Saarinen AM, Baravati B, Goode MR, Laloudakis V, Kaschner EK, Olson TL, Craciunescu FM, Hansen DT, Liu J, Fromme P. Biophysical characterization and a roadmap towards the NMR solution structure of G0S2, a key enzyme in non-alcoholic fatty liver disease. PLoS One 2021; 16:e0249164. [PMID: 34260600 PMCID: PMC8279337 DOI: 10.1371/journal.pone.0249164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 03/13/2021] [Indexed: 11/19/2022] Open
Abstract
In the United States non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease, affecting an estimated 80 to 100 million people. It occurs in every age group, but predominantly in people with risk factors such as obesity and type 2 diabetes. NAFLD is marked by fat accumulation in the liver leading to liver inflammation, which may lead to scarring and irreversible damage progressing to cirrhosis and liver failure. In animal models, genetic ablation of the protein G0S2 leads to alleviation of liver damage and insulin resistance in high fat diets. The research presented in this paper aims to aid in rational based drug design for the treatment of NAFLD by providing a pathway for a solution state NMR structure of G0S2. Here we describe the expression of G0S2 in an E. coli system from two different constructs, both of which are confirmed to be functionally active based on the ability to inhibit the activity of Adipose Triglyceride Lipase. In one of the constructs, preliminary NMR spectroscopy measurements show dominant alpha-helical characteristics as well as resonance assignments on the N-terminus of G0S2, allowing for further NMR work with this protein. Additionally, the characterization of G0S2 oligomers are outlined for both constructs, suggesting that G0S2 may defensively exist in a multimeric state to protect and potentially stabilize the small 104 amino acid protein within the cell. This information presented on the structure of G0S2 will further guide future development in the therapy for NAFLD.
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Affiliation(s)
- Michael W. Moran
- Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America
- School of Molecular Sciences, Arizona State University, Tempe, AZ, United States of America
| | - Elizabeth P. Ramirez
- Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America
- School of Molecular Sciences, Arizona State University, Tempe, AZ, United States of America
| | - James D. Zook
- Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America
| | - Alicia M. Saarinen
- Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona Scottsdale, AZ, United States of America
- Department of Cardiovascular Medicine, Mayo Clinic in Arizona Scottsdale, AZ, United States of America
| | - Bobby Baravati
- Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America
- School of Molecular Sciences, Arizona State University, Tempe, AZ, United States of America
| | - Matthew R. Goode
- Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America
- School of Molecular Sciences, Arizona State University, Tempe, AZ, United States of America
| | - Vasiliki Laloudakis
- Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America
| | - Emily K. Kaschner
- Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America
- School of Molecular Sciences, Arizona State University, Tempe, AZ, United States of America
| | - Tien L. Olson
- Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America
- School of Molecular Sciences, Arizona State University, Tempe, AZ, United States of America
| | - Felicia M. Craciunescu
- Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America
| | - Debra T. Hansen
- Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America
- Biodesign Center for Innovations in Medicine, Arizona State University, Tempe, AZ, United States of America
| | - Jun Liu
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, United States of America
| | - Petra Fromme
- Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America
- School of Molecular Sciences, Arizona State University, Tempe, AZ, United States of America
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Pan H, Renaud L, Chaligne R, Bloehdorn J, Tausch E, Mertens D, Fink AM, Fischer K, Zhang C, Betel D, Gnirke A, Imielinski M, Moreaux J, Hallek M, Meissner A, Stilgenbauer S, Wu CJ, Elemento O, Landau DA. Discovery of Candidate DNA Methylation Cancer Driver Genes. Cancer Discov 2021; 11:2266-2281. [PMID: 33972312 DOI: 10.1158/2159-8290.cd-20-1334] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 02/25/2021] [Accepted: 04/15/2021] [Indexed: 02/07/2023]
Abstract
Epigenetic alterations, such as promoter hypermethylation, may drive cancer through tumor suppressor gene inactivation. However, we have limited ability to differentiate driver DNA methylation (DNAme) changes from passenger events. We developed DNAme driver inference-MethSig-accounting for the varying stochastic hypermethylation rate across the genome and between samples. We applied MethSig to bisulfite sequencing data of chronic lymphocytic leukemia (CLL), multiple myeloma, ductal carcinoma in situ, glioblastoma, and to methylation array data across 18 tumor types in TCGA. MethSig resulted in well-calibrated quantile-quantile plots and reproducible inference of likely DNAme drivers with increased sensitivity/specificity compared with benchmarked methods. CRISPR/Cas9 knockout of selected candidate CLL DNAme drivers provided a fitness advantage with and without therapeutic intervention. Notably, DNAme driver risk score was closely associated with adverse outcome in independent CLL cohorts. Collectively, MethSig represents a novel inference framework for DNAme driver discovery to chart the role of aberrant DNAme in cancer. SIGNIFICANCE: MethSig provides a novel statistical framework for the analysis of DNA methylation changes in cancer, to specifically identify candidate DNA methylation driver genes of cancer progression and relapse, empowering the discovery of epigenetic mechanisms that enhance cancer cell fitness.This article is highlighted in the In This Issue feature, p. 2113.
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Affiliation(s)
- Heng Pan
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, New York.,Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York.,Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York
| | - Loïc Renaud
- New York Genome Center, New York, New York.,Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York.,Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York.,Inserm, UMR-S 1172, Lille, France
| | - Ronan Chaligne
- New York Genome Center, New York, New York.,Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York.,Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York
| | | | - Eugen Tausch
- Department of Internal Medicine III, Ulm University, Ulm, Germany
| | - Daniel Mertens
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Anna Maria Fink
- German CLL Study Group, and Department I of Internal Medicine, and Center of Integrated Oncology ABCD, University of Cologne, Cologne, Germany
| | - Kirsten Fischer
- German CLL Study Group, and Department I of Internal Medicine, and Center of Integrated Oncology ABCD, University of Cologne, Cologne, Germany
| | - Chao Zhang
- Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York.,Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Doron Betel
- Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York.,Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Andreas Gnirke
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Marcin Imielinski
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, New York.,Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York.,New York Genome Center, New York, New York.,Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York.,Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Jérôme Moreaux
- IGH, CNRS, Univ Montpellier, France.,CHU Montpellier, Department of Biological Hematology, Montpellier, France.,UFR de Médecine, Univ Montpellier, Montpellier, France.,Institut Universitaire de France (IUF), France
| | - Michael Hallek
- German CLL Study Group, and Department I of Internal Medicine, and Center of Integrated Oncology ABCD, University of Cologne, Cologne, Germany
| | - Alexander Meissner
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts.,Max Planck Institute for Molecular Genetics, Berlin, Germany
| | | | - Catherine J Wu
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts.,Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Olivier Elemento
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, New York.,Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York.,Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York.,Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
| | - Dan A Landau
- Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York. .,New York Genome Center, New York, New York.,Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York.,Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York
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Wang X, Meng H, Ruan J, Chen W, Meng F. Low G0S2 gene expression levels in peripheral blood may be a genetic marker of acute myocardial infarction in patients with stable coronary atherosclerotic disease: A retrospective clinical study. Medicine (Baltimore) 2021; 100:e23468. [PMID: 33545927 PMCID: PMC7837852 DOI: 10.1097/md.0000000000023468] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 09/21/2020] [Accepted: 11/02/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The G0/G1 switch 2 (G0S2) gene is closely related to lipolysis, cell proliferation, apoptosis, oxidative phosphorylation, and the development of a variety of tumors. The aim of the present study was to expand the sample size to confirm the relationship between the expression of the G0S2 gene in peripheral blood and acute myocardial infarction (AMI) based on previous gene chip results. METHODS Three hundred patients were initially selected, of which 133 were excluded in accordance with the exclusion criteria. Peripheral blood leukocytes were collected from 92 patients with AMI and 75 patients with stable coronary atherosclerotic disease (CAD). mRNA expression levels of G0S2 in peripheral blood leukocytes was measured by RT-PCR, and protein expression levels by Western blot analysis. The results of these assays in the 2 groups were compared. RESULTS mRNA expression levels of GOS2 in the peripheral blood leukocytes of patients with AMI were 0.41-fold lower than those of patients with stable CAD (P < .05), and GOS2 protein expression levels were 0.45-fold lower. Multivariate logistic regression analysis indicated that low expression levels of the G0S2 gene increased the risk of AMI by 2.08-fold in stable CAD patients. CONCLUSIONS G0S2 gene expression in the peripheral blood leukocytes of AMI patients was lower than that of stable CAD patients. Low G0S2 gene expression in peripheral blood leukocytes is an independent risk factor for AMI in stable CAD patients.
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37
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Páez-Pérez E, Llamas-García ML, Benítez-Cardoza CG, Montero-Morán GM, Lara-González S. Bioinformatic Analysis and Biophysical Characterization Reveal Structural Disorder in G0S2 Protein. ACS OMEGA 2020; 5:25841-25847. [PMID: 33073109 PMCID: PMC7557935 DOI: 10.1021/acsomega.0c03171] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/23/2020] [Indexed: 06/11/2023]
Abstract
G0S2 is a small protein of 103 residues in length that is involved in multiple cellular processes. To date, several reports have shown that G0S2 functions by making direct protein-protein interactions with key proteins. In lipolysis, G0S2 specifically interacts with adipose triglyceride lipase, inhibiting its activity and resulting in lipolysis being downregulated. In a similar way, G0S2 also participates in the regulation of apoptosis, cell proliferation, and oxidative phosphorylation; however, information regarding G0S2 structural and biophysical properties is limited. In this work, we conducted a comparative structural analysis of human and mouse G0S2 proteins. Bioinformatics suggests the presence of a disordered C-terminal region in human G0S2. Experimental characterization by size-exclusion chromatography and dynamic light scattering showed that human and mouse G0S2 have different hydrodynamic properties. In comparison to the mouse G0S2, which behaves similar to a globular protein, the human G0S2 shows an elongated conformation, most likely by displaying a disordered C-terminal region. Further analysis of hydrodynamic properties under denaturing conditions suggests the presence of a structural element in the mouse protein that undergoes an order to disorder transition at low urea concentration. Structural analysis by circular dichroism revealed that in native conditions, both proteins are mainly unstructured, showing the presence of beta sheet structures. Further analysis of CD data suggests that both proteins belong to the premolten globule family of intrinsically disordered proteins. We suggest that the intrinsic disorder observed in the G0S2 protein may facilitate its interaction with multiple partners in the regulation of cellular metabolism.
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Affiliation(s)
- Edgar
D. Páez-Pérez
- IPICYT,
División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica
A. C., San Luis Potosí 78216, México
| | - Miriam Livier Llamas-García
- IPICYT,
División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica
A. C., San Luis Potosí 78216, México
| | - Claudia G. Benítez-Cardoza
- Laboratorio
de Investigación Bioquímica, Programa Institucional
en Biomedicina Molecular ENMyH-Instituto Politécnico Nacional, Ciudad de México 07320, México
| | - Gabriela M. Montero-Morán
- Facultad
de Ciencias Químicas, Laboratorio IBCM, Universidad Autónoma de San Luis Potosí, San Luis Potosí 78210, México
| | - Samuel Lara-González
- IPICYT,
División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica
A. C., San Luis Potosí 78216, México
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38
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Wang S, Wang W, Li X, Zhao X, Wang Y, Zhang H, Xu S. Cooperative application of transcriptomics and ceRNA hypothesis: LncRNA-107052630/miR-205a/G0S2 crosstalk is involved in ammonia-induced intestinal apoptotic injury in chicken. JOURNAL OF HAZARDOUS MATERIALS 2020; 396:122605. [PMID: 32334290 DOI: 10.1016/j.jhazmat.2020.122605] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/24/2020] [Accepted: 03/26/2020] [Indexed: 06/11/2023]
Abstract
Ammonia (NH3), as a harmful gas from agricultural production, plays an important role in air pollution, such as haze. Although numerous researchers have paid attention to health damage through NH3 inhalation, the exhaustive mechanism of NH3 induced intestinal toxicity remains unclear. A genes crosstalk named competing endogenous RNAs (ceRNA) can explain many regulatory manners from the molecular perspective. However, few studies have attempted to interpret the injury mechanism of air pollutants to the organism via ceRNA theory. Here, we thoroughly investigated the lncRNA-associated-ceRNA mechanism in jejunum samples from a 42-days-old NH3-exposed chicken model through deep RNA sequencing. We observed the occurrence of apoptosis in jejunum, obtained 46 significantly dysregulated lncRNAs and 30 dysregulated miRNAs, and then constructed lncRNA-associated-ceRNA networks in jejunum. Importantly, a network regulating G0S2 in NH3-induced apoptosis was discovered. Research results showed that G0S2 was upregulated in jejunum of NH3-exposed group and was associated with activation of the mitochondrial apoptosis pathway. G0S2 antagonized the anti-apoptotic effect of Bcl2, which could be reversed by miR-205a. Meanwhile, lncRNA-107052630 acted as ceRNA to affect G0S2 function. These data provide new insight for revealing the biological effect of NH3 toxicity, as well as the environmental research.
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Affiliation(s)
- Shengchen Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Wei Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Xiaojing Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Xia Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Yue Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Hongfu Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China.
| | - Shiwen Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
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Ferrero H, Corachán A, Aguilar A, Quiñonero A, Carbajo-García MC, Alamá P, Tejera A, Taboas E, Muñoz E, Pellicer A, Domínguez F. Single-cell RNA sequencing of oocytes from ovarian endometriosis patients reveals a differential transcriptomic profile associated with lower quality. Hum Reprod 2020; 34:1302-1312. [PMID: 31211846 DOI: 10.1093/humrep/dez053] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 01/30/2019] [Indexed: 12/20/2022] Open
Abstract
STUDY QUESTION Do oocytes from women with ovarian endometriosis (OE) have a different transcriptomic profile than those from healthy women? SUMMARY ANSWER Oocytes from endometriosis patients, independently of whether they came from the affected ovary, exhibited a differential transcriptomic profile compared to oocytes from healthy egg donors. WHAT IS KNOWN ALREADY Studies of endometriosis have sought to determine whether OE affects oocyte quality. While many reports indicate that oocytes recovered from endometriotic ovaries may be affected by the disease, other studies have found no significant differences among oocyte/embryo quality and fertilization, implantation and pregnancy rates in women with endometriosis. STUDY DESIGN, SIZE, DURATION This prospective study compared metaphase II (MII) oocytes (n = 16) from endometriosis patients (n = 7) to oocytes (n = 16) from healthy egg donors (n = 5) by single-cell RNA sequencing (scRNA-seq). Participants were recruited between December 2016 and February 2018 at IVI-RMA Valencia and Vigo clinics. PARTICIPANTS/MATERIALS, SETTING, METHODS Human MII oocytes were collected from healthy egg donors and OE patients aged 18-34 years, with a body mass index of <30 and >6 pre-antral follicles. RNA was extracted, cDNA was generated and libraries were constructed and sequenced. scRNA-seq data libraries were processed and statistically analysed. Selected genes were validated by quantitative real-time PCR. MAIN RESULTS AND THE ROLE OF CHANCE Our scRNA-seq results revealed an effect of endometriosis on global transcriptome behaviour in oocytes from endometriotic ovaries. The highest number of differentially expressed genes (DEGs) was found when oocytes from women with OE were compared to oocytes from healthy donors [520 DEGs (394 upregulated and 126 downregulated)], independently of whether oocytes came from an affected or unaffected ovary. Among the top 20 significant DEGs in this comparison, most were upregulated, including APOE, DUSP1, G0S2, H2AFZ, ID4, MGST1 and WEE1. PXK was the only downregulated gene. Subsequently, functional analysis showed 31 enriched functions deregulated in endometriosis patients (Benjamini P < 0.1), being 16 significant enriched functions considering Benjamini P < 0.05, which involved in biological processes and molecular functions, such as steroid metabolism, response to oxidative stress and cell growth regulation. In addition, our functional analysis showed enrichment for mitochondria, which are an important cellular component in oocyte development. Other functions important in embryo development, such as angiogenesis and methylation, were also significantly enriched. LARGE SCALE DATA All raw sequencing data are submitted in Gene Expression Omnibus (GEO) under accession number (PRJNA514416). LIMITATIONS, REASONS FOR CAUTION This study was restricted only to OE and thereby other anatomical entities, such as peritoneal and deep infiltrating endometriosis, were not considered. This is a descriptive study with a limited number of samples reflecting the difficulty to recruit human oocytes, especially from women with endometriosis. WIDER IMPLICATIONS OF THE FINDINGS This study suggests that OE exhibits a global transcriptomic effect on oocytes of patients in OE, independently if they come from an affected or unaffected ovary and alters key biological processes and molecular functions related to steroid metabolism, response to oxidative stress and cell growth regulation, which reduce oocyte quality. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by IVI Foundation, the Spanish Ministry of Economy and Competitiveness through the Miguel Servet programme (CPII018/00002 to F.D.), the Sara Borrell Program (CD15/00057 to H.F.) and the VALi+d Programe (Generalitat Valenciana); ACIF/2016/444 to A.C.). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER None.
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Affiliation(s)
- Hortensia Ferrero
- Fundación Instituto Valenciano de Infertilidad, Instituto Universitario IVI, Valencia, Spain.,INCLIVA Biomedical Research Institute, Valencia, Spain
| | - Ana Corachán
- Fundación Instituto Valenciano de Infertilidad, Instituto Universitario IVI, Valencia, Spain.,Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain
| | - Alejandra Aguilar
- Instituto Valenciano de Infertilidad-Reproductive Medicine Associates (IVI-RMA), London, UK
| | - Alicia Quiñonero
- Fundación Instituto Valenciano de Infertilidad, Instituto Universitario IVI, Valencia, Spain
| | | | - Pilar Alamá
- Instituto Valenciano de Infertilidad-Reproductive Medicine Associates (IVI-RMA) Valencia, Valencia, Spain
| | - Alberto Tejera
- Instituto Valenciano de Infertilidad-Reproductive Medicine Associates (IVI-RMA) Valencia, Valencia, Spain
| | - Esther Taboas
- Instituto Valenciano de Infertilidad-Reproductive Medicine Associates (IVI-RMA) Valencia, Vigo, Spain
| | - Elkin Muñoz
- Instituto Valenciano de Infertilidad-Reproductive Medicine Associates (IVI-RMA) Valencia, Vigo, Spain
| | - Antonio Pellicer
- Fundación Instituto Valenciano de Infertilidad, Instituto Universitario IVI, Valencia, Spain.,Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain
| | - Francisco Domínguez
- Fundación Instituto Valenciano de Infertilidad, Instituto Universitario IVI, Valencia, Spain.,Health Research Institute la Fe, Valencia, Spain
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Transcriptomic Response of Breast Cancer Cells MDA-MB-231 to Docosahexaenoic Acid: Downregulation of Lipid and Cholesterol Metabolism Genes and Upregulation of Genes of the Pro-Apoptotic ER-Stress Pathway. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17103746. [PMID: 32466294 PMCID: PMC7277693 DOI: 10.3390/ijerph17103746] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 05/20/2020] [Accepted: 05/22/2020] [Indexed: 12/18/2022]
Abstract
Despite considerable efforts in prevention and therapy, breast cancer remains a major public health concern worldwide. Numerous studies using breast cancer cell lines have shown the antiproliferative and pro-apoptotic effects of docosahexaenoic acid (DHA). Some studies have also demonstrated the inhibitory effect of DHA on the migration and invasion of breast cancer cells, making DHA a potential anti-metastatic agent. Thus, DHA has shown its potential as a chemotherapeutic adjuvant. However, the molecular mechanisms triggering DHA effects remain unclear, and the aim of this study was to provide a transcriptomic basis for further cellular and molecular investigations. Therefore, MDA-MB-231 cells were treated with 100 µM DHA for 12 h or 24 h before RNA-seq analysis. The results show the great impact of DHA-treatment on the transcriptome, especially after 24 h of treatment. The impact of DHA is particularly visible in genes involved in the cholesterol biosynthesis pathway that is strongly downregulated, and the endoplasmic reticulum (ER)-stress response that is, conversely, upregulated. This ER-stress and unfolded protein response could explain the pro-apoptotic effect of DHA. The expression of genes related to migration and invasion (especially SERPINE1, PLAT, and MMP11) is also impacted by DHA. In conclusion, this transcriptomic analysis supports the antiproliferative, pro-apoptotic and anti-invasive effects of DHA, and provides new avenues for understanding its molecular mechanisms.
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Hofer P, Taschler U, Schreiber R, Kotzbeck P, Schoiswohl G. The Lipolysome-A Highly Complex and Dynamic Protein Network Orchestrating Cytoplasmic Triacylglycerol Degradation. Metabolites 2020; 10:E147. [PMID: 32290093 PMCID: PMC7240967 DOI: 10.3390/metabo10040147] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 04/03/2020] [Accepted: 04/08/2020] [Indexed: 12/25/2022] Open
Abstract
The catabolism of intracellular triacylglycerols (TAGs) involves the activity of cytoplasmic and lysosomal enzymes. Cytoplasmic TAG hydrolysis, commonly termed lipolysis, is catalyzed by the sequential action of three major hydrolases, namely adipose triglyceride lipase, hormone-sensitive lipase, and monoacylglycerol lipase. All three enzymes interact with numerous protein binding partners that modulate their activity, cellular localization, or stability. Deficiencies of these auxiliary proteins can lead to derangements in neutral lipid metabolism and energy homeostasis. In this review, we summarize the composition and the dynamics of the complex lipolytic machinery we like to call "lipolysome".
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Affiliation(s)
- Peter Hofer
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; (P.H.); (U.T.); (R.S.)
| | - Ulrike Taschler
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; (P.H.); (U.T.); (R.S.)
| | - Renate Schreiber
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; (P.H.); (U.T.); (R.S.)
| | - Petra Kotzbeck
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria;
| | - Gabriele Schoiswohl
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; (P.H.); (U.T.); (R.S.)
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Kulminskaya N, Oberer M. Protein-protein interactions regulate the activity of Adipose Triglyceride Lipase in intracellular lipolysis. Biochimie 2020; 169:62-68. [DOI: 10.1016/j.biochi.2019.08.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 08/06/2019] [Indexed: 12/31/2022]
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Integrated exome and RNA sequencing of dedifferentiated liposarcoma. Nat Commun 2019; 10:5683. [PMID: 31831742 PMCID: PMC6908635 DOI: 10.1038/s41467-019-13286-z] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 10/28/2019] [Indexed: 01/06/2023] Open
Abstract
The genomic characteristics of dedifferentiated liposarcoma (DDLPS) that are associated with clinical features remain to be identified. Here, we conduct integrated whole exome and RNA sequencing analysis in 115 DDLPS tumors and perform comparative genomic analysis of well-differentiated and dedifferentiated components from eight DDLPS samples. Several somatic copy-number alterations (SCNAs), including the gain of 12q15, are identified as frequent genomic alterations. CTDSP1/2-DNM3OS fusion genes are identified in a subset of DDLPS tumors. Based on the association of SCNAs with clinical features, the DDLPS tumors are clustered into three groups. This clustering can predict the clinical outcome independently. The comparative analysis between well-differentiated and dedifferentiated components identify two categories of genomic alterations: shared alterations, associated with tumorigenesis, and dedifferentiated-specific alterations, associated with malignant transformation. This large-scale genomic analysis reveals the mechanisms underlying the development and progression of DDLPS and provides insights that could contribute to the refinement of DDLPS management. Understanding the genomic features of dedifferentiated liposarcoma (DDLPS) is likely to uncover new options for management. Here, the authors reveal three prognostic groups, and highlight molecular markers associated with malignant transformation.
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Cho E, Kwon YJ, Ye DJ, Baek HS, Kwon TU, Choi HK, Chun YJ. G0/G1 Switch 2 Induces Cell Survival and Metastasis through Integrin-Mediated Signal Transduction in Human Invasive Breast Cancer Cells. Biomol Ther (Seoul) 2019; 27:591-602. [PMID: 31272137 PMCID: PMC6824625 DOI: 10.4062/biomolther.2019.063] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/24/2019] [Accepted: 06/04/2019] [Indexed: 12/25/2022] Open
Abstract
Human breast cancer cell line, MDA-MB-231, is highly invasive and aggressive, compared to less invasive cell line, MCF-7. To explore the genes that might influence the malignancy of MDA-MB-231, DNA microarray analysis was performed. The results showed that G0/G1 switch 2 (G0S2) was one of the most highly expressed genes among the genes upregulated in MDA-MB-231. Although G0S2 acts as a direct inhibitor of adipose triglyceride lipase, action of G0S2 in cancer progression is not yet understood. To investigate whether G0S2 affects invasiveness of MDA-MB-231 cells, G0S2 expression was inhibited using siRNA, which led to decreased cell proliferation, migration, and invasion of MDA-MB-231 cells. Consequently, G0S2 inhibition inactivated integrinregulated FAK-Src signaling, which promoted Hippo signaling and inactivated ERK1/2 signaling. In addition, G0S2 downregulation decreased β-catenin expression, while E-cadherin expression was increased. It was demonstrated for the first time that G0S2 mediates the Hippo pathway and induces epithelial to mesenchymal transition (EMT). Taken together, our results suggest that G0S2 is a major factor contributing to cell survival and metastasis of MDA-MB-231 cells.
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Affiliation(s)
- Eunah Cho
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974,
Republic of Korea
| | - Yeo-Jung Kwon
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974,
Republic of Korea
| | - Dong-Jin Ye
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974,
Republic of Korea
| | - Hyoung-Seok Baek
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974,
Republic of Korea
| | - Tae-Uk Kwon
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974,
Republic of Korea
| | - Hyung-Kyoon Choi
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974,
Republic of Korea
| | - Young-Jin Chun
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974,
Republic of Korea
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Kovacheva M, Zepp M, Schraad M, Berger S, Berger MR. Conditional Knockdown of Osteopontin Inhibits Breast Cancer Skeletal Metastasis. Int J Mol Sci 2019; 20:E4918. [PMID: 31590218 PMCID: PMC6801824 DOI: 10.3390/ijms20194918] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 09/28/2019] [Accepted: 09/30/2019] [Indexed: 02/07/2023] Open
Abstract
High osteopontin (OPN) expression is linked to breast cancer bone metastasis. In this study we modulated osteopontin levels conditionally and investigated any related antineoplastic effects. Therefore, we established cell clones from human breast cancer MDA-MB-231 cells, in which the expression of OPN is regulated by the Tet-Off tet-off system. These cells, which conditionally express a specific miRNA targeting OPN, were used for in vitro studies as well as for a bone metastasis model in nude rats. Changes in whole-genome expression elicited by conditional OPN knockdown and vesicle formation were also analyzed. The alkylphosphocholine erufosine was used for combination therapy. Conditional OPN knockdown caused mild anti-proliferative, but more intensive anti-migratory and anti clonogenic effects, as well as partial and complete remissions of soft tissue and osteolytic lesions. These effects were associated with specific gene and protein expression modulations following miRNA-mediated OPN knockdown. Furthermore, high levels of OPN were detected in vesicles derived from rats harboring breast cancer skeletal metastases. Finally, the combination of OPN inhibition and erufosine treatment caused an additive reduction of OPN levels in the investigated breast cancer cells. Thus, knockdown of OPN alone or in combination with erufosine is a promising strategy in breast cancer skeletal metastasis treatment.
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Affiliation(s)
- Marineta Kovacheva
- German Cancer Research Center (DKFZ), Toxicology and Chemotherapy Unit, 69120 Heidelberg, Germany.
| | - Michael Zepp
- German Cancer Research Center (DKFZ), Toxicology and Chemotherapy Unit, 69120 Heidelberg, Germany.
| | - Muriel Schraad
- German Cancer Research Center (DKFZ), Toxicology and Chemotherapy Unit, 69120 Heidelberg, Germany.
| | - Stefan Berger
- Central Institute of Mental Health, Department of Molecular Biology, 68159 Mannheim, Germany.
| | - Martin R Berger
- German Cancer Research Center (DKFZ), Toxicology and Chemotherapy Unit, 69120 Heidelberg, Germany.
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Jeffrey JD, Jeffries KM, Suski CD. Physiological status of silver carp (Hypophthalmichthys molitrix) in the Illinois River: An assessment of fish at the leading edge of the invasion front. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY D-GENOMICS & PROTEOMICS 2019; 32:100614. [PMID: 31419603 DOI: 10.1016/j.cbd.2019.100614] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 07/08/2019] [Accepted: 07/24/2019] [Indexed: 01/29/2023]
Abstract
Silver carp (Hypophthalmichthys molitrix) are invasive to North America, and their range has expanded within the Mississippi River Basin, seemingly unchecked, since their introduction in the late 1970s, with the exception of the upper reaches of the Illinois River. With the imminent threat of their movement into the Great Lakes, the goal of the present study was to assess whether differences in the physiological status between silver carp at the leading edge of their invasion front and core population sites could explain their lack of expansion upstream toward Lake Michigan over the past decade. A transcriptomic approach using RNA sequencing and analysis of plasma variables were used to quantify differences among fish at the leading edge and two downstream core population sites. Leading-edge fish exhibited upregulation of genes associated with xenobiotic defense (e.g., ATP-binding cassette C1 [abcc1], abcc2, abcc6), decreased cell integrity (i.e., macroautophagy and apoptosis; autophagy-related protein 9A [atg9a], caspase 3b [casp3b]), and cholesterol metabolism (e.g., abca1, apolipoprotein A1 [apoa1], sterol O-acyltransferase [soat1]) and downregulation of genes associated with DNA repair (e.g., tumor suppressor p53-binding protein 1 [tp53bp1]) compared to core population sites. Transcriptomic profiles of leading-edge fish were consistent with fish inhabiting a polluted environment and suggest that poorer water quality conditions upstream of the leading edge may represent a non-permanent barrier to silver carp range expansion. The present study provides potential molecular targets for monitoring the physiological status of silver carp over time and in response to future improvements in water quality upstream of their leading edge.
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Affiliation(s)
- Jennifer D Jeffrey
- Department of Natural Resources and Environmental Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
| | - Ken M Jeffries
- Department of Biology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Cory D Suski
- Department of Natural Resources and Environmental Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA
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Diao XY, Lin T. Progress in therapeutic strategies based on cancer lipid metabolism. Thorac Cancer 2019; 10:1741-1743. [PMID: 31328418 PMCID: PMC6718024 DOI: 10.1111/1759-7714.13146] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 01/01/2023] Open
Affiliation(s)
- Xia-Yao Diao
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Tianxin Lin
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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Lipolytic inhibitor G0S2 modulates glioma stem-like cell radiation response. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:147. [PMID: 30953555 PMCID: PMC6451284 DOI: 10.1186/s13046-019-1151-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 03/21/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Ionizing radiation (IR) therapy is the standard first-line treatment for newly diagnosed patients with glioblastoma (GBM), the most common and malignant primary brain tumor. However, the effects of IR are limited due to the aberrant radioresistance of GBM. METHODS Transcriptome analysis was performed using RNA-seq in radioresistant patient-derived glioma stem-like cells (GSCs). Survival of glioma patient and mice bearing-brain tumors was analyzed by Kaplan-Meier survival analysis. Lipid droplet and γ-H2AX foci-positive cells were evaluated using immunofluorescence staining. RESULTS Lipolytic inhibitor G0/G1 switch gene 2 (G0S2) is upregulated in radioresistant GSCs and elevated in clinical GBM. GBM patients with high G0S2 expression had significantly shorter overall survival compared with those with low expression of G0S2. Using genetic approaches targeting G0S2 in glioma cells and GSCs, we found that knockdown of G0S2 promoted lipid droplet turnover, inhibited GSC radioresistance, and extended survival of xenograft tumor mice with or without IR. In contrast, overexpression of G0S2 promoted glioma cell radiation resistance. Mechanistically, high expression of G0S2 reduced lipid droplet turnover and thereby attenuated E3 ligase RNF168-mediated 53BP1 ubiquitination through activated the mechanistic target of rapamycin (mTOR)-ribosomal S6 kinase (S6K) signaling and increased 53BP1 protein stability in response to IR, leading to enhanced DNA repair and glioma radioresistance. CONCLUSIONS Our findings uncover a new function for lipolytic inhibitor G0S2 as an important regulator for GSC radioresistance, suggesting G0S2 as a potential therapeutic target for treating gliomas.
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Doroszko M, Chrusciel M, Stelmaszewska J, Slezak T, Anisimowicz S, Plöckinger U, Quinkler M, Bonomi M, Wolczynski S, Huhtaniemi I, Toppari J, Rahman NA. GnRH antagonist treatment of malignant adrenocortical tumors. Endocr Relat Cancer 2019; 26:103-117. [PMID: 30400009 PMCID: PMC6215908 DOI: 10.1530/erc-17-0399] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 08/21/2018] [Indexed: 12/11/2022]
Abstract
Aberrantly expressed G protein-coupled receptors in tumors are considered as potential therapeutic targets. We analyzed the expressions of receptors of gonadotropin-releasing hormone (GNRHR), luteinizing hormone/chorionic gonadotropin (LHCGR) and follicle-stimulating hormone (FSHR) in human adrenocortical carcinomas and assessed their response to GnRH antagonist therapy. We further studied the effects of the GnRH antagonist cetrorelix acetate (CTX) on cultured adrenocortical tumor (ACT) cells (mouse Cα1 and Y-1, and human H295R), and in vivo in transgenic mice (SV40 T-antigen expression under inhibin α promoter) bearing Lhcgr and Gnrhr in ACT. Both models were treated with control (CT), CTX, human chorionic gonadotropin (hCG) or CTX+hCG, and their growth and transcriptional changes were analyzed. In situ hybridization and qPCR analysis of human adrenocortical carcinomas (n = 11-13) showed expression of GNRHR in 54/73%, LHCGR in 77/100% and FSHR in 0%, respectively. CTX treatment in vitro decreased cell viability and proliferation, and increased caspase 3/7 activity in all treated cells. In vivo, CTX and CTX+hCG (but not hCG alone) decreased ACT weights and serum LH and progesterone concentrations. CTX treatment downregulated the tumor markers Lhcgr and Gata4. Upregulated genes included Grb10, Rerg, Nfatc and Gnas, all recently found to be abundantly expressed in healthy adrenal vs ACT. Our data suggest that CTX treatment may improve the therapy of human adrenocortical carcinomas by direct action on GNRHR-positive cancer cells inducing apoptosis and/or reducing gonadotropin release, directing tumor cells towards a healthy adrenal gene expression profile.
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Affiliation(s)
| | | | - Joanna Stelmaszewska
- Department of Reproduction and Gynecological EndocrinologyMedical University of Bialystok, Bialystok, Poland
| | - Tomasz Slezak
- Department of Biochemistry and Molecular BiologyUniversity of Chicago, Chicago, Illinois, USA
| | | | - Ursula Plöckinger
- Interdisciplinary Center of Metabolism: EndocrinologyDiabetes and Metabolism, Charité University Medicine Berlin, Berlin, Germany
| | - Marcus Quinkler
- Endocrinology in CharlottenburgBerlin, Germany
- Department of Clinical EndocrinologyCharité Campus Mitte, Charité University Medicine Berlin, Berlin, Germany
| | - Marco Bonomi
- Department of Clinical Sciences & Community HealthUniversity of Milan, Milan, Italy
| | - Slawomir Wolczynski
- Department of Reproduction and Gynecological EndocrinologyMedical University of Bialystok, Bialystok, Poland
| | - Ilpo Huhtaniemi
- Institute of BiomedicineUniversity of Turku, Turku, Finland
- Department of Surgery and CancerFaculty of Medicine, Imperial College London, London, U.K.
| | - Jorma Toppari
- Institute of BiomedicineUniversity of Turku, Turku, Finland
- Department of PediatricsTurku University Hospital, Turku, Finland
| | - Nafis A Rahman
- Institute of BiomedicineUniversity of Turku, Turku, Finland
- Department of Reproduction and Gynecological EndocrinologyMedical University of Bialystok, Bialystok, Poland
- Correspondence should be addressed to N Rahman:
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Methylation dependent down-regulation of G0S2 leads to suppression of invasion and improved prognosis of IDH1-mutant glioma. PLoS One 2018; 13:e0206552. [PMID: 30388142 PMCID: PMC6214530 DOI: 10.1371/journal.pone.0206552] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 10/15/2018] [Indexed: 11/23/2022] Open
Abstract
Isocitrate dehydrogenase (IDH) mutations are a prognostic factor in diffuse glioma. However, the mechanism by which these mutations improve prognosis are not clear. In a subset of IDH-mutant glioma, remodeling of the methylome results in the glioma-CpG island methylator phenotype (G-CIMP) and transcriptional reorganization. In this study, we focus on G0/G1 switch 2 (G0S2), which is highly downregulated in G-CIMP glioma. We found that G0S2 expression tended to increase as the WHO grade increased, and G0S2 knockdown inhibited glioma invasion. Additionally, we revealed that the overexpression of the DNA demethylase Ten-eleven translocation 2 (TET2) in IDH1-plasmid transfected glioblastoma multiforme (GBM) cells restored G0S2 expression. These results indicate that G0S2 is epigenetically silenced in IDH1-mutant glioma. In addition, the stereotactic delivery of glioma cells with decreased G0S2 expression in the mouse brain resulted in prolonged survival. The Cancer Genome Atlas (TCGA) analysis also indicated that survival is longer in the lower G0S2 expression group than in the higher G0S2 expression group. Moreover, G0S2 expression was higher in recurrent tumor specimens than at the initial diagnosis in the same patient. These results provide one explanation for the improved survival in IDH1-mutant glioma as well as a new epigenetic target for glioma treatment.
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