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Pham DT, Tran TD. Drivergene.net: A Cytoscape app for the identification of driver nodes of large-scale complex networks and case studies in discovery of drug target genes. Comput Biol Med 2024; 179:108888. [PMID: 39047507 DOI: 10.1016/j.compbiomed.2024.108888] [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: 02/23/2024] [Revised: 06/15/2024] [Accepted: 07/11/2024] [Indexed: 07/27/2024]
Abstract
There are no tools to identify driver nodes of large-scale networks in approach of competition-based controllability. This study proposed a novel method for this computation of large-scale networks. It implemented the method in a new Cytoscape plug-in app called Drivergene.net. Experiments of the software on large-scale biomolecular networks have shown outstanding speed and computing power. Interestingly, 86.67% of the top 10 driver nodes found on these networks are anticancer drug target genes that reside mostly at the innermost K-cores of the networks. Finally, compared method with those of five other researchers and confirmed that the proposed method outperforms the other methods on identification of anticancer drug target genes. Taken together, Drivergene.net is a reliable tool that efficiently detects not only drug target genes from biomolecular networks but also driver nodes of large-scale complex networks. Drivergene.net with a user manual and example datasets are available https://github.com/tinhpd/Drivergene.git.
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Affiliation(s)
- Duc-Tinh Pham
- Complex Systems and Bioinformatics Lab, Hanoi University of Industry, 298 Cau Dien Street, Bac Tu Liem District, Hanoi, Viet Nam; Graduate University of Science and Technology, Academy of Science and Technology Viet Nam, 18 Hoang Quoc Viet Street, Cau Giay District, Hanoi, Viet Nam
| | - Tien-Dzung Tran
- Complex Systems and Bioinformatics Lab, Hanoi University of Industry, 298 Cau Dien Street, Bac Tu Liem District, Hanoi, Viet Nam; Faculty of Information and Communication Technology, Hanoi University of Industry, 298 Cau Dien Street, Bac Tu Liem District, Hanoi, Viet Nam.
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Lu Y, Zhao C, Wang C, Cai H, Hu Y, Chen L, Yu S, Zhu H, Liu P, Wan'e W, Zhang H. The effect and mechanism of Qingre Huashi formula in the treatment of chronic hepatitis B with Gan-dan-shi-Re syndrome: An integrated transcriptomic and targeted metabolomic analysis. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117092. [PMID: 37634751 DOI: 10.1016/j.jep.2023.117092] [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: 06/20/2023] [Revised: 08/20/2023] [Accepted: 08/24/2023] [Indexed: 08/29/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Qingre Huashi (QRHS) formula is an empirical prescription for the treatment of Gan-Dan-Shi-Re syndrome (GDSR) syndrome in traditional Chinese medicine (TCM). GDSR is one of the typical TCM syndromes in chronic hepatitis B (CHB). However, little is known about the mechanism of the QRHS formula in treating CHB patients with GDSR. The biological basis of GDSR also remains largely unknown. AIM OF THE STUDY GDSR mostly occurs in the acute and early stages of chronic liver disease. Effectively alleviating GDSR stalls disease development and benefits patients. The purpose of this study was to explore the molecular basis of GDSR in CHB and then study the mechanism of the QRHS formula treating GDSR using transcriptomics and metabolomics. MATERIALS AND METHODS The transcriptome and metabolome of CHB patients with GDSR syndrome were detected using RNA microarray combined with ultra-high performance liquid chromatography/mass spectrometry and information mining. The potential biomarkers were identified from differentially expressed genes and metabolites, and the metabolic pathway was analyzed. We also investigated the callback of metabolic biomarkers after treatment with the QRHS formula, an empirical prescription for the treatment of GDSR syndrome. RT-PCR analysis was carried out in an independent patient cohort of CHB for validation. RESULTS Four candidate genes-GPT2, HK2, DDIT3, and HIF1A-and 14 candidate metabolic biomarkers, including L-alpha-aminobutyric acid, selenomethionine, and fructose 1,6-bisphosphate, were identified and validated. All four transcripts of GPT2, HK2, DDIT3, and HIF1A were significantly differentially expressed between the GDSR and non-GDSR groups through independent microarray data and RT-PCR. After treatment with the QRHS formula, the clinical indexes and TCM syndrome were significantly improved, and the 14 disturbed biomarkers were obviously corrected. Three metabolic pathways were confirmed to be perturbed in CHB GDSR patients: alanine, aspartate, and glutamate metabolism, arginine biosynthesis, and aminoacyl-tRNA biosynthesis. CONCLUSION Using integrated transcriptomic and targeted metabolomic methods, we identified the potential biomarkers and dysregulated metabolic pathways in CHB patients with GDSR syndrome, which was alleviated by the QRHS formula treatment. These results may provide the mechanism of metabolic dysregulation in GDSR syndrome as well as that underlying the curative effect of the QRHS formula.
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Affiliation(s)
- Yiyu Lu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Chaoqun Zhao
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Chengbao Wang
- Shandong Medical College, Jinan, Shandong, 250004, China
| | - Hong Cai
- Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361015, China
| | - Yuting Hu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Long Chen
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Shanghai Yu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Huiming Zhu
- Fifth People's Hospital of Suzhou, Jiangsu, 215007, China
| | - Ping Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Wang Wan'e
- Huai'an Fourth People's Hospital, Huai'an, Jiangsu, 223300, China.
| | - Hua Zhang
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Kühn JP, Speicher S, Linxweiler B, Körner S, Rimbach H, Wagner M, Solomayer EF, Schick B, Linxweiler M. Dual Sec62/Ki67 immunocytochemistry of liquid-based cytological preparations represents a highly valid biomarker for non-invasive detection of head and neck squamous cell carcinomas. Cytopathology 2024; 35:113-121. [PMID: 37787092 DOI: 10.1111/cyt.13310] [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: 07/20/2023] [Revised: 09/01/2023] [Accepted: 09/06/2023] [Indexed: 10/04/2023]
Abstract
BACKGROUND Head and neck squamous cell carcinomas (HNSCC) are frequently diagnosed in advanced stages, which limits therapeutic options and results in persistently poor patient outcomes. The aim of this study was to use liquid-based swab cytology (LBC) in combination with dual immunocytochemical detection of migration and proliferation markers Sec62 and Ki67 in order to allow non-invasive early detection of HNSCC as well as to analyse the diagnostic validity of this method for predicting the malignancy of suspicious oral lesions. METHODS 104 HNSCC patients and 28 control patients, including healthy patients (n = 17), papilloma (n = 1) and leukoplakia patients (n = 10), were included in this study. For all patients, an LBC swab followed by simultaneous immunocytochemical detection of Sec62 and Ki67 was performed. Immunocytochemical as well as cytopathological results were correlated with histological diagnoses and clinical findings. RESULTS All HNSCC patients (100%) showed dual Sec62/Ki67 positivity, and all control patients except for the papilloma patient were negative for Sec62/Ki67 (96.4%), resulting in a 100% sensitivity and 96.4% specificity of Sec62/Ki67 dual stain for non-invasive detection of HNSCC. The positive predictive value was 99% and the negative predictive value was 100%. Sec62 expression levels showed a positive correlation with tumour de-differentiation (p = 0.0489). CONCLUSION Simultaneous immunocytochemical detection of Sec62/Ki67 using LBC represents a promising non-invasive and easy-to-apply tool for the early detection of HNSCC in routine clinical practice. This novel technique can help to avoid incisional biopsies and reduce the frequency with which general anaesthesia is used in diagnostic procedures in patients with suspicious oral lesions.
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Affiliation(s)
- Jan Philipp Kühn
- Department of Otorhinolaryngology, Saarland University Medical Center, Homburg/Saar, Germany
| | - Stefanie Speicher
- Department of Otorhinolaryngology, Saarland University Medical Center, Homburg/Saar, Germany
| | - Barbara Linxweiler
- Department of Gynecology, Saarland University Medical Center, Homburg/Saar, Germany
| | - Sandrina Körner
- Department of Otorhinolaryngology, Saarland University Medical Center, Homburg/Saar, Germany
| | - Hugo Rimbach
- Department of Otorhinolaryngology, Saarland University Medical Center, Homburg/Saar, Germany
| | - Mathias Wagner
- Department of Pathology, Saarland University Medical Center, Homburg/Saar, Germany
| | | | - Bernhard Schick
- Department of Otorhinolaryngology, Saarland University Medical Center, Homburg/Saar, Germany
| | - Maximilian Linxweiler
- Department of Otorhinolaryngology, Saarland University Medical Center, Homburg/Saar, Germany
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Linxweiler M, Schneider M, Körner S, Knebel M, Brust LA, Braun FL, Wemmert S, Wagner M, Hecht M, Schick B, Kühn JP. Expression of 3q Oncogene SEC62 Predicts Survival in Head and Neck Squamous Cell Carcinoma Patients Treated with Primary Chemoradiation. Cancers (Basel) 2023; 16:98. [PMID: 38201525 PMCID: PMC10778380 DOI: 10.3390/cancers16010098] [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: 12/04/2023] [Revised: 12/19/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Primary chemoradiotherapy (CRT) is an established treatment option for locally advanced head and neck squamous cell carcinomas (HNSCC) usually combining intensity modified radiotherapy with concurrent platinum-based chemotherapy. Though the majority of patients can be cured with this regimen, treatment response is highly heterogeneous and can hardly be predicted. SEC62 represents a metastasis stimulating oncogene that is frequently overexpressed in various cancer entities and is associated with poor outcome. Its role in HNSCC patients undergoing CRT has not been investigated so far. A total of 127 HNSCC patients treated with primary CRT were included in this study. The median follow-up was 5.4 years. Pretherapeutic tissue samples of the primary tumors were used for immunohistochemistry targeting SEC62. SEC62 expression, clinical and histopathological parameters, as well as patient outcome, were correlated in univariate and multivariate survival analyses. High SEC62 expression correlated with a significantly shorter overall survival (p = 0.015) and advanced lymph node metastases (p = 0.024). Further significant predictors of poor overall and progression-free survival included response to therapy (RECIST1.1), nodal status, distant metastases, tobacco consumption, recurrence of disease, and UICC stage. In a multivariate Cox hazard proportional regression analysis, only SEC62 expression (p = 0.046) and response to therapy (p < 0.0001) maintained statistical significance as independent predictors of the patients' overall survival. This study identified SEC62 as an independent prognostic biomarker in HNSCC patients treated with primary CRT. The role of SEC62 as a potential therapeutic target and its interaction with radiation-induced molecular alterations in head and neck cancer cells should further be investigated.
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Affiliation(s)
- Maximilian Linxweiler
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (M.S.); (S.K.); (M.K.); (L.A.B.); (S.W.); (B.S.); (J.P.K.)
| | - Matthias Schneider
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (M.S.); (S.K.); (M.K.); (L.A.B.); (S.W.); (B.S.); (J.P.K.)
| | - Sandrina Körner
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (M.S.); (S.K.); (M.K.); (L.A.B.); (S.W.); (B.S.); (J.P.K.)
| | - Moritz Knebel
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (M.S.); (S.K.); (M.K.); (L.A.B.); (S.W.); (B.S.); (J.P.K.)
| | - Lukas Alexander Brust
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (M.S.); (S.K.); (M.K.); (L.A.B.); (S.W.); (B.S.); (J.P.K.)
| | - Felix Leon Braun
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (M.S.); (S.K.); (M.K.); (L.A.B.); (S.W.); (B.S.); (J.P.K.)
| | - Silke Wemmert
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (M.S.); (S.K.); (M.K.); (L.A.B.); (S.W.); (B.S.); (J.P.K.)
| | - Mathias Wagner
- Department of General and Surgical Pathology, Saarland University Medical Center, D-66421 Homburg, Germany;
| | - Markus Hecht
- Department of Radiotherapy and Radiation Oncology, Saarland University Medical Center, D-66421 Homburg, Germany;
| | - Bernhard Schick
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (M.S.); (S.K.); (M.K.); (L.A.B.); (S.W.); (B.S.); (J.P.K.)
| | - Jan Philipp Kühn
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (M.S.); (S.K.); (M.K.); (L.A.B.); (S.W.); (B.S.); (J.P.K.)
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Radosa JC, Kasoha M, Doerk M, Cullmann A, Kaya AC, Linxweiler M, Radosa MP, Takacs Z, Tirincsi A, Lang S, Jung M, Puppe J, Linxweiler B, Wagner M, Bohle RM, Solomayer EF, Zimmermann JSM. The 3q Oncogene SEC62 Predicts Response to Neoadjuvant Chemotherapy and Regulates Tumor Cell Migration in Triple Negative Breast Cancer. Int J Mol Sci 2023; 24:ijms24119576. [PMID: 37298528 DOI: 10.3390/ijms24119576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 05/20/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
In the absence of targeted treatment options, neoadjuvant chemotherapy (NACT) is applied widely for triple-negative breast cancer (TNBC). Response to NACT is an important parameter predictive of oncological outcomes (progression-free and overall survival). An approach to the evaluation of predictive markers enabling therapy individualization is the identification of tumor driver genetic mutations. This study was conducted to investigate the role of SEC62, harbored at 3q26 and identified as a driver of breast cancer pathogenesis, in TNBC. We analyzed SEC62 expression in The Cancer Genome Atlas database, and immunohistologically investigated SEC62 expression in pre- and post-NACT tissue samples from 64 patients with TNBC treated at the Department of Gynecology and Obstetrics/Saarland University Hospital/Homburg between January 2010 and December 2018 and compared the effect of SEC62 on tumor cell migration and proliferation in functional assays. SEC62 expression dynamics correlated positively with the response to NACT (p ≤ 0.01) and oncological outcomes (p ≤ 0.01). SEC62 expression stimulated tumor cell migration (p ≤ 0.01). The study findings indicate that SEC62 is overexpressed in TNBC and serves as a predictive marker for the response to NACT, a prognostic marker for oncological outcomes, and a migration-stimulating oncogene in TNBC.
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Affiliation(s)
- Julia C Radosa
- Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Hospital, D-66421 Homburg, Germany
| | - Mariz Kasoha
- Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Hospital, D-66421 Homburg, Germany
| | - Merle Doerk
- Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Hospital, D-66421 Homburg, Germany
| | - Annika Cullmann
- Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Hospital, D-66421 Homburg, Germany
| | - Askin C Kaya
- Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Hospital, D-66421 Homburg, Germany
| | - Maximilian Linxweiler
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Hospital, D-66421 Homburg, Germany
| | - Marc P Radosa
- Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Hospital, D-66421 Homburg, Germany
- Department of Gynecology and Obstetrics, Klinikum Bremen Nord, D-28755 Bremen, Germany
| | - Zoltan Takacs
- Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Hospital, D-66421 Homburg, Germany
| | - Andrea Tirincsi
- Medical Biochemistry and Molecular Biology, Saarland University, D-66421 Homburg, Germany
| | - Sven Lang
- Medical Biochemistry and Molecular Biology, Saarland University, D-66421 Homburg, Germany
| | - Martin Jung
- Medical Biochemistry and Molecular Biology, Saarland University, D-66421 Homburg, Germany
| | - Julian Puppe
- Department of Gynecology, University Hospital Cologne, D-50931 Cologne, Germany
| | - Barbara Linxweiler
- Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Hospital, D-66421 Homburg, Germany
| | - Mathias Wagner
- Department of Pathology, Saarland University Hospital, D-66421 Homburg, Germany
| | - Rainer M Bohle
- Department of Pathology, Saarland University Hospital, D-66421 Homburg, Germany
| | - Erich-Franz Solomayer
- Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Hospital, D-66421 Homburg, Germany
| | - Julia S M Zimmermann
- Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Hospital, D-66421 Homburg, Germany
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Aljohani AI, Toss MS, Green AR, Rakha EA. The clinical significance of cyclin B1 (CCNB1) in invasive breast cancer with emphasis on its contribution to lymphovascular invasion development. Breast Cancer Res Treat 2023; 198:423-435. [PMID: 36418517 PMCID: PMC10036284 DOI: 10.1007/s10549-022-06801-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 11/03/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Lymphovascular invasion (LVI) is regulated through complex molecular mechanisms. Cyclin B1 (CCNB1) was previously determined as being associated with LVI using large cohorts of breast cancer (BC) and artificial neural network (ANN) technique. In this study, we aimed to assess the association between CCNB1 and LVI, other clinicopathological and other LVI-related biomarkers at the molecular (RNA transcriptomic) and proteomic levels in BC. METHODS Two transcriptomic BC cohorts (n = 2834) were used to assess the association between the expression of CCNB1 at the mRNA level and clinicopathological characteristics and patient outcome. Tissue microarrays (TMAs) from a well-characterised BC cohort (n = 2480) with long-term outcome were also used to assess the clinical significance of CCNB1 protein expression using immunohistochemistry. RESULTS High CCNB1 mRNA expression was associated with aggressive tumour behaviour, including LVI, larger size, higher tumour grade, high lymph nodal stage, hormonal receptor negativity, HER2 positivity and poor clinical outcome (all p < 0.0001). Similarly, high CCNB1 protein expression was associated with higher tumour grade, hormonal receptor negativity and HER2 positivity (all p < 0.0001). Additionally, there was a significant association between CCNB1- and LVI-related biomarkers including N-cadherin, P-cadherin and TWIST2 at the transcriptomic and proteomic level. Multivariate analysis revealed that CCNB1 was an independent predictor of shorter BC-specific survival (HR = 1.3; 95% CI 1.2-1.5; p = 0.010). CONCLUSION CCNB1 is a key gene associated with LVI in BC and has prognostic value. More functional studies are warranted to unravel the mechanistic role of CCNB1 in the development of LVI.
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Affiliation(s)
- Abrar I Aljohani
- Academic Unit for Translational Medical Sciences, School of Medicine, Nottingham Breast Cancer Research Centre, University of Nottingham Biodiscovery Institute, University Park, Nottingham, NG7 2RD, UK
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia
| | - Michael S Toss
- Academic Unit for Translational Medical Sciences, School of Medicine, Nottingham Breast Cancer Research Centre, University of Nottingham Biodiscovery Institute, University Park, Nottingham, NG7 2RD, UK
| | - Andrew R Green
- Academic Unit for Translational Medical Sciences, School of Medicine, Nottingham Breast Cancer Research Centre, University of Nottingham Biodiscovery Institute, University Park, Nottingham, NG7 2RD, UK
| | - Emad A Rakha
- Academic Unit for Translational Medical Sciences, School of Medicine, Nottingham Breast Cancer Research Centre, University of Nottingham Biodiscovery Institute, University Park, Nottingham, NG7 2RD, UK.
- Histopathology Department, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt.
- Department of Histopathology, Nottingham University Hospital NHS Trust, City Hospital Campus, Hucknall Road, Nottingham, NG5 1PB, UK.
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Tran TD, Nguyen MT. C-Biomarker.net: A Cytoscape app for the identification of cancer biomarker genes from cores of large biomolecular networks. Biosystems 2023; 226:104887. [PMID: 36990379 DOI: 10.1016/j.biosystems.2023.104887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 03/22/2023] [Accepted: 03/24/2023] [Indexed: 03/30/2023]
Abstract
Although there have been many studies revealing that biomarker genes for early cancer detection can be found in biomolecular networks, no proper tool exists to discover the cancer biomarker genes from various biomolecular networks. Accordingly, we developed a novel Cytoscape app called C-Biomarker.net, which can identify cancer biomarker genes from cores of various biomolecular networks. Derived from recent research, we designed and implemented the software based on parallel algorithms proposed in this study for working on high-performance computing devices. We tested our software on various network sizes and found the suitable size for each running mode on CPU or GPU. Interestingly, using the software for 17 cancer signaling pathways, we found that on average 70.59% of the top three nodes residing at the innermost core of each pathway are biomarker genes of the cancer respectively to the pathway. Similarly, by the software, we also found 100% of the top ten nodes at both cores of Human Gene Regulatory (HGR) network and Human Protein-Protein Interaction (HPPI) network are multi-cancer biomarkers. These case studies are reliable evidence for performance of cancer biomarker prediction function in the software. Through the case studies, we also suggest that true cores of directed complex networks should be identified by the algorithm of R-core rather than K-core as usual. Finally, we compared the prediction result of our software with those of other researchers and confirmed that our prediction method outperforms the other methods. Taken together, C-Biomarker.net is a reliable tool that efficiently detects biomarker nodes from cores of various large biomolecular networks. The software is available at https://github.com/trantd/C-Biomarker.net.
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Xie C, Hu J, Hu Q, Jiang L, Chen W. Classification of the mitochondrial ribosomal protein-associated molecular subtypes and identified a serological diagnostic biomarker in hepatocellular carcinoma. Front Surg 2023; 9:1062659. [PMID: 36684217 PMCID: PMC9853988 DOI: 10.3389/fsurg.2022.1062659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 12/12/2022] [Indexed: 01/07/2023] Open
Abstract
Purpose The objective of this study was to sort out innovative molecular subtypes associated with mitochondrial ribosomal proteins (MRPs) to predict clinical therapy response and determine the presence of circulating markers in hepatocellular carcinoma (HCC) patients. Methods Using an unsupervised clustering method, we categorized the relative molecular subtypes of MRPs in HCC patients. The prognosis, biological properties, immune checkpoint inhibitor and chemotherapy response of the patients were clarified. A signature and nomogram were developed to evaluate the prognosis. Enzyme-linked immunosorbent assay (ELISA) measured serum mitochondrial ribosomal protein L9 (MRPL9) levels in liver disease patients and normal individuals. Receiver operating characteristic (ROC) curves were conducted to calculate the diagnostic effect. The Cell Counting Kit 8 was carried out to examine cell proliferation, and flow cytometry was used to investigate the cell cycle. Transwell assay was applied to investigate the potential of cell migration and invasion. Western blot detected corresponding changes of biological markers. Results Participants were classified into two subtypes according to MRPs expression levels, which were characterized by different prognoses, biological features, and marked differences in response to chemotherapy and immune checkpoint inhibitors. Serum MRPL9 was significantly higher in HCC patients than in normal individuals and the benign liver disease group. ROC curve analysis showed that MRPL9 was superior to AFP and Ferritin in differentiating HCC from healthy and benign patients, or alone. Overexpressed MRPL9 could enhance aggressiveness and facilitate the G1/S progression in HCC cells. Conclusion We constructed novel molecular subtypes based on MRPs expression in HCC patients, which provided valuable strategies for the prediction of prognosis and clinical personalized treatment. MRPL9 might act as a reliable circulating diagnostic biomarker and therapeutic target for HCC patients.
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Affiliation(s)
| | | | | | | | - Weixian Chen
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Zimmermann JSM, Linxweiler J, Radosa JC, Linxweiler M, Zimmermann R. The endoplasmic reticulum membrane protein Sec62 as potential therapeutic target in SEC62 overexpressing tumors. Front Physiol 2022; 13:1014271. [PMID: 36262254 PMCID: PMC9574383 DOI: 10.3389/fphys.2022.1014271] [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: 08/08/2022] [Accepted: 09/16/2022] [Indexed: 11/30/2022] Open
Abstract
The human SEC62 gene is located on chromosome 3q, was characterized as a tumor driver gene and is found to be overexpressed in an ever-growing number of tumors, particularly those with 3q26 amplification. Where analyzed, SEC62 overexpression was associated with poor prognosis. Sec62 protein is a membrane protein of the endoplasmic reticulum (ER) and has functions in endoplasmic reticulum protein import, endoplasmic reticulum-phagy and -in cooperation with the cytosolic protein calmodulin- the maintenance of cellular calcium homeostasis. Various human tumors show SEC62 overexpression in immunohistochemistry and corresponding cell lines confirm this phenomenon in western blots and immunofluorescence. Furthermore, these tumor cells are characterized by increased stress tolerance and migratory as well as invasive potential, three hallmarks of cancer cells. Strikingly, plasmid-driven overexpression of SEC62 in non-SEC62 overexpressing cells introduces the same three hallmarks of cancer into the transfected cells. Depletion of Sec62 from either type of SEC62 overexpressing tumor cells by treatment with SEC62-targeting siRNAs leads to reduced stress tolerance and reduced migratory as well as invasive potential. Where tested, treatment of SEC62 overexpressing tumor cells with the small molecule/calmodulin antagonist trifluoperazine (TFP) phenocopied the effect of SEC62-targeting siRNAs. Recently, first phase II clinical trials with the prodrug mipsagargin/G202, which targets cellular calcium homeostasis in prostate cells as well as neovascular tissue in various tumors were started. According to experiments with tumor cell lines, however, SEC62 overexpressing tumor cells may be less responsive or resistant against such treatment. Therefore, murine tumor models for tumor growth or metastasis were evaluated with respect to their responsiveness to treatment with a mipsagargin analog (thapsigargin), or trifluoperazine, which had previously been in clinical use for the treatment of schizophrenia, or with the combination of both drugs. So far, no additive effect of the two drugs was observed but trifluoperazine had an inhibitory effect on tumor growth and metastatic potential in the models. Here, we review the state of affairs.
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Affiliation(s)
- Julia S. M. Zimmermann
- Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University, Homburg, Germany
| | - Johannes Linxweiler
- Department of Urology and Pediatric Urology, Saarland University, Homburg, Germany
| | - Julia C. Radosa
- Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University, Homburg, Germany
| | - Maximilian Linxweiler
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University, Homburg, Germany
| | - Richard Zimmermann
- Competence Center for Molecular Medicine, Saarland University, Homburg, Germany
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10
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Gao Q, Fan L, Chen Y, Cai J. Identification of the hub and prognostic genes in liver hepatocellular carcinoma via bioinformatics analysis. Front Mol Biosci 2022; 9:1000847. [PMID: 36250027 PMCID: PMC9557295 DOI: 10.3389/fmolb.2022.1000847] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 09/06/2022] [Indexed: 11/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy. However, the molecular mechanisms of the progression and prognosis of HCC remain unclear. In the current study, we merged three Gene Expression Omnibus (GEO) datasets and combined them with The Cancer Genome Atlas (TCGA) dataset to screen differentially expressed genes. Furthermore, protein‒protein interaction (PPI) and weighted gene coexpression network analysis (WGCNA) were used to identify key gene modules in the progression of HCC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that the terms were associated with the cell cycle and DNA replication. Then, four hub genes were identified (AURKA, CCNB1, DLGAP5, and NCAPG) and validated via the expression of proteins and transcripts using online databases. In addition, we established a prognostic model using univariate Cox proportional hazards regression and least absolute shrinkage and selection operator (LASSO) regression. Eight genes were identified as prognostic genes, and four genes (FLVCR1, HMMR, NEB, and UBE2S) were detrimental gens. The areas under the curves (AUCs) at 1, 3 and 5 years were 0.622, 0.69, and 0.684 in the test dataset, respectively. The effective of prognostic model was also validated using International Cancer Genome Consortium (ICGC) dataset. Moreover, we performed multivariate independent prognostic analysis using multivariate Cox proportional hazards regression. The results showed that the risk score was an independent risk factor. Finally, we found that all prognostic genes had a strong positive correlation with immune infiltration. In conclusion, this study identified the key hub genes in the development and progression of HCC and prognostic genes in the prognosis of HCC, which was significant for the future diagnosis and prognosis of HCC.
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Affiliation(s)
- Qiannan Gao
- State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Luyun Fan
- State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yutong Chen
- Health Science Center, Peking University International Cancer Institute, Peking University, Beijing, China
| | - Jun Cai
- State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Hypertension Center, FuWai Hospital, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Jun Cai,
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11
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Linxweiler M, Müller CSL. Role of the SEC62 gene in dermato-oncology - impact on tumor cell biology, prognostication, and personalized therapy management. J Dtsch Dermatol Ges 2022; 20:1187-1199. [PMID: 36067526 DOI: 10.1111/ddg.14817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/19/2022] [Indexed: 11/27/2022]
Abstract
The SEC62 gene encodes for a transmembrane protein of the endoplasmic reticulum (ER). Sec62 protein is involved in the post-translational transport of secretory and membrane-bound proteins in eukaryotic cells, regulates intracellular calcium homeostasis through direct interaction with the Sec61 channel and makes a decisive contribution to the cellular compensation of ER stress in the context of recovER-phagy. A significantly increased expression of the SEC62 gene has already been demonstrated in various tumor entities. First approaches of a targeted therapy have been tested for various tumor entities in vitro and in vivo with promising results that motivate further preclinical and clinical studies. Nevertheless, many questions remain unanswered, in particular with regard to the molecular mechanisms underlying the observed clinical effects, and require further investigation in future studies. The protein also plays a relevant role in dermato-oncology. The overexpression of SEC62 in atypical fibroxanthomas and malignant melanomas has already been demonstrated and a correlation of SEC62 expression with various clinical and pathological features has been observed. Future studies, especially in vivo and clinical, will show whether Sec62 can be established as a prognostic marker in dermato-oncology and whether it can serve as a starting point for targeted therapy.
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Affiliation(s)
- Maximilian Linxweiler
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, Homburg, Germany
| | - Cornelia S L Müller
- Medical Supply Center for Histology, Cytology and Molecular Diagnostics Trier GmbH, Trier, Germany
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12
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Linxweiler M, Müller CSL. Rolle des SEC62-Gens in der Dermatoonkologie - Relevanz für die Tumorzellbiologie, Prognoseeinschätzung und personalisierte Therapieplanung. J Dtsch Dermatol Ges 2022; 20:1187-1200. [PMID: 36162019 DOI: 10.1111/ddg.14817_g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/19/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Maximilian Linxweiler
- Klinik für Hals-, Nasen- und Ohrenheilkunde, Kopf- und Hals-Chirurgie, Universitätsklinikum des Saarlandes, Homburg
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13
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Körner S, Pick T, Bochen F, Wemmert S, Körbel C, Menger MD, Cavalié A, Kühn JP, Schick B, Linxweiler M. Antagonizing Sec62 function in intracellular Ca2+ homeostasis represents a novel therapeutic strategy for head and neck cancer. Front Physiol 2022; 13:880004. [PMID: 36045752 PMCID: PMC9421371 DOI: 10.3389/fphys.2022.880004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 06/30/2022] [Indexed: 12/24/2022] Open
Abstract
Various cancer types including head and neck squamous cell carcinomas (HNSCC) show a frequent amplification of chromosomal region 3q26 that encodes, among others, for the SEC62 gene. Located in the ER membrane, this translocation protein is known to play a critical role as a potential driver oncogene in cancer development. High SEC62 expression levels were observed in various cancer entities and were associated with a poor outcome and increased metastatic burden. Because of its intracellular localization the SEC62 protein is poorly accessible for therapeutic antibodies, therefore a functional SEC62 knockdown represents the most promising mechanism of a potential antineoplastic targeted therapy. By stimulating the Ca2+ efflux from the ER lumen and thereby increasing cellular stress levels, a functional inhibition of SEC62 bears the potential to limit tumor growth and metastasis formation. In this study, two potential anti-metastatic and -proliferative agents that counteract SEC62 function were investigated in functional in vitro assays by utilizing an immortalized human hypopharyngeal cancer cell line as well as a newly established orthotopic murine in vivo model. Additionally, a CRISPR/Cas9 based SEC62 knockout HNSCC cell line was generated and functionally characterized for its relevance in HNSCC cell proliferation and migration as well as sensitivity to SEC62 targeted therapy in vitro.
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Affiliation(s)
- Sandrina Körner
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, Homburg, Germany
| | - Tillman Pick
- Experimental and Clinical Pharmacology and Toxicology, Pre-Clinical Center for Molecular Signalling (PSMZ), Saarland University, Homburg, Germany
| | - Florian Bochen
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, Homburg, Germany
| | - Silke Wemmert
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, Homburg, Germany
| | - Christina Körbel
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany
| | - Michael D. Menger
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany
| | - Adolfo Cavalié
- Experimental and Clinical Pharmacology and Toxicology, Pre-Clinical Center for Molecular Signalling (PSMZ), Saarland University, Homburg, Germany
| | - Jan-Philipp Kühn
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, Homburg, Germany
| | - Bernhard Schick
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, Homburg, Germany
| | - Maximilian Linxweiler
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, Homburg, Germany
- *Correspondence: Maximilian Linxweiler,
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14
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Su S, Shi YT, Chu Y, Jiang MZ, Wu N, Xu B, Zhou H, Lin JC, Jin YR, Li XF, Liang J. Sec62 promotes gastric cancer metastasis through mediating UPR-induced autophagy activation. Cell Mol Life Sci 2022; 79:133. [PMID: 35165763 PMCID: PMC11073224 DOI: 10.1007/s00018-022-04143-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 01/09/2022] [Accepted: 01/10/2022] [Indexed: 12/28/2022]
Abstract
BACKGROUND AND AIMS Sec62 is a membrane protein of the endoplasmic reticulum that facilitates protein transport. Its role in cancer is increasingly recognised, but remains largely unknown. We investigated the functional role of Sec62 in gastric cancer (GC) and its underlying mechanism. METHODS Bioinformatics, tissue microarray, immunohistochemistry (IHC), western blotting (WB), quantitative polymerase chain reaction (qPCR), and immunofluorescence were used to examine the expression of target genes. Transwell, scratch healing assays, and xenograft models were used to evaluate cell migration and invasion. Transmission electron microscopy and mRFP-GFP-LC3 double-labeled adenoviruses were used to monitor autophagy. Co-immunoprecipitation (CO-IP) was performed to evaluate the binding activity between the proteins. RESULTS Sec62 expression was upregulated in GC, and Sec62 upregulation was an independent predictor of poor prognosis. Sec62 overexpression promoted GC cell migration and invasion both in vitro and in vivo. Sec62 promoted migration and invasion by affecting TIMP-1 and MMP2/9 balance. Moreover, Sec62 could activate autophagy by upregulating PERK/ATF4 expression and binding to LC3II with concomitant FIP200/Beclin-1/Atg5 activation. Furthermore, autophagy blockage impaired the promotive effects of Sec62 on GC cell migration and invasion, whereas autophagy activation rescued the inhibitory effect of Sec62 knockdown on GC metastasis. Notably, Sec62 inhibition combined with autophagy blockage exerted a synergetic anti-metastatic effect in vitro and in vivo. CONCLUSION Sec62 promotes GC metastasis by activating autophagy and subsequently regulating TIMP-1 and MMP2/9 balance. The activation of autophagy by Sec62 may involve the unfolded protein response (UPR)-related PERK/ATF4 pathway and binding of LC3II during UPR recovery involving FIP200/Beclin-1/Atg5 upregulation. Specifically, the dual inhibition of Sec62 and autophagy may provide a promising therapeutic strategy for GC metastasis.
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Affiliation(s)
- Song Su
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University (Air Force Medical University), Changle West Road 127, Xi'an, Shaanxi, 710032, China
- The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100071, China
| | - Yan-Ting Shi
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University (Air Force Medical University), Changle West Road 127, Xi'an, Shaanxi, 710032, China
| | - Yi Chu
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University (Air Force Medical University), Changle West Road 127, Xi'an, Shaanxi, 710032, China
| | - Ming-Zuo Jiang
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University (Air Force Medical University), Changle West Road 127, Xi'an, Shaanxi, 710032, China
| | - Nan Wu
- College of Life Sciences, Northwest University, Xi'an, Shaanxi, 710069, China
| | - Bing Xu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. School of Medicine, Northwest University, 229 Taibai North Road, Xi'an, Shaanxi, 710069, China
| | - He Zhou
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University (Air Force Medical University), Changle West Road 127, Xi'an, Shaanxi, 710032, China
| | - Jun-Chao Lin
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University (Air Force Medical University), Changle West Road 127, Xi'an, Shaanxi, 710032, China
| | - Yi-Rong Jin
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University (Air Force Medical University), Changle West Road 127, Xi'an, Shaanxi, 710032, China
| | - Xiao-Fei Li
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University (Air Force Medical University), Changle West Road 127, Xi'an, Shaanxi, 710032, China
| | - Jie Liang
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University (Air Force Medical University), Changle West Road 127, Xi'an, Shaanxi, 710032, China.
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15
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Meng Y, Zhao H, Zhao Z, Yin Z, Chen Z, Du J. Sec62 promotes pro-angiogenesis of hepatocellular carcinoma cells under hypoxia. Cell Biochem Biophys 2021; 79:747-755. [PMID: 34120320 DOI: 10.1007/s12013-021-01008-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/28/2021] [Indexed: 12/14/2022]
Abstract
This study aimed to investigate the underlying molecular pathogenic mechanism of Sec62 in hepatocellular carcinoma (HCC). Microarray analysis was conducted to profile the global gene expression in the HCC cell line Huh7 cells transfected with Sec62high vs. NC and Sec62low vs. NC. Ingenuity pathway analysis and gene set enrichment analysis were used to perform Sec62-related signaling pathway analysis from screened differentially expressed genes (DEGs). A protein-protein interaction network was constructed. Experimental validation of the expression of key DEGs was conducted. Hypoxia-induced tube formation was undertaken to investigate the role of Sec62 in angiogenesis. A total of 74 intersected DEGs were identified from Huh7 cells with Sec62high vs. NC and Sec62low vs. NC. Among them, 65 DEGs were correlated with the expression of Sec62. The P53 signaling pathway was found to be enriched in Huh7 cells with Sec62high vs. NC, while the acute phase response signaling pathway was enriched in Huh7 cells with Sec62low vs. NC. DEGs, such as serine protease inhibitor E (SERPINE) and tumor necrosis factor receptor superfamily, member 11B (TNFRSF11B), were not only identified as the lead genes of these enriched pathways, but were also found to be closely related to Sec62. Moreover, knockdown of Sec62 decreased the expression of SERPINE1 (plasminogen activator inhibitor type 1 (PAI-1)) and TNFRSF11B, whereas overexpression of Sec62 had the opposite effects. In addition, knockdown of Sec62 inhibited hypoxia-induced tube formation via PAI-1. Sec62 promoted pro-angiogenesis of HCC under hypoxia by regulating PAI-1, and it may be a crucial angiogenic switch in HCC.
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Affiliation(s)
- Yongbin Meng
- Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Hetong Zhao
- Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhihao Zhao
- Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zifei Yin
- Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhe Chen
- Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Juan Du
- Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai, China.
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16
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Qiang R, Zhao Z, Tang L, Wang Q, Wang Y, Huang Q. Identification of 5 Hub Genes Related to the Early Diagnosis, Tumour Stage, and Poor Outcomes of Hepatitis B Virus-Related Hepatocellular Carcinoma by Bioinformatics Analysis. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2021; 2021:9991255. [PMID: 34603487 PMCID: PMC8483908 DOI: 10.1155/2021/9991255] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 07/25/2021] [Accepted: 08/30/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND The majority of primary liver cancers in adults worldwide are hepatocellular carcinomas (HCCs, or hepatomas). Thus, a deep understanding of the underlying mechanisms for the pathogenesis and carcinogenesis of HCC at the molecular level could facilitate the development of novel early diagnostic and therapeutic treatments to improve the approaches and prognosis for HCC patients. Our study elucidates the underlying molecular mechanisms of HBV-HCC development and progression and identifies important genes related to the early diagnosis, tumour stage, and poor outcomes of HCC. METHODS GSE55092 and GSE121248 gene expression profiling data were downloaded from the Gene Expression Omnibus (GEO) database. There were 119 HCC samples and 128 nontumour tissue samples. GEO2R was used to screen for differentially expressed genes (DEGs). Volcano plots and Venn diagrams were drawn by using the ggplot2 package in R. A heat map was generated by using Heatmapper. By using the clusterProfiler R package, KEGG and GO enrichment analyses of DEGs were conducted. Through PPI network construction using the STRING database, key hub genes were identified by cytoHubba. Finally, KM survival curves and ROC curves were generated to validate hub gene expression. RESULTS By GO enrichment analysis, 694 DEGs were enriched in the following GO terms: organic acid catabolic process, carboxylic acid catabolic process, carboxylic acid biosynthetic process, collagen-containing extracellular matrix, blood microparticle, condensed chromosome kinetochore, arachidonic acid epoxygenase activity, arachidonic acid monooxygenase activity, and monooxygenase activity. In the KEGG pathway enrichment analysis, DEGs were enriched in arachidonic acid epoxygenase activity, arachidonic acid monooxygenase activity, and monooxygenase activity. By PPI network construction and analysis of hub genes, we selected the top 10 genes, including CDK1, CCNB2, CDC20, BUB1, BUB1B, CCNB1, NDC80, CENPF, MAD2L1, and NUF2. By using TCGA and THPA databases, we found five genes, CDK1, CDC20, CCNB1, CENPF, and MAD2L1, that were related to the early diagnosis, tumour stage, and poor outcomes of HBV-HCC. CONCLUSIONS Five abnormally expressed hub genes of HBV-HCC are informative for early diagnosis, tumour stage determination, and poor outcome prediction.
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Affiliation(s)
- Rui Qiang
- Department of Infectious Diseases, Guang'anmen Hospital, China Academy of Traditional Chinese Medicine, Beijing 100053, China
| | - Zitong Zhao
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Lu Tang
- Department of Traditional Chinese Medicine, Kunming Second People's Hospital, Kunming, 650000 Yunnan, China
| | - Qian Wang
- Department of Basic Medicine, Yunnan University of Business Management, Kunming, 650000 Yunnan, China
| | - Yanhong Wang
- Department of Second Internal Medicine, Chongming Branch of Yueyang Integrated Hospital of Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Chongming, 202150 Shanghai, China
| | - Qian Huang
- Department of Oncology, Shanghai Xinhua Hospital Chongming Branch Affiliated to Shanghai Jiaotong University School of Medicine, 25 Nanmen Road, Chengqiao Town, Chongming District, 200000 Shanghai, China
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17
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Yang X, Tian M, Zhang W, Chai T, Shen Z, Kang M, Lin J. Identification of potential core genes in esophageal carcinoma using bioinformatics analysis. Medicine (Baltimore) 2021; 100:e26428. [PMID: 34232175 PMCID: PMC8270608 DOI: 10.1097/md.0000000000026428] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 06/03/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is a common human malignancy worldwide. The tumorigenesis mechanism in ESCC is unclear. MATERIALS AND METHODS To explore potential therapeutic targets for ESCC, we analyzed 3 microarray datasets (GSE20347, GSE38129, and GSE67269) derived from the gene expression omnibus (GEO) database. Then, the GEO2R tool was used to screen out differently expressed genes (DEGs) between ESCC and normal tissue. Gene ontology function and kyoto encyclopedia of genes and genomes pathway enrichment analysis were performed using the database for annotation, visualization and integrated discovery to identify the pathways and functional annotation of DEGs. Protein-protein interaction of these DEGs was analyzed based on the search tool for the retrieval of interacting genes database and visualized by Cytoscape software. In addition, we used encyclopedia of RNA interactomes (ENCORI), gene expression profiling interactive analysis (GEPIA), and the human protein atlas to confirm the expression of hub genes in ESCC. Finally, GEPIA was used to evaluate the prognostic value of hub genes expression in ESCC patients and we estimated the associations between hub genes expression and immune cell populations (B Cell, CD8+ T Cell, CD4+ T Cell, Macrophage, Neutrophil, and Dendritic Cell) in esophageal carcinoma (ESCA) using tumor immune estimation resource (TIMER). RESULTS In this study, 707 DEGs (including 385 upregulated genes and 322 downregulated genes) and 6 hub genes (cyclin B1 [CCNB1], cyclin dependent kinase 1 [CDK1], aurora kinase A [AURKA], ubiquitin conjugating enzyme E2C [UBE2C], cyclin A2 [CCNA2], and cell division cycle 20 [CDC20]) were identified. All of the 6 hub genes were highly expressed in ESCC tissues. Among of them, only CCNB1 and CDC20 were associated with stage of ESCC and all of them were not associated with survival time of patients. CONCLUSION DEGs and hub genes were confirmed in our study, providing a thorough, scientific and comprehensive research goals for the pathogenesis of ESCC.
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Affiliation(s)
| | - Mengyue Tian
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | | | - Tianci Chai
- Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou
- Department of Anesthesiology, Xinyi People's Hospital, Xuzhou
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18
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Meng Z, Wu J, Liu X, Zhou W, Ni M, Liu S, Guo S, Jia S, Zhang J. Identification of potential hub genes associated with the pathogenesis and prognosis of hepatocellular carcinoma via integrated bioinformatics analysis. J Int Med Res 2021; 48:300060520910019. [PMID: 32722976 PMCID: PMC7391448 DOI: 10.1177/0300060520910019] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Objective The objective was to identify potential hub genes associated with the pathogenesis and prognosis of hepatocellular carcinoma (HCC). Methods Gene expression profile datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between HCC and normal samples were identified via an integrated analysis. A protein–protein interaction network was constructed and analyzed using the STRING database and Cytoscape software, and enrichment analyses were carried out through DAVID. Gene Expression Profiling Interactive Analysis and Kaplan–Meier plotter were used to determine expression and prognostic values of hub genes. Results We identified 11 hub genes (CDK1, CCNB2, CDC20, CCNB1, TOP2A, CCNA2, MELK, PBK, TPX2, KIF20A, and AURKA) that might be closely related to the pathogenesis and prognosis of HCC. Enrichment analyses indicated that the DEGs were significantly enriched in metabolism-associated pathways, and hub genes and module 1 were highly associated with cell cycle pathway. Conclusions In this study, we identified key genes of HCC, which indicated directions for further research into diagnostic and prognostic biomarkers that could facilitate targeted molecular therapy for HCC.
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Affiliation(s)
- Ziqi Meng
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xinkui Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Wei Zhou
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Mengwei Ni
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shuyu Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Siyu Guo
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shanshan Jia
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jingyuan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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19
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Zhang Y, Tang Y, Guo C, Li G. Integrative analysis identifies key mRNA biomarkers for diagnosis, prognosis, and therapeutic targets of HCV-associated hepatocellular carcinoma. Aging (Albany NY) 2021; 13:12865-12895. [PMID: 33946043 PMCID: PMC8148482 DOI: 10.18632/aging.202957] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 03/23/2021] [Indexed: 02/05/2023]
Abstract
Hepatitis C virus-associated HCC (HCV-HCC) is a prevalent malignancy worldwide and the molecular mechanisms are still elusive. Here, we screened 240 differentially expressed genes (DEGs) of HCV-HCC from Gene expression omnibus (GEO) and the Cancer Genome Atlas (TCGA), followed by weighted gene coexpression network analysis (WGCNA) to identify the most significant module correlated with the overall survival. 10 hub genes (CCNB1, AURKA, TOP2A, NEK2, CENPF, NUF2, CDKN3, PRC1, ASPM, RACGAP1) were identified by four approaches (Protein-protein interaction networks of the DEGs and of the significant module by WGCNA, and diagnostic and prognostic values), and their abnormal expressions, diagnostic values, and prognostic values were successfully verified. A four hub gene-based prognostic signature was built using the least absolute shrinkage and selection operator (LASSO) algorithm and a multivariate Cox regression model with the ICGC-LIRI-JP cohort (N =112). Kaplan-Meier survival plots (P = 0.0003) and Receiver Operating Characteristic curves (ROC = 0.778) demonstrated the excellent predictive potential for the prognosis of HCV-HCC. Additionally, upstream regulators including transcription factors and miRNAs of hub genes were predicted, and candidate drugs or herbs were identified. These findings provide a firm basis for the exploration of the molecular mechanism and further clinical biomarkers development of HCV-HCC.
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MESH Headings
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/virology
- Computational Biology
- Datasets as Topic
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Gene Regulatory Networks
- Hepatitis C, Chronic/genetics
- Hepatitis C, Chronic/pathology
- Hepatitis C, Chronic/virology
- Humans
- Kaplan-Meier Estimate
- Liver/pathology
- Liver/virology
- Liver Neoplasms/diagnosis
- Liver Neoplasms/genetics
- Liver Neoplasms/mortality
- Liver Neoplasms/virology
- MicroRNAs/metabolism
- Predictive Value of Tests
- Prognosis
- Protein Interaction Maps/genetics
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Risk Assessment/methods
- Transcription Factors/metabolism
- Transcriptome/genetics
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Affiliation(s)
- Yongqiang Zhang
- Molecular Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, P.R. China
- West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, P.R. China
| | - Yuqin Tang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P.R. China
| | - Chengbin Guo
- Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, P.R. China
| | - Gen Li
- Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, P.R. China
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Sicking M, Lang S, Bochen F, Roos A, Drenth JPH, Zakaria M, Zimmermann R, Linxweiler M. Complexity and Specificity of Sec61-Channelopathies: Human Diseases Affecting Gating of the Sec61 Complex. Cells 2021; 10:1036. [PMID: 33925740 PMCID: PMC8147068 DOI: 10.3390/cells10051036] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/15/2021] [Accepted: 04/17/2021] [Indexed: 12/14/2022] Open
Abstract
The rough endoplasmic reticulum (ER) of nucleated human cells has crucial functions in protein biogenesis, calcium (Ca2+) homeostasis, and signal transduction. Among the roughly one hundred components, which are involved in protein import and protein folding or assembly, two components stand out: The Sec61 complex and BiP. The Sec61 complex in the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER and provides a conduit for Ca2+ ions from the ER lumen to the cytosol. The second component, the Hsp70-type molecular chaperone immunoglobulin heavy chain binding protein, short BiP, plays central roles in protein folding and assembly (hence its name), protein import, cellular Ca2+ homeostasis, and various intracellular signal transduction pathways. For the purpose of this review, we focus on these two components, their relevant allosteric effectors and on the question of how their respective functional cycles are linked in order to reconcile the apparently contradictory features of the ER membrane, selective permeability for precursor polypeptides, and impermeability for Ca2+. The key issues are that the Sec61 complex exists in two conformations: An open and a closed state that are in a dynamic equilibrium with each other, and that BiP contributes to its gating in both directions in cooperation with different co-chaperones. While the open Sec61 complex forms an aqueous polypeptide-conducting- and transiently Ca2+-permeable channel, the closed complex is impermeable even to Ca2+. Therefore, we discuss the human hereditary and tumor diseases that are linked to Sec61 channel gating, termed Sec61-channelopathies, as disturbances of selective polypeptide-impermeability and/or aberrant Ca2+-permeability.
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Affiliation(s)
- Mark Sicking
- Department of Medical Biochemistry & Molecular Biology, Saarland University, D-66421 Homburg, Germany;
| | - Sven Lang
- Department of Medical Biochemistry & Molecular Biology, Saarland University, D-66421 Homburg, Germany;
| | - Florian Bochen
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (F.B.); (M.L.)
| | - Andreas Roos
- Department of Neuropediatrics, Essen University Hospital, D-45147 Essen, Germany;
| | - Joost P. H. Drenth
- Department of Molecular Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands;
| | - Muhammad Zakaria
- Department of Genetics, Hazara University, Mansehra 21300, Pakistan;
| | - Richard Zimmermann
- Department of Medical Biochemistry & Molecular Biology, Saarland University, D-66421 Homburg, Germany;
| | - Maximilian Linxweiler
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (F.B.); (M.L.)
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Miller DR, Thorburn A. Autophagy and organelle homeostasis in cancer. Dev Cell 2021; 56:906-918. [PMID: 33689692 PMCID: PMC8026727 DOI: 10.1016/j.devcel.2021.02.010] [Citation(s) in RCA: 134] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/11/2021] [Accepted: 02/09/2021] [Indexed: 12/16/2022]
Abstract
Beginning with the earliest studies of autophagy in cancer, there have been indications that autophagy can both promote and inhibit cancer growth and progression; autophagy regulation of organelle homeostasis is similarly complicated. In this review we discuss pro- and antitumor effects of organelle-targeted autophagy and how this contributes to several hallmarks of cancer, such as evading cell death, genomic instability, and altered metabolism. Typically, the removal of damaged or dysfunctional organelles prevents tumor development but can also aid in proliferation or drug resistance in established tumors. By better understanding how organelle-specific autophagy takes place and can be manipulated, it may be possible to go beyond the brute-force approach of trying to manipulate all autophagy in order to improve therapeutic targeting of this process in cancer.
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Affiliation(s)
- Dannah R Miller
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Andrew Thorburn
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
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22
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Müller CSL, Pföhler C, Wahl M, Bochen F, Körner S, Kühn JP, Bozzato A, Schick B, Linxweiler M. Expression of SEC62 Oncogene in Benign, Malignant and Borderline Melanocytic Tumors-Unmasking the Wolf in Sheep's Clothing? Cancers (Basel) 2021; 13:cancers13071645. [PMID: 33915997 PMCID: PMC8036965 DOI: 10.3390/cancers13071645] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/29/2021] [Accepted: 03/30/2021] [Indexed: 01/09/2023] Open
Abstract
Simple Summary Amplification and overexpression of the SEC62 oncogene was reported in a variety of human cancers and was associated with poor prognosis as well as lymph node and distant metastases. In this study, SEC62 expression was analyzed in benign, borderline, and malignant melanocytic lesions of 209 patients. We found the highest expression in Spitz nevi, followed by melanoma metastases, primary melanoma, congenital nevi, and blue nevi. In melanoma patients, high Sec62 levels correlated with shorter overall and progression-free survival. Significantly higher Sec62 levels were found in melanomas with lymph node and distant metastases compared with those without. Taken together, these data suggest a relevant role of SEC62 as a metastasis-stimulating oncogene in melanoma development, which represents a promising therapeutic target. Abstract SEC62 oncogene located at chromosomal region 3q26 encodes for a transmembrane protein of the endoplasmic reticulum (ER) and is expressed at high levels in numerous human malignancies. SEC62 overexpression has been associated with worse prognosis and high risk for lymphatic and distant metastases in head and neck cancer, cervical cancer, hepatocellular cancer, and lung cancer. However, its role in the development and tumor biology of melanocytic lesions has not been investigated so far. An immunohistochemical study including 209 patients with melanocytic lesions (malignant melanoma (MM), n = 93; melanoma metastases (MET), n = 28; Spitz nevi (SN), n = 29; blue nevi (BN), n = 21; congenital nevi (CN), n = 38) was conducted and SEC62 expression was correlated with clinical data including patient survival and histopathological characteristics. SN showed the highest SEC62 expression levels followed by MET, MM, CN, and BN. High SEC62 expression correlated with a shorter overall and progression-free survival in MM patients. Additionally, high Sec62 levels correlated significantly with higher tumor size (T stage), the presence of tumor ulceration, and the presence of lymph node as well as distant metastases. Strikingly, SEC62 expression showed a strong correlation with Clark level. Taken together, these data demonstrate that SEC62 is a promising prognostic marker in MM and has the potential to predict biological behavior and clinical aggressiveness of melanocytic lesions.
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Affiliation(s)
- Cornelia S. L. Müller
- Department of Dermatology, Venerology and Allergology, Saarland University Medical Center, D-66421 Homburg, Germany; (C.S.L.M.); (C.P.); (M.W.)
| | - Claudia Pföhler
- Department of Dermatology, Venerology and Allergology, Saarland University Medical Center, D-66421 Homburg, Germany; (C.S.L.M.); (C.P.); (M.W.)
| | - Maria Wahl
- Department of Dermatology, Venerology and Allergology, Saarland University Medical Center, D-66421 Homburg, Germany; (C.S.L.M.); (C.P.); (M.W.)
| | - Florian Bochen
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (F.B.); (S.K.); (J.P.K.); (A.B.); (B.S.)
| | - Sandrina Körner
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (F.B.); (S.K.); (J.P.K.); (A.B.); (B.S.)
| | - Jan Philipp Kühn
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (F.B.); (S.K.); (J.P.K.); (A.B.); (B.S.)
| | - Alessandro Bozzato
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (F.B.); (S.K.); (J.P.K.); (A.B.); (B.S.)
| | - Bernhard Schick
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (F.B.); (S.K.); (J.P.K.); (A.B.); (B.S.)
| | - Maximilian Linxweiler
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany; (F.B.); (S.K.); (J.P.K.); (A.B.); (B.S.)
- Correspondence: ; Tel.: +49-6841-162-2928
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Wang J, Lou Y, Lu J, Luo Y, Lu A, Chen A, Fu J, Liu J, Zhou X, Yang J. A Deep Look into the Program of Rapid Tumor Growth of Hepatocellular Carcinoma. J Clin Transl Hepatol 2021; 9:22-31. [PMID: 33604252 PMCID: PMC7868698 DOI: 10.14218/jcth.2020.00084] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/12/2020] [Accepted: 12/01/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND AND AIMS Great efforts have been made towards increasing our understanding of the pathogenesis involved in hepatocellular carcinoma (HCC), but the rapid growth inherent to such tumor development remains to be explored. METHODS We identified distinct gene coexpression modes upon liver tumor growth using weighted gene coexpression network analysis. Modeling of tumor growth as signaling activity was employed to understand the main cascades responsible for the growth. Hub genes in the modules were determined, examined in vitro, and further assembled into the growth signature. RESULTS We revealed modules related to the different growth states in HCC, especially the fastest growth module, which is preserved among different HCC cohorts. Moreover, signaling flux in the cell cycle pathway was found to act as a driving force for rapid growth. Twenty hub genes in the module were identified and assembled into the growth signature, and two genes (NCAPH, and RAD54L) were tested for their growth potential in vitro. Genetic alteration of the growth signature affected the global gene expression. The activity of the signature was associated with tumor metabolism and immunity in HCC. Finally, the prognosis effect of the growth signature was reproduced in nine cancers. CONCLUSIONS These results collectively demonstrate the molecule organization of rapid tumor growth in HCC, which is a highly synergistic process, with implications for the future management of patients.
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Affiliation(s)
- Jie Wang
- Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Department of Liver Disease, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yi Lou
- Department of Occupational Medicine, Hangzhou Red Cross Hospital, Zhejiang Provincial Integrated Chinese and Western Medicine Hospital, Hangzhou, Zhejiang, China
| | - Jianmin Lu
- Department of Orthopedics, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yuxiao Luo
- Department of Orthopedics, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Anqian Lu
- Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Anna Chen
- Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jiantao Fu
- Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jing Liu
- Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Department of Liver Disease, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Xiang Zhou
- Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Department of Liver Disease, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Correspondence to: Jin Yang, Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang 310015, China. Tel: +86-571-88358062, E-mail: ; Xiang Zhou, Department of Liver Disease, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang 310015, China. Tel: +86-571-88303403, E-mail:
| | - Jin Yang
- Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Department of Liver Disease, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Correspondence to: Jin Yang, Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang 310015, China. Tel: +86-571-88358062, E-mail: ; Xiang Zhou, Department of Liver Disease, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang 310015, China. Tel: +86-571-88303403, E-mail:
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Casper M, Linxweiler M, Linxweiler J, Zimmermann R, Glanemann M, Lammert F, Weber SN. SEC62 and SEC63 Expression in Hepatocellular Carcinoma and Tumor-Surrounding Liver Tissue. Visc Med 2021; 37:110-115. [PMID: 33977099 DOI: 10.1159/000513293] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/19/2020] [Indexed: 12/14/2022] Open
Abstract
Introduction The endoplasmic reticulum transmembrane proteins Sec61, Sec62, and Sec63 are responsible for the intracellular trafficking of precursor proteins and affect intracellular signaling. SEC62 overexpression has been linked to various human cancers. Our aim was to investigate SEC62 and SEC63 expression in hepatocellular carcinoma (HCC) and surrounding liver tissue. Patients and Methods Primary liver tissue was collected from 11 consecutive patients (70 ± 9 years; 10 men) who underwent HCC resection. In the HCC and the tumor-surrounding liver tissue we investigated SEC62 und SEC63 mRNA expression using quantitative real-time PCR. For Sec62, immunohistochemistry was performed. Results SEC62and SEC63 total mRNA contents were significantly (p = 0.001) higher in HCCs (CT 22.5 ± 0.4 and 22.6 ± 0.3) when compared to the surrounding tissue (CT 24.6 ± 0.6 and 25.1 ± 0.9). Using the comparative CTmethod, SEC62 and SEC63 expression in HCC was increased 5- and 8.1-fold, respectively, in comparison to surrounding tissue. For Sec62 immunohistochemistry, the mean immunoreactive scores (IRS) were 7.9 ± 2.9 for HCC and 4.8 ± 1.2 for non-tumorous liver (p = 0.027). The mean IRS in HCC were 5.7 ± 3.5 and 8.9 ± 2.3 for patients without (n = 3) and with tumor recurrence (n = 8), respectively. Conclusions Overexpression of SEC62 and SEC63 is a common feature of HCC. The role of Sec62 as a prognostic marker for tumor recurrence after surgery and its potential role in treatment stratification must be addressed in future studies.
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Affiliation(s)
- Markus Casper
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Maximilian Linxweiler
- Department of Medical Biochemistry and Molecular Biology, Saarland University Medical Center, Homburg, Germany
| | - Johannes Linxweiler
- Department of Urology and Pediatric Urology, Saarland University Medical Center, Homburg, Germany
| | - Richard Zimmermann
- Department of Medical Biochemistry and Molecular Biology, Saarland University Medical Center, Homburg, Germany
| | - Matthias Glanemann
- Department of Urology and Pediatric Urology, Saarland University Medical Center, Homburg, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Susanne N Weber
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
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Constructing the Logical Regression Model to Predict the Target of Jianpi Jiedu Decoction in the Treatment of Hepatocellular Carcinoma. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2020:8859558. [PMID: 33424998 PMCID: PMC7781689 DOI: 10.1155/2020/8859558] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 11/23/2020] [Accepted: 12/14/2020] [Indexed: 01/04/2023]
Abstract
Objectives The purpose of this study was to identify the molecular mechanism and prognosis-related genes of Jianpi Jiedu decoction in the treatment of hepatocellular carcinoma. Methods The gene expression data of hepatocellular carcinoma samples and normal tissue samples were downloaded from TCGA database, and the potential targets of drug composition of Jianpi Jiedu decoction were obtained from TCMSP database. The genes were screened out in order to obtain the expression of these target genes in patients with hepatocellular carcinoma. The differential expression of target genes was analyzed by R software, and the genes related to prognosis were screened by univariate Cox regression analysis. Then, the LASSO model was constructed for risk assessment and survival analysis between different risk groups. At the same time, independent prognostic analysis, GSEA analysis, and prognostic analysis of single gene in patients with hepatocellular carcinoma were performed. Results 174 compounds of traditional Chinese medicine were screened by TCMSP database, corresponding to 122 potential targets. 39 upregulated genes and 9 downregulated genes were screened out. A total of 20 candidate prognostic related genes were screened out by univariate Cox analysis, of which 12 prognostic genes were involved in the construction of the LASSO regression model. There was a significant difference in survival time between the high-risk group and low-risk group (p < 0.05). Among the genes related to prognosis, the expression levels of CCNB1, NQO1, NUF2, and CHEK1 were high in tumor tissues (p < 0.05). Survival analysis showed that the high expression levels of these four genes were significantly correlated with poor prognosis of HCC (p < 0.05). GSEA analysis showed that the main KEGG enrichment pathways were lysine degradation, folate carbon pool, citrate cycle, and transcription factors. Conclusions In the study, we found that therapy target genes of Jianpi Jiedu decoction were mainly involved in metabolism and apoptosis in hepatocellular carcinoma, and there was a close relationship between the prognosis of hepatocellular carcinoma and the genes of CCNB1, NQO1, NUF2, and CHEK1.
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Gao L, Xia S, Zhang K, Lin C, He X, Zhang Y. Gene expression profile of THZ1-treated nasopharyngeal carcinoma cell lines indicates its involvement in the inhibition of the cell cycle. Transl Cancer Res 2021; 10:445-460. [PMID: 35116274 PMCID: PMC8799269 DOI: 10.21037/tcr-19-2888] [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: 12/20/2019] [Accepted: 09/30/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND The aim of this study was to identify downstream target genes and pathways regulated by THZ1 in nasopharyngeal carcinoma (NPC). METHODS The gene expression profile of GSE95750 in two NPC cell lines, untreated group and treated with THZ1 group, was analyzed. Differentially expressed genes (DEGs) were compared using the R-software. Then Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) was analyzed using Database for Annotation, Visualization, and Integrated Discovery (DAVID). Cytoscape was used for protein-protein interaction (PPI) analysis. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to verified the gene expression. RESULTS We identified 25 genes with increased expression and 567 genes with decreased expression in THZ1-treated NPC cells. The top 10 significantly DEGs between untreated group and THZ1 treated group were identified by qRT-PCR and the results were in agreement with RNA-seq. The total 592 DEGs were found enriched in 1,148 GO terms and 38 KEGG pathways. The most important enriched pathways identified were cell cycle related, and several related node genes were identified, such as CDC6, CDC34, CDK7, CDK9, CCNA2, CCNB1, CDT1, KIF11, LIN9, PLK1, and POLR family, which consistent with RNA-seq. CONCLUSIONS Our results emphasize the differential genes and pathways occurring in THZ1-treated NPC cells, which increases our understanding of the anti-tumor mechanisms of THZ1.
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Affiliation(s)
- Lijuan Gao
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
- Department of Radiation Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Shuang Xia
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Kunyi Zhang
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
- Department of Radiation Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Chengguang Lin
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
- Department of Radiation Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Xuyu He
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Ying Zhang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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Li W, He P, Huang Y, Li YF, Lu J, Li M, Kurihara H, Luo Z, Meng T, Onishi M, Ma C, Jiang L, Hu Y, Gong Q, Zhu D, Xu Y, Liu R, Liu L, Yi C, Zhu Y, Ma N, Okamoto K, Xie Z, Liu J, He RR, Feng D. Selective autophagy of intracellular organelles: recent research advances. Theranostics 2021; 11:222-256. [PMID: 33391472 PMCID: PMC7681076 DOI: 10.7150/thno.49860] [Citation(s) in RCA: 287] [Impact Index Per Article: 71.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/04/2020] [Indexed: 12/11/2022] Open
Abstract
Macroautophagy (hereafter called autophagy) is a highly conserved physiological process that degrades over-abundant or damaged organelles, large protein aggregates and invading pathogens via the lysosomal system (the vacuole in plants and yeast). Autophagy is generally induced by stress, such as oxygen-, energy- or amino acid-deprivation, irradiation, drugs, etc. In addition to non-selective bulk degradation, autophagy also occurs in a selective manner, recycling specific organelles, such as mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes and lipid droplets (LDs). This capability makes selective autophagy a major process in maintaining cellular homeostasis. The dysfunction of selective autophagy is implicated in neurodegenerative diseases (NDDs), tumorigenesis, metabolic disorders, heart failure, etc. Considering the importance of selective autophagy in cell biology, we systemically review the recent advances in our understanding of this process and its regulatory mechanisms. We emphasize the 'cargo-ligand-receptor' model in selective autophagy for specific organelles or cellular components in yeast and mammals, with a focus on mitophagy and ER-phagy, which are finely described as types of selective autophagy. Additionally, we highlight unanswered questions in the field, helping readers focus on the research blind spots that need to be broken.
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Lei X, Jing J, Zhang M, Guan B, Dong Z, Wang C. Bioinformatic Identification of Hub Genes and Analysis of Prognostic Values in Colorectal Cancer. Nutr Cancer 2020; 73:2568-2578. [PMID: 33153324 DOI: 10.1080/01635581.2020.1841249] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/30/2020] [Accepted: 10/15/2020] [Indexed: 12/24/2022]
Abstract
The purpose of this study is to discover novel hub genes which are helpful for diagnosis, prognosis, and targeted therapy in colorectal cancer (CRC) by using bioinformatics analysis. GSE74602, GSE110225, and GSE113513 were extracted from the gene expression omnibus (GEO). Differentially expressed genes (DEGs) in expression profiles were identified by GEO2R. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses of the DEGs were carried out in the Database for Annotation, Visualization, and Integrated Discovery (DAVID). String database and cytoscape were used for building protein-protein interaction (PPI) network and module analysis. The UALCAN was used for in-depth analysis of data of CRC patients from The Cancer Genome Atlas (TCGA) to identify expression levels and overall survival rates of hub genes. The DEGs included 107 up-regulation genes and 232 down-regulation genes. Twenty-nine (29) hub genes and two significant modules were screened from PPI network. The expression levels of hub genes in TCGA were verified. Survival analysis curve indicated high expression of CCNA2, CCNB1, DLGAP5, were related to high survival rates, and low expression of TIMP1 were associated with high survival rates. These results suggest that DEGs may be the hub genes of CRC, and CCNA2, CCNB1, DLGAP5, TIMP1 may be the potential prognostic markers of CRC.
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Affiliation(s)
- Xinyi Lei
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jing Jing
- Department of Endocrinology, Municipal Hospital, Qingdao, China
| | - Miao Zhang
- Department of Respiratory, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Bingsheng Guan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zhiyong Dong
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Cunchuan Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
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Ji Y, Yin Y, Zhang W. Integrated Bioinformatic Analysis Identifies Networks and Promising Biomarkers for Hepatitis B Virus-Related Hepatocellular Carcinoma. Int J Genomics 2020; 2020:2061024. [PMID: 32775402 PMCID: PMC7407030 DOI: 10.1155/2020/2061024] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 06/09/2020] [Accepted: 06/27/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with hepatitis B virus (HBV) has long been recognized as a dominant hazard factor for hepatocellular carcinoma (HCC) and accounts for at least half of HCC instances globally. However, the underlying molecular mechanism of HBV-linked HCC has not been completely elucidated. Here, three microarray datasets, totally containing 170 tumoral samples and 181 adjacent normal tissues from the liver of patients suffering from HBV-related HCC assembled from the Gene Expression Omnibus (GEO) database, were subjected to integrated analysis of differentially expressed genes (DEGs). Subsequently, the analysis of function and pathway enrichment as well as the protein-protein interaction network (PPI) was performed. The ten hub genes screened out from the PPI network were further subjected to expression profile and survival analysis. Overall, 329 DEGs (67 upregulated and 262 downregulated) were identified. Ten DEGs with the highest degree of connectivity included cyclin-dependent kinase 1 (CDK1), cyclin B1 (CCNB1), cyclin B2 (CCNB2), PDZ-binding kinase (PBK), abnormal spindle microtubule assembly (ASPM), nuclear division cycle 80 (NDC80), aurora kinase A (AURKA), targeting protein for xenopus kinesin-like protein 2 (TPX2), kinesin family member 2C (KIF2C), and centromere protein F (CENPF). Kaplan-Meier analysis unveiled that overexpression levels of KIF2C and TPX2 were relevant to both the poor overall survival and relapse-free survival. In summary, the hub genes validated in the present study may provide promising targets for the diagnosis, prognosis, and therapy of HBV-associated HCC. Additionally, our work uncovers various crucial biological components (e.g., extracellular exosome) and signaling pathways that participate in the progression of HCC induced by HBV, serving comprehensive knowledge of the mechanisms regarding HBV-related HCC.
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Affiliation(s)
- Yun Ji
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China
| | - Yue Yin
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China
| | - Weizhen Zhang
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China
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Li J, Xia T, Cao J, He D, Chen Z, Liang B, Song J. RP11-295G20.2 facilitates hepatocellular carcinoma progression via the miR-6884-3p/CCNB1 pathway. Aging (Albany NY) 2020; 12:14918-14932. [PMID: 32687483 PMCID: PMC7425504 DOI: 10.18632/aging.103552] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 06/04/2020] [Indexed: 02/07/2023]
Abstract
Objective: An increasing number of studies have indicated that long noncoding RNAs (lncRNAs) play an important role in the pathogenesis of hepatocellular carcinoma (HCC). In this study, we aimed to clarify the roles of RP11-295G20.2 in HCC progression and the underlying molecular mechanisms. Results: Bioinformatics analyses based TCGA data suggested that RP11-295G20.2 was significantly upregulated in HCC tissues and increased RP11-295G20.2 expression level correlated with poor overall survival of patients with HCC. The results of RT-PCR further showed that RP11-295G20.2 was upregulated in HCC tissues and cell lines. Functionally, RP11-295G20.2 knockdown significantly inhibited the proliferation, colony formation, invasion and migration, but induced the apoptosis of HCC cells. In line with this, downregulation of RP11-295G20.2 in HCC lines markedly suppressed the tumor growth in vivo. Mechanistically, RP11-295G20.2 could upregulate CCNB1 through targeting miR-6884-3p. More importantly, our rescue experiments revealed that miR-6884-3p/CCNB1 axis was involved in RP11-295G20.2-meditated tumorigenic behaviors of HCC cells. Conclusions: RP11-295G20.2 can contribute to HCC progression at least partly via the miR-6884-3p/CCNB1 axis, suggesting that RP11-295G20.2 may be a potential target for HCC therapy. Methods: RT-qPCR was employed to examine the expression levels of RP11-295G20.2, miR-6884-3p, and CCNB1 in HCC tissues and cell lines. CCK8 assay, transwell assay, colony formation assay and flow cytometry analysis were performed to evaluate the biological function of RP11-295G20.2 in HCC cells. The xenograft tumor assay was used to assess the effect of RP11-295G20.2 on the in vivo growth of HCC cells. The luciferase reporter assay, RIP assay and Spearman's correlation analysis were performed to explore the potential mechanisms underlying the roles of RP11-295G20.2 in HCC progression.
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Affiliation(s)
- Jing Li
- Center of Digestive Endoscopy, Guangdong Second Provincial General Hospital, Guangzhou 510317, China.,Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou 510632, China
| | - Tingting Xia
- Center for Reproductive Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong, China
| | - Junyan Cao
- Department of Medical Ultrasonic, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong, China
| | - Donghong He
- Center of Digestive Endoscopy, Guangdong Second Provincial General Hospital, Guangzhou 510317, China
| | - Zhaocong Chen
- Department of Rehabilitation Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong, China
| | - Biao Liang
- Center of Digestive Endoscopy, Guangdong Second Provincial General Hospital, Guangzhou 510317, China
| | - Jie Song
- Center of Digestive Endoscopy, Guangdong Second Provincial General Hospital, Guangzhou 510317, China
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Zhang L, Makamure J, Zhao D, Liu Y, Guo X, Zheng C, Liang B. Bioinformatics analysis reveals meaningful markers and outcome predictors in HBV-associated hepatocellular carcinoma. Exp Ther Med 2020; 20:427-435. [PMID: 32537007 PMCID: PMC7281962 DOI: 10.3892/etm.2020.8722] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Accepted: 12/05/2019] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of malignant neoplasm of the liver with high morbidity and mortality. Extensive research into the pathology of HCC has been performed; however, the molecular mechanisms underlying the development of hepatitis B virus-associated HCC have remained elusive. Thus, the present study aimed to identify critical genes and pathways associated with the development and progression of HCC. The expression profiles of the GSE121248 dataset were downloaded from the Gene Expression Omnibus database and the differentially expressed genes (DEGs) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) analyses were performed by using the Database for Annotation, Visualization and Integrated Discovery. Subsequently, protein-protein interaction (PPI) networks were constructed for detecting hub genes. In the present study, 1,153 DEGs (777 upregulated and 376 downregulated genes) were identified and the PPI network yielded 15 hub genes. GO analysis revealed that the DEGs were primarily enriched in ‘protein binding’, ‘cytoplasm’ and ‘extracellular exosome’. KEGG analysis indicated that DEGs were accumulated in ‘metabolic pathways’, ‘chemical carcinogenesis’ and ‘fatty acid degradation’. After constructing the PPI network, cyclin-dependent kinase 1, cyclin B1, cyclin A2, mitotic arrest deficient 2 like 1, cyclin B2, DNA topoisomerase IIα, budding uninhibited by benzimidazoles (BUB)1, TTK protein kinase, non-SMC condensin I complex subunit G, NDC80 kinetochore complex component, aurora kinase A, kinesin family member 11, cell division cycle 20, BUB1B and abnormal spindle microtubule assembly were identified as hub genes based on the high degree of connectivity by using Cytoscape software. In addition, overall survival (OS) and disease-free survival (DFS) analyses were performed using the Gene Expression Profiling Interactive Analysis online database, which revealed that the increased expression of all hub genes were associated with poorer OS and DFS outcomes. Receiver operating characteristic curves were constructed using GraphPad prism 7.0 software. The results confirmed that 15 hub genes were able to distinguish HCC form normal tissues. Furthermore, the expression levels of three key genes were analyzed in tumor and normal samples of the Human Protein Atlas database. The present results may provide further insight into the underlying mechanisms of HCC and potential therapeutic targets for the treatment of this disease.
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Affiliation(s)
- Lijie Zhang
- Department of Radiology, Hubei Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Joyman Makamure
- Department of Radiology, Hubei Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Dan Zhao
- Department of Radiology, Hubei Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yiming Liu
- Department of Radiology, Hubei Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Xiaopeng Guo
- Department of Radiology, Hubei Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Chuansheng Zheng
- Department of Radiology, Hubei Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Bin Liang
- Department of Radiology, Hubei Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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Zhang X, Wang L, Yan Y. Identification of potential key genes and pathways in hepatitis B virus-associated hepatocellular carcinoma by bioinformatics analyses. Oncol Lett 2020; 19:3477-3486. [PMID: 32269621 PMCID: PMC7138035 DOI: 10.3892/ol.2020.11470] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 01/24/2020] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus (HBV) is one of the leading causes of hepatocellular carcinoma (HCC). The precise molecular mechanisms by which HBV contributes to HCC development are not fully understood. The key genes and pathways involved in the transformation of nontumor hepatic tissues into HCC tissues in patients with HBV infection are essential to guide the treatment of HBV-associated HCC. Five datasets were collected from the Gene Expression Omnibus database to form a large cohort. Differentially expressed genes (DEGs) were identified between HCC tissues and nontumor hepatic tissues from HBV-infected patients using the ‘limma’ package. The top 50 upregulated and top 50 downregulated DEGs in HCC vs. nontumor tissues were demonstrated in subsets by heat maps. Based on the DEGs, Gene Ontology functional and Kyoto Encyclopedia of Genes and Genomes pathways enrichment analyses were performed. Several key pathways of the up- and downregulated DEGs were identified and presented by protein-protein interaction (PPI) networks. A total of 1,934 DEGs were identified. The upregulated DEGs were primarily associated with the ‘cell cycle’. Among the DEGs enriched in the ‘cell cycle’ pathway, 6 genes had a log2-fold change >2: SFN, BUB1B, TTK, CCNB1, CDK1 and CDC20. The downregulated DEGs were primarily associated with the metabolic pathways, such as ‘carbon metabolism’, ‘glycine, serine and threonine metabolism’, ‘tryptophan metabolism’, ‘retinol metabolism’ and ‘alanine, aspartate and glutamate metabolism’. The DEGs in the ‘cell cycle’ and ‘metabolic pathways’ were presented by the PPI networks respectively. Overall, the present study provides new insights into the specific etiology of HCC and molecular mechanisms for the transformation of nontumor hepatic tissues into HCC tissues in patients with a history of HBV infection and several potential therapeutic targets for targeted therapy in these patients.
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Affiliation(s)
- Xiang Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Lingchen Wang
- Department of Biostatistics and Epidemiology, School of Public Health, Nanchang University, Nanchang, Jiangxi 330006, P.R. China.,Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yehong Yan
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Shi Z, Xiao Z, Hu L, Gao Y, Zhao J, Liu Y, Shen G, Xu Q, Huang D. The genetic association between type 2 diabetic and hepatocellular carcinomas. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:380. [PMID: 32355824 PMCID: PMC7186634 DOI: 10.21037/atm.2020.02.13] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background Type 2 diabetes mellitus (T2DM) and hepatocellular carcinoma (HCC) are both major health problems throughout the world. It has been reported that T2DM is an independent risk factor for HCC, although the pathophysiology is still unclear. Methods In order to identify differentially expressed genes (DEGs) in T2DM and HCC, gene expression datasets for T2DM (GSE15653), HCC (GSE60502) and metformin-treated cells (GSE69850) were obtained from the Gene Expression Omnibus database repository. Protein-protein interaction (PPI) networks for the DEGs were constructed and gene clusters selected for functional enrichment analysis. Ten genes with the highest degree of connectivity were selected as hub genes and prognostic analysis together with analysis of gene expression and protein distribution were performed for these genes. Lastly, we investigated associations between the hub genes and genes associated with metformin treatment in hepatocarcinoma cells. Results In total, 256 common DEGs, including 155 up-regulated genes and 101 down-regulated genes, were identified. Enrichment analyses showed that the genes of the major module were largely associated with the cell cycle. All of the 10 hub genes (CCNA2, CCNB1, MAD2L1, BU1B, RACGAP1, CHEK1, BUB1, ASPM, NCAPG and TTK) have a strong association with lower overall survival in liver cancer patients and four genes (CCNA2, CCNB1, CHEK1 and BUB1) have reduced expression in metformin-treated samples. Conclusions This study identified a number of genes that may play important roles in the association of T2DM and HCC, including four genes which may be the target of metformin treatment for diabetes and HCC. The specific mechanisms involved remain to be identified.
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Affiliation(s)
- Zhan Shi
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310014, China
| | - Zunqiang Xiao
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310014, China
| | - Linjun Hu
- The Medical College of Qingdao University, Qingdao 266071, China
| | - Yuling Gao
- Department of Genetic Laboratory, Shaoxing Women and Children Hospital, Shaoxing 312030, China
| | - Junjun Zhao
- Graduate Department, Bengbu Medical College, Bengbu 233030, China
| | - Yang Liu
- The Medical College of Qingdao University, Qingdao 266071, China
| | - Guoliang Shen
- Department of Hepatopancreatobiliary Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
| | - Qiuran Xu
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China
| | - Dongsheng Huang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China
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Carmona S, Brunel JM, Bonier R, Sbarra V, Robert S, Borentain P, Lombardo D, Mas E, Gerolami R. A squalamine derivative, NV669, as a novel PTP1B inhibitor: in vitro and in vivo effects on pancreatic and hepatic tumor growth. Oncotarget 2019; 10:6651-6667. [PMID: 31803360 PMCID: PMC6877102 DOI: 10.18632/oncotarget.27286] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Accepted: 10/02/2019] [Indexed: 12/14/2022] Open
Abstract
NV669 is an aminosterol derived from squalamine found to possess strong anticancer effects. The aim of this study was to investigate NV669’s beneficial effects on human pancreatic and hepatic cancer models and to decipher the cellular and molecular mechanisms involved in tumor growth decrease upon treatment with NV669. Pancreatic (BxPC3, MiaPaCa-2) and hepatic (HepG2, Huh7) cancer cells were treated with NV669, and the effects recorded on proliferation, cell cycle and death. Results showed that NV669 inhibited the viability of cancer cells, induced cell cycle arrest and subsequently promoted apoptosis. This was accompanied by a decrease in the expression of cyclin B1 and phosphorylated Cdk1 and by a cleavage of pro-apoptotic caspase-8 and PARP-1. Taken together, our studies showed that NV669 inhibits the proliferation of pancreatic and hepatic cancer cells through the regulation of G2/M phase transition via the cyclin B1-Cdk1 complex. In vitro NV669 inhibits PTP1B activity and FAK expression. NV669 impacts on the expression of adhesion molecules CDH-1, -2 and -3 in BxPC3 and Huh7 lines that form cell monolayers. Consecutively NV669 induces cell detachment. This suggests that NV669 by inhibiting PTP1B induces cell detachment and apoptosis.
Subsequently, our in vivo results showed that NV669 inhibited the growth of pancreatic and hepatic tumor xenografts with a significant cell cycle arrest in pre-mitotic phase and an increase of tumor cell apoptosis. Therefore, NV669 may serve as an alternative anticancer agent, used alone or in association with other medications, for the treatment of pancreatic adenocarcinoma and hepatocellular carcinoma.
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Affiliation(s)
- Sylvie Carmona
- Aix Marseille Univ, INSERM, CRO2, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de médecine, Marseille, France.,Aix Marseille Univ, CNRS, INP, Institut de Neuro-Physiopathologie, Faculté de médecine, Marseille, France
| | | | - Rénaté Bonier
- Aix Marseille Univ, INSERM, CRO2, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de médecine, Marseille, France.,Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Centre de Recherche en Cancérologie de Marseille, Marseille, France
| | - Véronique Sbarra
- Aix Marseille Univ, INSERM, CRO2, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de médecine, Marseille, France.,Aix Marseille Univ, INSERM, INRA, C2VN, Faculté de médecine, Marseille, France
| | - Stéphane Robert
- Aix Marseille Univ, INSERM, INRA, C2VN AMUTICYT Core facility, Faculté de pharmacie, Marseille, France
| | - Patrick Borentain
- Aix Marseille Univ, INSERM, CRO2, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de médecine, Marseille, France.,Aix Marseille Univ, AP-HM, Assistance Publique des Hôpitaux de Marseille, Centre Hospitalo-Universitaire Timone, Service d'Hépato-Gastro-Entérologie, Marseille, France
| | - Dominique Lombardo
- Aix Marseille Univ, INSERM, CRO2, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de médecine, Marseille, France
| | - Eric Mas
- Aix Marseille Univ, INSERM, CRO2, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de médecine, Marseille, France.,Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Centre de Recherche en Cancérologie de Marseille, Marseille, France
| | - René Gerolami
- Aix Marseille Univ, INSERM, CRO2, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de médecine, Marseille, France.,Aix Marseille Univ, AP-HM, Assistance Publique des Hôpitaux de Marseille, Centre Hospitalo-Universitaire Timone, Service d'Hépato-Gastro-Entérologie, Marseille, France
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Zhang YB, Jiang Y, Wang J, Ma J, Han S. Evaluation of core serous epithelial ovarian cancer genes as potential prognostic markers and indicators of the underlying molecular mechanisms using an integrated bioinformatics analysis. Oncol Lett 2019; 18:5508-5522. [PMID: 31612059 PMCID: PMC6781641 DOI: 10.3892/ol.2019.10884] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Accepted: 08/23/2019] [Indexed: 12/31/2022] Open
Abstract
Ovarian cancer is a major cause of mortality in women. However, the molecular events underlying the pathogenesis of the disease are yet to be fully elucidated. In the present study, an integrated bioinformatics analysis was performed to identify core genes involved in serous epithelial ovarian cancer. A total of three expression datasets were downloaded from the Gene Expression Omnibus database, and included 46 serous epithelial ovarian cancer and 30 ovarian surface epithelium samples. The three datasets were merged, and batch normalization was performed. The normalized merged data were subsequently analyzed for differentially expressed genes (DEGs). In total, 2,212 DEGs were identified, including 1,300 upregulated and 912 downregulated genes. Gene Ontology analysis revealed that these DEGs were primarily involved in ‘regulation of cell cycle’, ‘mitosis’, ‘DNA packaging’ and ‘nucleosome assembly’. The main cellular components included ‘extracellular region part’, ‘chromosome’, ‘extracellular matrix’ and ‘condensed chromosome kinetochore’, whereas the molecular functions included ‘Calcium ion binding’, ‘polysaccharide binding’, ‘enzyme inhibitor activity’, ‘growth factor activity’, ‘cyclin-dependent protein kinase regulator activity’, ‘microtubule motor activity’ and ‘Wnt receptor activity’. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that these DEGs were predominantly involved in ‘Wnt signaling pathway’, ‘pathways in cancer’, ‘PI3K-Akt signaling pathway’, ‘cell cycle’, ‘ECM-receptor interaction’, ‘p53 signaling pathway’ and ‘focal adhesion’. The 20 most significant DEGs were identified from the protein-protein interaction network, and Oncomine analysis of these core genes revealed that 13 were upregulated and two were downregulated in serous epithelial ovarian cancer. Survival analysis revealed that cyclin B1, polo like kinase 1, G protein subunit γ transducin 1 and G protein subunit γ 12 are key molecules that may be involved in the prognosis of serous epithelial ovarian cancer. These core genes may provide novel treatment targets, although their roles in the carcinogenesis and prognosis of serous epithelial ovarian cancer require further study.
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Affiliation(s)
- Yu-Bo Zhang
- Department of Gynecology and Obstetrics, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yuhan Jiang
- Department of Gynecology, The Affiliated Hospital of Jining Medical College, Jining, Shandong 272000, P.R. China
| | - Jiao Wang
- Department of Gynecology and Obstetrics, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Jing Ma
- Department of Gynecology and Obstetrics, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Shiyu Han
- Department of Gynecology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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Chen EB, Qin X, Peng K, Li Q, Tang C, Wei YC, Yu S, Gan L, Liu TS. HnRNPR-CCNB1/CENPF axis contributes to gastric cancer proliferation and metastasis. Aging (Albany NY) 2019; 11:7473-7491. [PMID: 31527303 PMCID: PMC6782008 DOI: 10.18632/aging.102254] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Accepted: 09/02/2019] [Indexed: 02/06/2023]
Abstract
Gastric cancer (GC) is a common disease globally with high mortality rate. It is therefore necessary to develop novel therapies targeting specific events in the pathogenesis of GC. Some hnRNP family members are involved in multiple cancer biological behaviors. However, the potential function and mechanism of hnRNPR, a new molecule of hnRNP family in GC remains unknown. We found that the expression of hnRNPR was significantly overexpressed in multiple cancers compared to the normal tissues. Functionally, hnRNPR promoted cancer cell proliferation, migration, and invasion. Knockdown of hnRNPR in two type mice models, with two types of tumors models decreased the tumor aggressiveness and metastasis. Mechanistically, hnRNPR targeted oncogenic pathways by stabilizing the expression of CCNB1 and CENPF mRNA level. Knockdown of CCNB1 and CENPF abolished the hnRNPR-induced cell growth and invasion, respectively. Furthermore, the protein level of hnRNPR in the tumor was positively correlated with the expression of CCNB1 and CENPF in clinical samples. Together, these results indicate that overexpression of hnRNPR promoted the aggressiveness of GC by increasing the mRNA expression of CCNB1 and CENPF. HnRNPR-CCNB1/CENPF axis may be a potential therapeutic target for GC treatment.
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Affiliation(s)
- Er-Bao Chen
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xuan Qin
- School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, China
| | - Ke Peng
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qian Li
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cheng Tang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yi-Chou Wei
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shan Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lu Gan
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tian-Shu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
- Center of Evidence-based Medicine, Fudan University, Shanghai, China
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Liu J, Ma Z, Liu Y, Wu L, Hou Z, Li W. Screening of potential biomarkers in hepatitis C virus-induced hepatocellular carcinoma using bioinformatic analysis. Oncol Lett 2019; 18:2500-2508. [PMID: 31452738 PMCID: PMC6676667 DOI: 10.3892/ol.2019.10578] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 06/06/2019] [Indexed: 01/10/2023] Open
Abstract
Evidence suggests that hepatitis C virus (HCV) infection is among the main causes of hepatocellular carcinoma (HCC). In addition, HCV-induced HCC (HCV-HCC) exhibits adverse clinical outcomes and limited therapeutic treatments are available for this condition. To investigate key biomarkers in the occurrence and development of HCV-HCC, microarray datasets GSE62232, GSE69715 and GSE107170 were downloaded from the Gene Expression Omnibus database for analysis. The differentially expressed genes between HCV-HCC and normal tissue were identified using the GEO2R online tool. The function enrichment analyses including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were performed using the Database for Annotation, Visualization and Integrated Discovery online tool. A protein-protein interaction network was constructed using the Search Tool for the Retrieval of Interacting Genes database and visualized using Cytoscape. A total of 368 DEGs were identified, and the top 10 hub genes with a high degree of connectivity were selected for further analysis. Subsequently, overall survival and disease-free survival analysis revealed that there was a significant association between altered expression of HMMR, CCNB1 and KIF20A, and poor clinical outcome. In summary, these results indicate that HMMR, CCNB1 and KIF20A are potential targets for diagnosis and therapy of HCV-HCC.
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Affiliation(s)
- Jun Liu
- Department of Laboratory Medicine, Yue Bei People's Hospital, Shaoguan, Guangdong 512026, P.R. China
| | - Zhanzhong Ma
- Department of Laboratory Medicine, Yue Bei People's Hospital, Shaoguan, Guangdong 512026, P.R. China
| | - Yanming Liu
- Department of Laboratory Medicine, Yue Bei People's Hospital, Shaoguan, Guangdong 512026, P.R. China
| | - Liangyin Wu
- Department of Laboratory Medicine, Yue Bei People's Hospital, Shaoguan, Guangdong 512026, P.R. China
| | - Zhiwei Hou
- Reproductive Medicine Center, Yue Bei People's Hospital, Shaoguan, Guangdong 512026, P.R. China
| | - Wenli Li
- Reproductive Medicine Center, Yue Bei People's Hospital, Shaoguan, Guangdong 512026, P.R. China
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Yan Y, Lu Y, Mao K, Zhang M, Liu H, Zhou Q, Lin J, Zhang J, Wang J, Xiao Z. Identification and validation of a prognostic four-genes signature for hepatocellular carcinoma: integrated ceRNA network analysis. Hepatol Int 2019; 13:618-630. [PMID: 31321712 PMCID: PMC6744548 DOI: 10.1007/s12072-019-09962-3] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 06/14/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, with a poor long-term prognosis worldwide. The functional deregulations of global transcriptome were associated with the genesis and development of HCC, but lacks systematic research and validation. METHODS A total of 519 postoperative HCC patients were included. We built an interactive and visual competing endogenous RNA network. The prognostic signature was established with the least absolute shrinkage and selection operator algorithm. Multivariate Cox regression analysis was used to screen for independent prognostic factors for HCC overall survival. RESULTS In the training set, we identified a four-gene signature (PBK, CBX2, CLSPN, and CPEB3) and effectively predicted the overall survival. The survival times of patients in the high-score group were worse than those in the low-score group (p = 0.0004), and death was also more likely in the high-score group (HR 2.444, p < 0.001). The results were validated in internal validation set (p = 0.0057) and two external validation cohorts (HR 2.467 and 2.6). The signature (AUCs of 1, 2, 3 years were 0.716, 0.726, 0.714, respectively) showed high prognostic accuracy in the complete TCGA cohort. CONCLUSIONS In conclusion, we successfully built a more extensive ceRNA network for HCC and then identified a four-gene-based signature, enabling prediction of the overall survival of patients with HCC.
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Affiliation(s)
- Yongcong Yan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road 107#, Guangzhou, 510120, China.,RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Yingjuan Lu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Department of Oral and Maxillofacial Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Kai Mao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road 107#, Guangzhou, 510120, China.,RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Mengyu Zhang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Haohan Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road 107#, Guangzhou, 510120, China.,RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Qianlei Zhou
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road 107#, Guangzhou, 510120, China.,RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Jianhong Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road 107#, Guangzhou, 510120, China.,RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Jianlong Zhang
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road 107#, Guangzhou, 510120, China
| | - Jie Wang
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road 107#, Guangzhou, 510120, China.
| | - Zhiyu Xiao
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road 107#, Guangzhou, 510120, China.
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Long J, Bai Y, Yang X, Lin J, Yang X, Wang D, He L, Zheng Y, Zhao H. Construction and comprehensive analysis of a ceRNA network to reveal potential prognostic biomarkers for hepatocellular carcinoma. Cancer Cell Int 2019; 19:90. [PMID: 31007608 PMCID: PMC6458652 DOI: 10.1186/s12935-019-0817-y] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 04/05/2019] [Indexed: 12/15/2022] Open
Abstract
Background Long noncoding RNAs (lncRNAs) can act as microRNA (miRNA) sponges to regulate protein-coding gene expression; therefore, lncRNAs are considered a major part of the competitive endogenous RNA (ceRNA) network and have attracted growing attention. The present study explored the regulatory mechanisms and functional roles of lncRNAs as ceRNAs in hepatocellular carcinoma (HCC) and their potential impact on HCC patient prognosis. Methods In this study, we systematically studied the expression profiles and prognostic value of lncRNA, miRNA, and mRNA from a total of 838 HCC patients from five HCC cohorts (TCGA, GSE54236, GSE76427, GSE64041 and GSE14520). The TCGA, GSE54236 and GSE76427 HCC cohorts were utilized to establish a prognosis-related network of dysregulated ceRNAs by bioinformatics methods. The GSE64041 and GSE14520 HCC cohorts were utilized to verify the expression of candidate genes. Results In total, 721 lncRNAs, 73 miRNAs, and 1563 mRNAs were aberrantly expressed in HCC samples. A ceRNA network including 26 lncRNAs, four miRNAs, and six mRNAs specific to HCC was established. The survival analysis showed that four lncRNAs (MYCNOS, DLX6-AS1, LINC00221, and CRNDE) and two mRNAs (CCNB1 and SHCBP1) were prognostic biomarkers for patients with HCC in both the TCGA and GEO databases. Conclusion The proposed ceRNA network may help elucidate the regulatory mechanism by which lncRNAs function as ceRNAs and contribute to the pathogenesis of HCC. Importantly, the candidate lncRNAs, miRNAs, and mRNAs involved in the ceRNA network can be further evaluated as potential therapeutic targets and prognostic biomarkers for HCC. Electronic supplementary material The online version of this article (10.1186/s12935-019-0817-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Junyu Long
- 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yi Bai
- 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaobo Yang
- 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jianzhen Lin
- 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xu Yang
- 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Dongxu Wang
- 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Li He
- 2Department of Medicine, University of Alabama at Birmingham, Birmingham, AL USA
| | - Yongchang Zheng
- 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Haitao Zhao
- 1Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Takacs FZ, Radosa JC, Linxweiler M, Kasoha M, Bohle RM, Bochen F, Unger C, Solomayer EF, Schick B, Juhasz-Böss I. Identification of 3q oncogene SEC62 as a marker for distant metastasis and poor clinical outcome in invasive ductal breast cancer. Arch Gynecol Obstet 2019; 299:1405-1413. [PMID: 30747329 DOI: 10.1007/s00404-019-05081-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 02/02/2019] [Indexed: 12/11/2022]
Abstract
PURPOSE In previous studies, we have shown that SEC62 has an essential function in cell migration, epithelial-to-mesenchymal transition, and endoplasmic reticulum stress tolerance of cancer cells. SEC62 expression correlated with distant and lymph node metastasis and poor outcome in different cancer entities. In this initial study, we investigated SEC62 expression and its possible role as a prognostic and predictive biomarker in breast cancer (BC). METHODS Formalin-fixed, paraffin-embedded tissue samples of 53 BC patients were analyzed by immunohistochemistry. The immunoreactive score (IRS) according to Remmele and Stegner was evaluated and correlated with clinico-pathological findings and overall survival (OS). RESULTS We found increased SEC62 protein levels in tumor tissue compared to tumor-free tissue samples from the same patients. Tumors with high SEC62 expression (IRS > 8), or containing isolated cells with high SEC62 staining intensity, independent of the IRS, had more frequently distant metastases (48.4% vs. 18.2%; p = 0.024 and 47.4 vs. 6.7%; p = 0.005, respectively). Overall survival was significantly worse in BC patients with high SEC62 expression (SEC62 IRS > 8) (54.8% vs. 81.8%; p = 0.011) and in cases with isolated high-intensity SEC62 staining cells independently of SEC62 IRS (55.3% vs 93.3%; p = 0.024). CONCLUSIONS We are the first to describe the SEC62 expression and its correlation to clinicopathological parameters in mammary carcinoma. Our results suggest that SEC62 expression may serve as a prognostic marker for patients with invasive ductal breast cancer.
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Affiliation(s)
- Ferenc Zoltan Takacs
- Department of Obstetrics and Gynecology, University of Saarland, 66424, Homburg, Saar, Germany.
| | - Julia Caroline Radosa
- Department of Obstetrics and Gynecology, University of Saarland, 66424, Homburg, Saar, Germany
| | - Maximilian Linxweiler
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Saarland, 66424, Homburg, Saar, Germany
| | - Mariz Kasoha
- Department of Obstetrics and Gynecology, University of Saarland, 66424, Homburg, Saar, Germany.,Department of General and Surgical Pathology, University of Saarland, 66424, Homburg, Saar, Germany
| | - Rainer M Bohle
- Department of General and Surgical Pathology, University of Saarland, 66424, Homburg, Saar, Germany
| | - Florian Bochen
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Saarland, 66424, Homburg, Saar, Germany
| | - Clara Unger
- Department of Obstetrics and Gynecology, University of Saarland, 66424, Homburg, Saar, Germany
| | - Erich-Franz Solomayer
- Department of Obstetrics and Gynecology, University of Saarland, 66424, Homburg, Saar, Germany
| | - Bernard Schick
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Saarland, 66424, Homburg, Saar, Germany
| | - Ingolf Juhasz-Böss
- Department of Obstetrics and Gynecology, University of Saarland, 66424, Homburg, Saar, Germany
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Wu M, Liu Z, Zhang A, Li N. Identification of key genes and pathways in hepatocellular carcinoma: A preliminary bioinformatics analysis. Medicine (Baltimore) 2019; 98:e14287. [PMID: 30702595 PMCID: PMC6380748 DOI: 10.1097/md.0000000000014287] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. However, the precise mechanisms of the development and progression of HCC remain unclear. The present study attempted to identify and functionally analyze the differentially expressed genes between HCC and cirrhotic tissues by using comprehensive bioinformatics analyses. METHODS The GSE63898 gene expression profile was downloaded from the Gene Expression Omnibus (GEO) and analyzed using the online tool GEO2R to identify differentially expressed genes (DEGs). Gene ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEGs were performed in DAVID. The STRING database was used to evaluate the interactions of DEGs and to construct a protein-protein interaction (PPI) network using Cytoscape software. Hub genes were selected using the cytoHubba plugin and were validated with the cBioPortal database. RESULTS A total of 301 DEGs were identified between HCC and cirrhotic tissues. The GO analysis results showed that these DEGs were significantly enriched in certain biological processes including negative regulation of growth and cell chemotaxis. Several significant pathways, including the p53 signaling pathway, were identified as being closely associated with these DEGs. The top 12 hub genes were screened and included TTK, NCAPG, TOP2A, CCNB1, CDK1, PRC1, RRM2, UBE2C, ZWINT, CDKN3, AURKA, and RACGAP1. The cBioPortal analysis found that alterations in hub genes could result in significantly reduced disease-free survival in HCC. CONCLUSION The present study identified a series of key genes and pathways that may be involved in the tumorigenicity and progression of HCC, providing a new understanding of the underlying molecular mechanisms of carcinogenesis in HCC.
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Affiliation(s)
- Min Wu
- Department of General surgery
| | | | - Aiying Zhang
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Ning Li
- Department of General surgery
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
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Gu J, Liu X, Li J, He Y. MicroRNA-144 inhibits cell proliferation, migration and invasion in human hepatocellular carcinoma by targeting CCNB1. Cancer Cell Int 2019; 19:15. [PMID: 30651720 PMCID: PMC6332595 DOI: 10.1186/s12935-019-0729-x] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 01/04/2019] [Indexed: 12/13/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common malignancies with a high morbidity and mortality worldwide. MicroRNAs are key regulators of HCC genesis. However, the regulatory role and underlying mechanisms of microRNA in HCC is still limited. Methods Cyclin B1 (CCNB1) mRNA levels were examined in non-tumor and liver cancer of The Cancer Genome Atlas (TCGA) cohort. CCNB1 was knockdown to evaluate the HCC cell proliferation, migration and invasion. MicroRNA-144 targeting CCNB1 was identified with TargetScan analysis and confirmed with reporter assay. Overexpression of MicroRNA-144 was achieved using microRNA mimics and function of microRNA-144 was tested in vitro HCC cell line proliferation and in vivo tumor formation experiments. Results Here, we found that the high level expression of CCNB1 was closely associated with poor prognosis in HCC patients. Knockdown of CCNB1 by RNA interference significantly inhibited cell proliferation, migration and invasion in HCC. Furthermore, we found that miR-144 directly targeted CCNB1 and inhibited CCNB1 expression. Moreover, in vivo experiments of subcutaneous tumor formation further demonstrated that miR-144 delayed tumor formation by negative regulation of CCNB1. Conclusion Therefore, we conclude that microRNA-144/CCNB1 axis plays an important role in human HCC. Therapies targeting microRNA-144 could potentially improve HCC treatment. Electronic supplementary material The online version of this article (10.1186/s12935-019-0729-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Junsheng Gu
- Department of infectious disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan People's Republic of China
| | - Xiaorui Liu
- Department of infectious disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan People's Republic of China
| | - Juan Li
- Department of infectious disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan People's Republic of China
| | - Yuting He
- Department of infectious disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan People's Republic of China
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Liu W, Ouyang S, Zhou Z, Wang M, Wang T, Qi Y, Zhao C, Chen K, Dai L. Identification of genes associated with cancer progression and prognosis in lung adenocarcinoma: Analyses based on microarray from Oncomine and The Cancer Genome Atlas databases. Mol Genet Genomic Med 2018; 7:e00528. [PMID: 30556321 PMCID: PMC6393652 DOI: 10.1002/mgg3.528] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 10/28/2018] [Accepted: 11/07/2018] [Indexed: 12/27/2022] Open
Abstract
Background Lung adenocarcinoma (LUAD) accounts for approximately 40% of all lung cancer patients. There is an urgent need to understand the mechanisms of cancer progression in LUAD and to identify useful biomarkers to predict prognosis. Methods In this study, Oncomine database was used to identify potential genes contributed to cancer progression. Bioinformatics analysis including pathway enrichment and text mining was used to explain the potential roles of identified genes in LUAD. The Cancer Genome Atlas database was used to analyze the association of gene expression with survival result. Results Our results indicated that 80 genes were significantly dysregulated in LUAD according to four microarrays covering 356 cases of LUAD and 164 cases of normal lung tissues. Twenty genes were consistently and stably dysregulated by more than twofold. Ten of 20 genes had a relationship with overall survival or disease‐free survival in a cohort of 516 LUAD patients, and 19 genes were associated with tumor stage, gender, age, lymph node, or smoking. Low expression of AGER and high expression of CCNB1 were specifically associated with poor survival. Conclusion Our findings implicate AGER and CCNB1 might be potential biomarkers for diagnosis and prognosis targets for LUAD.
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Affiliation(s)
- Wei Liu
- Department of Gastroenterology in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Songyun Ouyang
- Department of Respiratory and Sleep Medicine in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Zhigang Zhou
- Department of Radiology in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Meng Wang
- Department of Radiology in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Tingting Wang
- Department of Medical Examination in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Yu Qi
- Department of Thoracic Surgery in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Chunling Zhao
- Department of Respiratory and Sleep Medicine in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Kuisheng Chen
- Department of Pathology in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Liping Dai
- Department of Respiratory and Sleep Medicine in the First Affiliated HospitalZhengzhou UniversityZhengzhouChina
- Department of Tumor Research in the Institute of Medical and Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina
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Menyhárt O, Nagy Á, Győrffy B. Determining consistent prognostic biomarkers of overall survival and vascular invasion in hepatocellular carcinoma. ROYAL SOCIETY OPEN SCIENCE 2018; 5:181006. [PMID: 30662724 PMCID: PMC6304123 DOI: 10.1098/rsos.181006] [Citation(s) in RCA: 334] [Impact Index Per Article: 47.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 11/08/2018] [Indexed: 05/03/2023]
Abstract
Background: Potential prognostic biomarker candidates for hepatocellular carcinoma (HCC) are abundant, but their generalizability is unexplored. We cross-validated markers of overall survival (OS) and vascular invasion in independent datasets. Methods: The literature search yielded 318 genes related to survival and 52 related to vascular invasion. Validation was performed in three datasets (RNA-seq, n = 371; Affymetrix arrays, n = 91; Illumina gene chips, n = 135) by uni- and multivariate Cox regression and Mann-Whitney U-test, separately for Asian and Caucasian patients. Results: One hundred and eighty biomarkers remained significant in Asian and 128 in Caucasian subjects at p < 0.05. After multiple testing correction BIRC5 (p = 1.9 × 10-10), CDC20 (p = 2.5 × 10-9) and PLK1 (p = 3 × 10-9) endured as best performing genes in Asian patients; however, none remained significant in the Caucasian cohort. In a multivariate analysis, significance was reached by stage (p = 0.0018) and expression of CENPH (p = 0.0038) and CDK4 (p = 0.038). KIF18A was the only gene predicting vascular invasion in the Affymetrix and Illumina cohorts (p = 0.003 and p = 0.025, respectively). Conclusion: Overall, about half of biomarker candidates failed to retain prognostic value and none were better than stage predicting OS. Impact: Our results help to eliminate biomarkers with limited capability to predict OS and/or vascular invasion.
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Affiliation(s)
- Otília Menyhárt
- 2nd Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary
- MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
| | - Ádám Nagy
- 2nd Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary
- MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
| | - Balázs Győrffy
- 2nd Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary
- MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
- Author for correspondence: Balázs Győrffy e-mail:
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Müller CSL, Kreie L, Bochen F, Pfuhl T, Smola S, Gräber S, Vogt T, Schick B, Linxweiler M. Expression of 3q oncogene SEC62 in atypical fibroxanthoma-immunohistochemical analysis of 41 cases and correlation with clinical, viral and histopathologic features. Oncol Lett 2018; 17:1768-1776. [PMID: 30675236 PMCID: PMC6341582 DOI: 10.3892/ol.2018.9767] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Accepted: 10/26/2018] [Indexed: 12/30/2022] Open
Abstract
Atypical fibroxanthoma (AFX) is a rare mesenchymal tumor with predominance in older male patients located mainly in chronically UV-exposed skin. Differentiation from clinically more aggressive pleomorphic dermal sarcoma (PDS) is still under debate and immunohistochemical markers are not available yet. An immunohistochemical study, including 41 cases of AFX was conducted to investigate the expression of 3q encoded oncogene SEC62 in AFX and determine the associations with histomorphologic, clinical and viral parameters. Our cohort displayed a mean of 79.9 years at the onset of the disease. In total, 90.2% (37/41) AFXs were located in the head and neck area, whereas, four were located at the extremities (9.7%). Tumor diameter ranged between 0.06 and 40 cm2 with a mean of 5.7 cm2. SEC62 expression was markedly increased in lesional tissue compared with the adjacent healthy squamous epithelium. We found significantly higher expression of SEC62 in cases of AFX with tumor necrosis. Tendency of higher Sec62-IRS-scores were found for tumors with higher Clark levels and a tumor size >5 cm2. Sec62 is involved in endoplasmic reticulum stress tolerance and cell migration, and has been identified as a novel prognostic marker for non-small cell lung cancer as well as head and neck squamous cell carcinoma. For the first time, to the best of our knowledge, we suggest a role of 3q oncogene SEC62 in AFX and discuss a potential prognostic relevance in cases of disputable AFX with unfavorable histomorphologic features and may initiate a discussion on Sec62 serving as discriminating marker between AFX and PDS.
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Affiliation(s)
- Cornelia S L Müller
- Department of Dermatology, Venereology and Allergology, Saarland University Medical Center, D-66421 Homburg, Germany
| | - Léa Kreie
- Department of Dermatology, Venereology and Allergology, Saarland University Medical Center, D-66421 Homburg, Germany
| | - Florian Bochen
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany
| | - Thorsten Pfuhl
- Institute of Virology, Saarland University Medical Center, D-66421 Homburg, Germany
| | - Sigrun Smola
- Institute of Virology, Saarland University Medical Center, D-66421 Homburg, Germany
| | - Stefan Gräber
- Institute of Biometry, Epidemiology and Medical Informatics, Saarland University Medical Center, D-66421 Homburg, Germany
| | - Thomas Vogt
- Department of Dermatology, Venereology and Allergology, Saarland University Medical Center, D-66421 Homburg, Germany
| | - Bernhard Schick
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany
| | - Maximilian Linxweiler
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, D-66421 Homburg, Germany
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Daskalaki I, Gkikas I, Tavernarakis N. Hypoxia and Selective Autophagy in Cancer Development and Therapy. Front Cell Dev Biol 2018; 6:104. [PMID: 30250843 PMCID: PMC6139351 DOI: 10.3389/fcell.2018.00104] [Citation(s) in RCA: 122] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 08/13/2018] [Indexed: 01/07/2023] Open
Abstract
Low oxygen availability, a condition known as hypoxia, is a common feature of various pathologies including stroke, ischemic heart disease, and cancer. Hypoxia adaptation requires coordination of intricate pathways and mechanisms such as hypoxia-inducible factors (HIFs), the unfolded protein response (UPR), mTOR, and autophagy. Recently, great effort has been invested toward elucidating the interplay between hypoxia-induced autophagy and cancer cell metabolism. Although novel types of selective autophagy have been identified, including mitophagy, pexophagy, lipophagy, ERphagy and nucleophagy among others, their potential interface with hypoxia response mechanisms remains poorly understood. Autophagy activation facilitates the removal of damaged cellular compartments and recycles components, thus promoting cell survival. Importantly, tumor cells rely on autophagy to support self-proliferation and metastasis; characteristics related to poor disease prognosis. Therefore, a deeper understanding of the molecular crosstalk between hypoxia response mechanisms and autophagy could provide important insights with relevance to cancer and hypoxia-related pathologies. Here, we survey recent findings implicating selective autophagy in hypoxic responses, and discuss emerging links between these pathways and cancer pathophysiology.
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Affiliation(s)
- Ioanna Daskalaki
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece
- Department of Biology, University of Crete, Heraklion, Greece
| | - Ilias Gkikas
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece
- Department of Biology, University of Crete, Heraklion, Greece
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece
- Department of Basic Sciences, Medical School, University of Crete, Heraklion, Greece
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Regulation of the homeostasis of hepatic endoplasmic reticulum and cytochrome P450 enzymes by autophagy. LIVER RESEARCH 2018; 2:138-145. [PMID: 31807367 PMCID: PMC6894516 DOI: 10.1016/j.livres.2018.08.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The endoplasmic reticulum (ER) is an intracellular organelle consisting of a continuous network of membranes. In the liver, the ER is highly active in protein modification, lipid metabolism, and xenobiotic detoxification. Maintaining these complicated processes requires elaborate control of the ER lumen environment as well as the ER volume. Increasing evidence suggests that autophagy plays a critical role in regulating the homeostasis of hepatic ER contents and levels of cytochrome P450 (CYP) enzymes via selective ER-phagy. This review will provide an overview of ER-phagy, summarizing the possible roles of recently identified ER-phagy receptor proteins in regulating the homeostasis of hepatic ER and CYP enzymes as well as outlining the various implications of ER-phagy in ER-related liver diseases.
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Liang S, Zou Y, Gao J, Liu X, Lin W, Yin Z, Du J, Zhang Y, Chen Q, Li S, Cheng B, Ling C. The Chinese Medicine, Jiedu Recipe, Inhibits the Epithelial Mesenchymal Transition of Hepatocellular Carcinoma via the Regulation of Smad2/3 Dependent and Independent Pathways. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2018; 2018:5629304. [PMID: 30174709 PMCID: PMC6106903 DOI: 10.1155/2018/5629304] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 07/29/2018] [Indexed: 12/25/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. In China, traditional Chinese herb medicine has been widely used in the treatment of HCC. Jiedu Recipe (JR) is a common used prescription which has shown good results against HCC. However, the exact mechanisms of JR are still unknown. Therefore, we investigated the efficacy of JR on HCC in the current study. JR inhibited the cell viability of both SMMC-7721 and Huh7 cells in both time- and dose-dependent manners. Transwell assay revealed that JR decreased the number of migrated cells of SMMC-7721 cells. JR treatment increased the E-cadherin expression level and decreased the levels of p-Smad2/3 and Smad2/3. Further study showed that JR reversed the effect of TGFβ1 on the expression of E-cadherin, vimentin, N-cadherin, and MMP2/9. JR also significantly inhibited TGFβ1-induced migration and invasion of SMMC-7721 and Huh7 cells determined by wound healing assay and transwell assay. TGFβ1 treatment increased the phosphorylation of Smad2/3, p38 MAPK, JNK, ERK1/2, and Akt in SMMC-7721 cells and pretreatment with JR blocked TGFβ1-induced activation of Smad2/3 and Akt and MAPKs. In conclusion, JR inhibits liver cancer cells migration and invasion through epithelial mesenchymal transition (EMT) inhibition via Smad2/3 dependent and independent pathways, suggesting it is an effective therapeutic strategy against HCC metastasis.
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Affiliation(s)
- Shufang Liang
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Yong Zou
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Jingdong Gao
- Department of Oncology, Suzhou Hospital of Traditional Chinese Medicine, Suzhou, Jiangsu 215009, China
| | - Xiaolin Liu
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Wanfu Lin
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Zifei Yin
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Juan Du
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Ya'ni Zhang
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Qunwei Chen
- Department of Oncology, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Zhejiang 310006, China
| | - Shu Li
- Department of Gastroenterology, Baoshan Branch, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201900, China
| | - Binbin Cheng
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Changquan Ling
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
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Tran TD, Kwon YK. Hierarchical closeness-based properties reveal cancer survivability and biomarker genes in molecular signaling networks. PLoS One 2018; 13:e0199109. [PMID: 29912931 PMCID: PMC6005509 DOI: 10.1371/journal.pone.0199109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 05/31/2018] [Indexed: 02/06/2023] Open
Abstract
Specific molecular signaling networks underlie different cancer types and quantitative analyses on those cancer networks can provide useful information about cancer treatments. Their structural metrics can reveal survivability of cancer patients and be used to identify biomarker genes for early cancer detection. In this study, we devised a novel structural metric called hierarchical closeness (HC) entropy and found that it was negatively correlated with 5-year survival rates. We also made an interesting observation that a network of higher HC entropy was likely to be more robust against mutations. This finding suggested that cancers of high HC entropy tend to be incurable because their signaling networks are robust to perturbations caused by treatment. We also proposed a novel core identification method based on the reachability factor in the HC measure. The cores were permitted to decompose such that the negative relationship between HC entropy and cancer survival rate was consistently conserved in every core level. Interestingly, we observed that many promising biomarker genes for early cancer detection reside in the innermost core of a signaling network. Taken together, the proposed analyses of the hierarchical structure of cancer signaling networks may be useful in developing future novel cancer treatments.
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Affiliation(s)
- Tien-Dzung Tran
- Complex Systems and Bioinformatics Lab, Hanoi University of Industry, Hanoi, Viet Nam
- * E-mail: (TDT); (YKK)
| | - Yung-Keun Kwon
- School of IT Convergence, University of Ulsan, Ulsan, Republic of Korea
- * E-mail: (TDT); (YKK)
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Eat it right: ER-phagy and recovER-phagy. Biochem Soc Trans 2018; 46:699-706. [PMID: 29802216 PMCID: PMC6008593 DOI: 10.1042/bst20170354] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 04/28/2018] [Accepted: 05/02/2018] [Indexed: 02/06/2023]
Abstract
The endoplasmic reticulum (ER) is the site of protein, lipid, phospholipid, steroid and oligosaccharide synthesis and modification, calcium ion storage, and detoxification of endogenous and exogenous products. Its volume (and activity) must be maintained under normal growth conditions, must be expanded in a controlled manner on activation of ER stress programs and must be reduced to pre-stress size during the recovery phase that follows ER stress termination. ER-phagy is the constitutive or regulated fragmentation and delivery of ER fragments to lysosomal compartments for clearance. It gives essential contribution to the maintenance of cellular homeostasis, proteostasis, lipidostasis and oligosaccharidostasis (i.e. the capacity to produce the proteome, lipidome and oligosaccharidome in appropriate quality and quantity). ER turnover is activated on ER stress, nutrient deprivation, accumulation of misfolded polypeptides, pathogen attack and by activators of macroautophagy. The selectivity of these poorly characterized catabolic pathways is ensured by proteins displayed at the limiting membrane of the ER subdomain to be removed from cells. These proteins are defined as ER-phagy receptors and engage the cytosolic macroautophagy machinery via specific modules that associate with ubiquitin-like, cytosolic proteins of the Atg8/LC3/GABARAP family. In this review, we give an overview on selective ER turnover and on the yeast and mammalian ER-phagy receptors identified so far.
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