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Cheng CY, Chen YL, Ho H, Huang CY, Chu SE, Liang YJ. Prognostic Significance of DNAJB4 Expression in Gastric Cancer: Correlation with CD31, Caspase-3, and Tumor Progression. Diagnostics (Basel) 2025; 15:652. [PMID: 40149995 PMCID: PMC11941126 DOI: 10.3390/diagnostics15060652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 02/28/2025] [Accepted: 03/03/2025] [Indexed: 03/29/2025] Open
Abstract
Background/Objectives: Gastric cancer is one of the most common and lethal cancers worldwide, with particularly high incidence and mortality rates in East Asia and Europe. DNAJB4 has been shown to have prognostic implications in other cancer types; however, its expression patterns and role in gastric cancer have not been extensively studied. This study aimed to analyze DNAJB4 expression in gastric cancer and explore its association with clinical characteristics, molecular markers, and patient outcomes. Methods: We selected suitable tumor samples from 189 gastric cancer patients who had not undergone chemotherapy or radiotherapy, with 188 patients ultimately included in the analysis. Tissue microarray and immunohistochemistry were used to evaluate DNAJB4 expression, and the samples were divided into high- and low-expression groups based on the H-score. Multivariate logistic regression and survival analysis were conducted to identify influencing factors. Results: High DNAJB4 expression was significantly correlated with increased CD31 levels but was inversely associated with advanced cancer stages. Subgroup analysis revealed that in patients with advanced gastric cancer, high DNAJB4 expression was associated with increased caspase-3 levels and with elevated CD31 and decreased E-cadherin levels. Conclusions: High DNAJB4 expression was associated with both angiogenesis and apoptosis, indicating its complex role in gastric cancer progression. Although DNAJB4 promoted angiogenesis by increasing CD31 levels, it may also enhance apoptosis in tumor cells through caspase-3-induced apoptosis.
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Affiliation(s)
- Chiao-Yin Cheng
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei 242062, Taiwan; (C.-Y.C.); (C.-Y.H.)
- Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan; (H.H.); (S.-E.C.)
| | - Yen-Lin Chen
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114201, Taiwan;
| | - Hua Ho
- Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan; (H.H.); (S.-E.C.)
| | - Chun-Yen Huang
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei 242062, Taiwan; (C.-Y.C.); (C.-Y.H.)
- Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan; (H.H.); (S.-E.C.)
| | - Sheng-En Chu
- Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan; (H.H.); (S.-E.C.)
- Department of Emergency Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliu City 640203, Taiwan
| | - Yao-Jen Liang
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei 242062, Taiwan; (C.-Y.C.); (C.-Y.H.)
- Department and Institute of Life Science, Fu-Jen Catholic University, New Taipei 242062, Taiwan
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Yao Y, Liu Y, Lu B, Ji G, Wang L, Dong K, Zhao Z, Lyu D, Wei M, Tu S, Lyu X, Li Y, Huang R, Zhou W, Xu G, Pan X, Cui X. Construction and validation of a regulatory T cells-based classification of renal cell carcinoma: an integrated bioinformatic analysis and clinical cohort study. Cell Oncol (Dordr) 2024:10.1007/s13402-024-01030-9. [PMID: 39714755 DOI: 10.1007/s13402-024-01030-9] [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] [Accepted: 12/18/2024] [Indexed: 12/24/2024] Open
Abstract
PURPOSE Renal cell carcinoma (RCC), exhibiting remarkable heterogeneity, can be highly infiltrated by regulatory T cells (Tregs). However, the relationship between Treg and the heterogeneity of RCC remains to be explored. METHODS We acquired single-cell RNA-seq profiles and 537 bulk RNA-seq profiles of TCGA-KIRC cohort. Through clustering, monocle2 pseudotime and prognostic analyses, we identified Treg states-related prognostic genes (TSRPGs), then constructing the RCC Treg states-related prognostic classification (RCC-TSC). We also explored its prognostic significance and multi-omics landmarks. Additionally, we utilized correlation analysis to establish regulatory networks, and predicted candidate inhibitors. More importantly, in Xinhua cohort of 370 patients with kidney neoplasm, we used immunohistochemical (IHC) staining for classification, then employing statistical analyses including Chi-square tests and multivariate Cox proportional hazards regression analysis to explore its clinical relevance. RESULTS We defined 44 TSRPGs in four different monocle states, and identified high immune infiltration RCC (HIRC, LAG3+, Mki67+) as the highly exhausted subtype with the worst prognosis in RCC-TSC (p < 0.001). BATF-LAG3-immune cells axis might be its underlying metastasis-related mechanism. Immunotherapy and inhibitors including sunitinib potentially conferred best therapeutic effects for HIRC. Furthermore, we successfully validated HIRC subtype as an independent prognostic factor within the Xinhua cohort (OS, HR = 16.68, 95% CI = 1.88-148.1, p = 0.011; PFS, HR = 4.43, 95% CI = 1.55-12.6, p = 0.005). CONCLUSION Through integrated bioinformatics analysis and a large-sample retrospective clinical study, we successfully established RCC-TSC and a diagnostic kit, which could stratify RCC patients with different prognosis and to guide personalized treatment.
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Affiliation(s)
- Yuntao Yao
- Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Yifan Liu
- Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Bingnan Lu
- Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Guo Ji
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lei Wang
- Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Keqin Dong
- Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Zihui Zhao
- Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Donghao Lyu
- Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Maodong Wei
- Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Siqi Tu
- Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Xukun Lyu
- Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Yuanan Li
- Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Runzhi Huang
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
| | - Wang Zhou
- Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
| | - Guofeng Xu
- Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
| | - Xiuwu Pan
- Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
| | - Xingang Cui
- Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
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Zhang J, Wen J, Dai Z, Zhang H, Zhang N, Lei R, Liu Z, Peng L, Cheng Q. Causal association and shared genetics between telomere length and COVID-19 outcomes: New evidence from the latest large-scale summary statistics. Comput Struct Biotechnol J 2024; 23:2429-2441. [PMID: 38882679 PMCID: PMC11176559 DOI: 10.1016/j.csbj.2024.05.012] [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: 11/13/2023] [Revised: 04/24/2024] [Accepted: 05/07/2024] [Indexed: 06/18/2024] Open
Abstract
BACKGROUND Observational studies suggested that leukocyte telomere length (LTL) is shortened in COVID-19 patients. However, the genetic association and causality remained unknown. METHODS Based on the genome-wide association of LTL (N = 472,174) and COVID-19 phenotypes (N = 1086,211-2597,856), LDSC and SUPERGNOVA were used to estimate the genetic correlation. Cross-trait GWAS meta-analysis, colocalization, fine-mapping analysis, and transcriptome-wide association study were conducted to explore the shared genetic etiology. Mendelian randomization (MR) was utilized to infer the causality. Upstream and downstream two-step MR was performed to investigate the potential mediating effects. RESULTS LDSC identified a significant genetic association between LTL and all COVID-19 phenotypes (rG < 0, p < 0.05). Six significant regions were observed for LTL and COVID-19 susceptibility and hospitalization, respectively. Colocalization analysis found rs144204502, rs34517439, and rs56255908 were shared causal variants between LTL and COVID-19 phenotypes. Numerous biological pathways associated with LTL and COVID-19 outcomes were identified, mainly involved in -immune-related pathways. MR showed that longer LTL was significantly associated with a lower risk of COVID-19 severity (OR [95% CI] = 0.81 [0.71-0.92], p = 1.24 ×10-3) and suggestively associated with lower risks of COVID-19 susceptibility (OR [95% CI] = 0.96 [0.92-1.00], p = 3.44 ×10-2) and COVID-19 hospitalization (OR [95% CI] = 0.89 [0.80-0.98], p = 1.89 ×10-2). LTL partially mediated the effects of BMI, smoking, and education on COVID-19 outcomes. Furthermore, six proteins partially mediated the causality of LTL on COVID-19 outcomes, including BNDF, QPCT, FAS, MPO, SFTPB, and APOF. CONCLUSIONS Our findings suggested that shorter LTL was genetically associated with a higher risk of COVID-19 phenotypes, with shared genetic etiology and potential causality.
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Affiliation(s)
- Jingwei Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- Hypothalamic Pituitary Research Centre, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Jie Wen
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- Hypothalamic Pituitary Research Centre, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Ziyu Dai
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- Hypothalamic Pituitary Research Centre, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Hao Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Nan Zhang
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Ruoyan Lei
- Xiangya School of Public Health, Central South University, Changsha, China
| | - Zhixiong Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- Hypothalamic Pituitary Research Centre, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Luo Peng
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- Hypothalamic Pituitary Research Centre, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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Splichal RC, Chen K, Walton SP, Chan C. The Role of Endoplasmic Reticulum Stress on Reducing Recombinant Protein Production in Mammalian Cells. Biochem Eng J 2024; 210:109434. [PMID: 39220803 PMCID: PMC11360842 DOI: 10.1016/j.bej.2024.109434] [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] [Indexed: 09/04/2024]
Abstract
Therapeutic recombinant protein production relies on industrial scale culture of mammalian cells to produce active proteins in quantities sufficient for clinical use. The combination of stresses from industrial cell culture environment and recombinant protein production can overwhelm the protein synthesis machinery in the endoplasmic reticulum (ER). This leads to a buildup of improperly folded proteins which induces ER stress. Cells respond to ER stress by activating the Unfolded Protein Response (UPR). To restore proteostasis, ER sensor proteins reduce global protein synthesis and increase chaperone protein synthesis, and if that is insufficient the proteins are degraded. If proteostasis is still not restored, apoptosis is initiated. Increasing evidence suggests crosstalk between ER proteostasis and DNA damage repair (DDR) pathways. External factors (e.g., metabolites) from the cellular environment as well as internal factors (e.g., transgene copy number) can impact genome stability. Failure to maintain genome integrity reduces cell viability and in turn protein production. This review focuses on the association between ER stress and processes that affect protein production and secretion. The processes mediated by ER stress, including inhibition of global protein translation, chaperone protein production, degradation of misfolded proteins, DNA repair, and protein secretion, impact recombinant protein production. Recombinant protein production can be reduced by ER stress through increased autophagy and protein degradation, reduced protein secretion, and reduced DDR response.
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Affiliation(s)
- R. Chauncey Splichal
- Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA
| | - Kevin Chen
- Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA
| | - S. Patrick Walton
- Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA
| | - Christina Chan
- Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA
- Department of Biochemistry and Molecular Biology, Michigan State University, MI, USA
- Department of Computer Science and Engineering, Michigan State University, MI, USA
- Institute for Quantitative Health Science and Engineering, Division of Medical Devices, Michigan State University, MI, USA
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Chen Y, Li J, Pu L, Hu J, Fang L, Zhou F, Zhang H, Yang Y, Rong X, Deng S, Hou L. DNAJB4 suppresses breast cancer progression and promotes tumor immunity by regulating the Hippo signaling pathway. Discov Oncol 2023; 14:144. [PMID: 37548821 PMCID: PMC10406735 DOI: 10.1007/s12672-023-00762-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 07/31/2023] [Indexed: 08/08/2023] Open
Abstract
PURPOSE Breast cancer is the most common cancer worldwide. Low DNAJB4 expression levels are strongly correlated with poor prognosis in breast cancer patients. However, the molecular mechanism by which DNAJB4 regulates breast cancer progression is unclear. METHODS The expression of DNAJB4 was validated in human breast cancer tissues, normal human breast tissues, and breast cancer cell lines. CCK-8, colony-forming, and wound healing assays were used to assess the biological effect of DNAJB4 overexpression on cell proliferation and migration in MCF-7 cell lines. Bioinformatic analysis was used to identify the DNAJB4 related pathways in breast cancer. Epithelial-mesenchymal transition (EMT)-related biomarkers and Hippo pathway components were quantified by Western blots. Luciferase and Western blot assays were used to validate which miRNA regulates DNAJB4. In addition, the effects of DNAJB4 on in vivo tumor growth were assessed in xenograft models. RESULTS DNAJB4 was expressed at low levels in human breast cancer tissues and breast cancer cell lines and correlated with poor prognosis. DNAJB4 overexpression significantly inhibited cell proliferation and migration in vitro by activating the Hippo pathway. The dual-luciferase assay showed that hsa-miR-183-5p targeted DNAJB4. Moreover, the effects of DNAJB4 could be reversed by miR-183-5p. In addition, the expression of DNAJB4 was strongly correlated with immune infiltration levels. Notably, DNAJB4 overexpression markedly enhanced CD4 + and CD8 + T cells and reduced PD-L1 levels in 4T1 tumors via the Hippo pathway, which retarded tumor growth in a subcutaneous xenograft tumor mouse model of 4T1 cells. CONCLUSIONS The present study demonstrated that DNAJB4 overexpression inhibited the malignant biological behavior of breast cancer by regulating the Hippo pathway and tumor immunosuppressive environment.
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Affiliation(s)
- Yanru Chen
- Academician (Expert) Workstation, Medical Imaging Key Laboratory of Sichuan Province, Biological Targeting Laboratory of Breast Cancer, Department of Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- Medical Imaging Key Laboratory of Sichuan Province, Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Jingjia Li
- Academician (Expert) Workstation, Medical Imaging Key Laboratory of Sichuan Province, Biological Targeting Laboratory of Breast Cancer, Department of Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- Medical Imaging Key Laboratory of Sichuan Province, Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Lulan Pu
- Academician (Expert) Workstation, Medical Imaging Key Laboratory of Sichuan Province, Biological Targeting Laboratory of Breast Cancer, Department of Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- Medical Imaging Key Laboratory of Sichuan Province, Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Jinghua Hu
- Academician (Expert) Workstation, Medical Imaging Key Laboratory of Sichuan Province, Biological Targeting Laboratory of Breast Cancer, Department of Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- Medical Imaging Key Laboratory of Sichuan Province, Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Lingyu Fang
- Academician (Expert) Workstation, Medical Imaging Key Laboratory of Sichuan Province, Biological Targeting Laboratory of Breast Cancer, Department of Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- Medical Imaging Key Laboratory of Sichuan Province, Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Fangfang Zhou
- Academician (Expert) Workstation, Medical Imaging Key Laboratory of Sichuan Province, Biological Targeting Laboratory of Breast Cancer, Department of Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- Medical Imaging Key Laboratory of Sichuan Province, Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Hongying Zhang
- The Fifth People's Hospital of Nanchong City, Nanchong, Sichuan, China
| | - Yi Yang
- Academician (Expert) Workstation, Medical Imaging Key Laboratory of Sichuan Province, Biological Targeting Laboratory of Breast Cancer, Department of Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- Medical Imaging Key Laboratory of Sichuan Province, Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Xinxin Rong
- Academician (Expert) Workstation, Medical Imaging Key Laboratory of Sichuan Province, Biological Targeting Laboratory of Breast Cancer, Department of Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- Medical Imaging Key Laboratory of Sichuan Province, Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Shishan Deng
- Academician (Expert) Workstation, Medical Imaging Key Laboratory of Sichuan Province, Biological Targeting Laboratory of Breast Cancer, Department of Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China.
- Medical Imaging Key Laboratory of Sichuan Province, Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, Sichuan, China.
| | - Lingmi Hou
- Academician (Expert) Workstation, Medical Imaging Key Laboratory of Sichuan Province, Biological Targeting Laboratory of Breast Cancer, Department of Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China.
- Medical Imaging Key Laboratory of Sichuan Province, Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, Sichuan, China.
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Fang F, Mo L, Pan X, Yang Z, Huang H, Zhu L, Wang Y, Jiang G. DNAJB4 promotes triple-negative breast cancer cell apoptosis via activation of the Hippo signaling pathway. Discov Oncol 2023; 14:40. [PMID: 37012515 PMCID: PMC10070573 DOI: 10.1007/s12672-023-00645-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 03/24/2023] [Indexed: 04/05/2023] Open
Abstract
INTRODUCTION Triple-negative breast cancer (TNBC) is currently the most malignant subtype of breast cancer without effective targeted therapies. DNAJB4 (Dnaj heat shock protein family (Hsp40) member B4) is a member of the human heat shock protein family (Hsp40). The clinical significance of DNAJB4 in breast cancer has been reported in our previous study. However, the biological function of DNAJB4 in TNBC cell apoptosis remains unclear to date. METHODS The expression of DNAJB4 in normal breast cells, breast cancer cells, four-paired TNBC tissues, and adjacent noncancerous tissues was quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assay. The role of DNAJB4 in TNBC cell apoptosis was investigated using a number of gain- and loss-of-function in vitro and in vivo assays. The underlying molecular mechanisms in TNBC cell apoptosis were elucidated via Western blot assay. RESULTS DNAJB4 expression was significantly downregulated in TNBC tissues and cell lines. DNAJB4 knockdown inhibited TNBC cell apoptosis and promoted tumorigenicity in vitro and in vivo, but DNAJB4 overexpression resulted in the opposite. Mechanically, DNAJB4 knockdown inhibited TNBC cell apoptosis through suppression of the Hippo signaling pathway, and the result was reversed after DNAJB4 overexpression. CONCLUSIONS DNAJB4 promotes TNBC cell apoptosis by activating the Hippo signaling pathway. Therefore, DNAJB4 may act as a prognostic biomarker and therapeutic target for TNBC.
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Affiliation(s)
- Fang Fang
- Department of Surgery, The Second Affiliated Hospital of Soochow University, 1055 San-Xiang Road, Suzhou, 215004, China
- Department of Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, 241001, China
| | - Linglong Mo
- Department of Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, 241001, China
| | - Xiaofeng Pan
- Department of Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, 241001, China
| | - Ziquan Yang
- Department of Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, 241001, China
| | - Haoyu Huang
- Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu, 241001, China
| | - Liangyu Zhu
- Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu, 241001, China
| | - Yingying Wang
- Department of Nuclear Medicine, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, 241001, China
| | - Guoqin Jiang
- Department of Surgery, The Second Affiliated Hospital of Soochow University, 1055 San-Xiang Road, Suzhou, 215004, China.
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Dicanio M, Giaccherini M, Clay‐Gilmour A, Macauda A, Sainz J, Machiela MJ, Rybicka‐Ramos M, Norman AD, Tyczyńska A, Chanock SJ, Barington T, Kumar SK, Bhatti P, Cozen W, Brown EE, Suska A, Haastrup EK, Orlowski RZ, Dudziński M, Garcia‐Sanz R, Kruszewski M, Martinez‐Lopez J, Beider K, Iskierka‐Jazdzewska E, Pelosini M, Berndt SI, Raźny M, Jamroziak K, Rajkumar SV, Jurczyszyn A, Vangsted AJ, Collado PG, Vogel U, Hofmann JN, Petrini M, Butrym A, Slager SL, Ziv E, Subocz E, Giles GG, Andersen NF, Mazur G, Watek M, Lesueur F, Hildebrandt MAT, Zawirska D, Ebbesen LH, Marques H, Gemignani F, Dumontet C, Várkonyi J, Buda G, Nagler A, Druzd‐Sitek A, Wu X, Kadar K, Camp NJ, Grzasko N, Waller RG, Vachon C, Canzian F, Campa D. A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk. Int J Cancer 2023; 152:239-248. [PMID: 36082445 PMCID: PMC9828677 DOI: 10.1002/ijc.34278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 06/01/2022] [Accepted: 06/07/2022] [Indexed: 01/12/2023]
Abstract
Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10-8 ) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10-7 ). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.
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Affiliation(s)
| | | | - Alyssa Clay‐Gilmour
- Department of Epidemiology and Biostatistics, Arnold School of Public HealthUniversity of South CarolinaGreenvilleSouth CarolinaUSA
| | - Angelica Macauda
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ)HeidelbergGermany
| | - Juan Sainz
- Genomic Oncology Area, GENYO. Center for Genomics and Oncological Research: PfizerUniversity of Granada/Andalusian Regional GovernmentGranadaSpain,Department of HematologyVirgen de las Nieves University HospitalGranadaSpain,Department of MedicineUniversity of GranadaGranadaSpain
| | - Mitchell J. Machiela
- Division of Cancer Epidemiology and Genetics, National Cancer InstituteNational Institues of HealthBethesdaMarylandUSA
| | | | - Aaron D. Norman
- Division of Epidemiology, Department of Health Sciences ResearchMayo ClinicRochesterOntarioUSA,Division of Biomedical Statistics and Informatics, Department of Health Sciences ResearchMayo ClinicRochesterOntarioUSA
| | - Agata Tyczyńska
- Department of Hematology and TransplantologyMedical University of GdańskGdańskPoland
| | - Stephen J. Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer InstituteNational Institues of HealthBethesdaMarylandUSA
| | | | - Shaji K. Kumar
- Division of Hematology, Department of Internal MedicineMayo ClinicRochesterOntarioUSA
| | - Parveen Bhatti
- Cancer Control ResearchBC CancerVancouverCanada,Program in Epidemiology, Public Health Sciences DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA
| | - Wendy Cozen
- Division of Hematology/Oncology, Department of Medicine, School of Medicine, Susan and Henry Samueli College of Health SciencesChao Family Comprehensive Cancer Center, University of CaliforniaIrvineCaliforniaUSA,Department of Pathology, School of Medicine, Susan and Henry Samueli College of Health SciencesChao Family Comprehensive Cancer Center, University of CaliforniaIrvineCaliforniaUSA
| | - Elizabeth E. Brown
- Department of Pathology, School of MedicineUniversity of Alabama at BirminghamBirminghamAlabamaUSA
| | - Anna Suska
- Plasma Cell Dyscrasia Center Department of Hematology Jagiellonian University Faculty of MedicineKrakówPoland
| | | | - Robert Z. Orlowski
- Department of Lymphoma ‐ Myeloma, Division of Cancer MedicineUniversity of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Marek Dudziński
- Department of Hematology, Institute of Medical Sciences, College of Medical SciencesUniversity of RzeszowRzeszowPoland
| | - Ramon Garcia‐Sanz
- Medina A. Department of Hematology, University Hospital of Salamanca (HUS/IBSAL)CIBERONC and Cancer Research Institute of Salamanca‐IBMCC (USAL‐CSIC)SalamancaSpain
| | - Marcin Kruszewski
- Department of HematologyUniversity Hospital No. 2 in BydgoszczBydgoszczPoland
| | | | - Katia Beider
- Hematology Division Chaim Sheba Medical CenterTel HashomerIsrael
| | | | - Matteo Pelosini
- U.O. Dipartimento di EmatologiaAzienda USL Toscana Nord OvestLivornoItaly,Present address:
Ospedale Santa ChiaraPisaItaly
| | - Sonja I. Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer InstituteNational Institues of HealthBethesdaMarylandUSA
| | | | - Krzysztof Jamroziak
- Department of HematologyInstitute of Hematology and Transfusion MedicineWarsawPoland
| | - S. Vincent Rajkumar
- Division of Hematology, Department of Internal MedicineMayo ClinicRochesterOntarioUSA
| | - Artur Jurczyszyn
- Plasma Cell Dyscrasia Center Department of Hematology Jagiellonian University Faculty of MedicineKrakówPoland
| | | | | | - Ulla Vogel
- National Research Center for the Working EnvironmentCopenhagenDenmark
| | - Jonathan N. Hofmann
- Division of Cancer Epidemiology and Genetics, National Cancer InstituteNational Institues of HealthBethesdaMarylandUSA
| | - Mario Petrini
- Hematology Unit, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Aleksandra Butrym
- Department of Cancer Prevention and TherapyWroclaw Medical UniversityWroclawPoland
| | - Susan L. Slager
- Division of Epidemiology, Department of Health Sciences ResearchMayo ClinicRochesterOntarioUSA
| | - Elad Ziv
- Department of MedicineUniversity of California San Francisco Helen Diller Family Comprehensive Cancer CenterSan FranciscoCaliforniaUSA
| | - Edyta Subocz
- Department of HematologyMilitary Institute of MedicineWarsawPoland
| | - Graham G. Giles
- Cancer Epidemiology DivisionCancer Council VictoriaMelbourneVictoriaAustralia,Center for Epidemiology and Biostatistics, School of Population and Global HealthThe University of MelbourneMelbourneVictoriaAustralia,Precision Medicine, School of Clinical Sciences at Monash HealthMonash UniversityClaytonVictoriaAustralia
| | | | - Grzegorz Mazur
- Department of Internal Diseases, Occupational Medicine, Hypertension and Clinical OncologyWroclaw Medical UniversityWroclawPoland
| | - Marzena Watek
- Department of HematologyInstitute of Hematology and Transfusion MedicineWarsawPoland,Department of HematologyHolycross Cancer CenterKielcePoland
| | - Fabienne Lesueur
- Inserm, U900, Institut Curie, PSL Research University, Mines ParisTechParisFrance
| | - Michelle A. T. Hildebrandt
- Department of Lymphoma ‐ Myeloma, Division of Cancer MedicineUniversity of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Daria Zawirska
- Department of HematologyUniversity Hospital in CracowCracowPoland
| | | | - Herlander Marques
- Life and Health Sciences Research Institute (ICVS), School of Health SciencesUniversity of Minho, Braga, Portugal and ICVS/3B's – PT Government Associate LaboratoryBraga/GuimarãesPortugal
| | | | | | - Judit Várkonyi
- Department of Hematology and Internal MedicineSemmelweis UniversityBudapestHungary
| | - Gabriele Buda
- Hematology Unit, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Arnon Nagler
- Hematology Division Chaim Sheba Medical CenterTel HashomerIsrael
| | - Agnieszka Druzd‐Sitek
- Department of Lymphoproliferative DiseasesMaria Skłodowska‐Curie National Research Institute of OncologyWarsawPoland
| | - Xifeng Wu
- Department of Epidemiology, Division of Cancer Prevention and Population SciencesUniversity of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Katalin Kadar
- Department of Hematology and Internal MedicineSemmelweis UniversityBudapestHungary
| | - Nicola J. Camp
- Division of Hematology and Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUtahUSA
| | - Norbert Grzasko
- Department of Experimental HematooncologyMedical University of LublinLublinPoland
| | - Rosalie G. Waller
- Division of Biomedical Statistics and Informatics, Department of Health Sciences ResearchMayo ClinicRochesterOntarioUSA
| | - Celine Vachon
- Division of Epidemiology, Department of Health Sciences ResearchMayo ClinicRochesterOntarioUSA
| | - Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ)HeidelbergGermany
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8
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Genetic Deletion of HLJ1 Does Not Affect Blood Coagulation in Mice. Int J Mol Sci 2022; 23:ijms23042064. [PMID: 35216179 PMCID: PMC8880458 DOI: 10.3390/ijms23042064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/11/2022] [Accepted: 02/11/2022] [Indexed: 12/10/2022] Open
Abstract
HLJ1 (also called DNAJB4) is a member of the DNAJ/Hsp40 family and plays an important role in regulating protein folding and activity. However, there is little information about the role of HLJ1 in the regulation of physiological function. In this study, we investigated the role of HLJ1 in blood coagulation using wild-type C57BL/6 mice and HLJ1-null (HLJ1-/-) mice. Western blot analysis and immunohistochemistry were used to assess the expression and distribution of HLJ1 protein, respectively. The tail bleeding assay was applied to assess the bleeding time and blood loss. A coagulation test was used for measuring the activity of extrinsic, intrinsic and common coagulation pathways. Thromboelastography was used to measure the coagulation parameters in the progression of blood clot formation. The results showed that HLJ1 was detectable in plasma and bone marrow. The distribution of HLJ1 was co-localized with CD41, the marker of platelets and megakaryocytes. However, genetic deletion of HLJ1 did not alter blood loss and the activity of extrinsic and intrinsic coagulation pathways, as well as blood clot formation, compared to wild-type mice. Collectively, these findings suggest that, although HLJ1 appears in megakaryocytes and platelets, it may not play a role in the function of blood coagulation under normal physiological conditions.
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9
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Fang SQ, Liu YH, Zhao KP, Zhang HX, Wang HW, Deng YH, Zhou YX, Ge GB, Ni HM, Chen QL. Transcriptional profiling and network pharmacology analysis identify the potential biomarkers from Chinese herbal formula Huosu Yangwei Formula treated gastric cancer in vivo. Chin J Nat Med 2021; 19:944-953. [PMID: 34961592 DOI: 10.1016/s1875-5364(22)60154-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Indexed: 02/07/2023]
Abstract
Huosu Yangwei (HSYW) Formula is a traditioanl Chinese herbal medicine that has been extensively used to treat chronic atrophic gastritis, precancerous lesions of gastric cancer and advanced gastric cancer. However, the effective compounds of HSYW and its related anti-tumor mechanisms are not completely understood. In the current study, 160 ingredients of HSYW were identified and 64 effective compounds were screened by the ADMET evaluation. Furthermore, 64 effective compounds and 2579 potential targets were mapped based on public databases. Animal experiments demonstrated that HSYW significantly inhibited tumor growth in vivo. Transcriptional profiles revealed that 81 mRNAs were differentially expressed in HSYW-treated N87-bearing Balb/c mice. Network pharmacology and PPI network showed that 12 core genes acted as potential markers to evaluate the curative effects of HSYW. Bioinformatics and qRT-PCR results suggested that HSYW might regulate the mRNA expression of DNAJB4, CALD, AKR1C1, CST1, CASP1, PREX1, SOCS3 and PRDM1 against tumor growth in N87-bearing Balb/c mice.
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Affiliation(s)
- Sheng-Quan Fang
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Yue-Han Liu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Kun-Peng Zhao
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hui-Xing Zhang
- School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hong-Wei Wang
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Yu-Hai Deng
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Yu-Xuan Zhou
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Guang-Bo Ge
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hong-Mei Ni
- School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Qi-Long Chen
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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10
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Collier MP, Benesch JLP. Small heat-shock proteins and their role in mechanical stress. Cell Stress Chaperones 2020; 25:601-613. [PMID: 32253742 PMCID: PMC7332611 DOI: 10.1007/s12192-020-01095-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2020] [Indexed: 12/13/2022] Open
Abstract
The ability of cells to respond to stress is central to health. Stress can damage folded proteins, which are vulnerable to even minor changes in cellular conditions. To maintain proteostasis, cells have developed an intricate network in which molecular chaperones are key players. The small heat-shock proteins (sHSPs) are a widespread family of molecular chaperones, and some sHSPs are prominent in muscle, where cells and proteins must withstand high levels of applied force. sHSPs have long been thought to act as general interceptors of protein aggregation. However, evidence is accumulating that points to a more specific role for sHSPs in protecting proteins from mechanical stress. Here, we briefly introduce the sHSPs and outline the evidence for their role in responses to mechanical stress. We suggest that sHSPs interact with mechanosensitive proteins to regulate physiological extension and contraction cycles. It is likely that further study of these interactions - enabled by the development of experimental methodologies that allow protein contacts to be studied under the application of mechanical force - will expand our understanding of the activity and functions of sHSPs, and of the roles played by chaperones in general.
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Affiliation(s)
- Miranda P Collier
- Department of Biology, Stanford University, 318 Campus Drive, Stanford, CA, 94305, USA
| | - Justin L P Benesch
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
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11
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Bure IV, Nemtsova MV, Zaletaev DV. Roles of E-cadherin and Noncoding RNAs in the Epithelial-mesenchymal Transition and Progression in Gastric Cancer. Int J Mol Sci 2019; 20:ijms20122870. [PMID: 31212809 PMCID: PMC6627057 DOI: 10.3390/ijms20122870] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 06/03/2019] [Accepted: 06/11/2019] [Indexed: 02/08/2023] Open
Abstract
The epithelial–mesenchymal transition (EMT) is thought to be at the root of invasive and metastatic cancer cell spreading. E-cadherin is an important player in this process, which forms the structures that establish and maintain cell–cell interactions. A partial or complete loss of E-cadherin expression in the EMT is presumably mediated by mechanisms that block the expression of E-cadherin regulators and involve the E-cadherin-associated transcription factors. The protein is involved in several oncogenic signaling pathways, such as the Wnt/β-catenin, Rho GTPase, and EGF/EGFR, whereby it plays a role in many tumors, including gastric cancer. Such noncoding transcripts as microRNAs and long noncoding RNAs—critical components of epigenetic control of gene expression in carcinogenesis—contribute to regulation of the E-cadherin function by acting directly or through numerous factors controlling transcription of its gene, and thus affecting not only cancer cell proliferation and metastasis, but also the EMT. This review focuses on the role of E-cadherin and the non-coding RNAs-mediated mechanisms of its expressional control in the EMT during stomach carcinogenesis.
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Affiliation(s)
- Irina V Bure
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia.
| | - Marina V Nemtsova
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia.
- Research Centre for Medical Genetics, Moskvorechie st., 1, Moscow 115522, Russia.
| | - Dmitry V Zaletaev
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia.
- Research Centre for Medical Genetics, Moskvorechie st., 1, Moscow 115522, Russia.
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12
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Endoplasmic reticulum proteostasis control and gastric cancer. Cancer Lett 2019; 449:263-271. [PMID: 30776479 DOI: 10.1016/j.canlet.2019.01.034] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 01/16/2019] [Accepted: 01/26/2019] [Indexed: 02/07/2023]
Abstract
The endoplasmic reticulum (ER) is the primary organelle responsible for the synthesis, modification, folding and secretion of proteins, especially in specialized secretory cells. It also contributes to the maintenance of cellular functions, such as Ca2+ storage, lipogenesis, gluconeogenesis, and organelle biogenesis. Cellular stress conditions, such as glucose deprivation, hypoxia and disturbance of Ca2+ homeostasis, may increase the risk of protein misfolding and perturb proteostasis. This activates ER stress and triggers the unfolded protein response (UPR), leading to either the restoration of homeostasis or cell death. ER stress and UPR have been shown to play crucial roles in the pathogenesis, progression and treatment response of various cancers. In gastric cancer (GC), one of the most aggressive cancer types, critical functions of ER stress signaling have also started to emerge. Herein, we summarize the current knowledge linking ER stress and UPR to GC; we also discuss the possible nodes of therapeutic intervention and propose directions of future research.
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13
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Figueiredo J, Melo S, Carneiro P, Moreira AM, Fernandes MS, Ribeiro AS, Guilford P, Paredes J, Seruca R. Clinical spectrum and pleiotropic nature of CDH1 germline mutations. J Med Genet 2019; 56:199-208. [PMID: 30661051 PMCID: PMC6581119 DOI: 10.1136/jmedgenet-2018-105807] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 12/05/2018] [Accepted: 12/10/2018] [Indexed: 12/12/2022]
Abstract
CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer—the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype–phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin’s pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.
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Affiliation(s)
- Joana Figueiredo
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Soraia Melo
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.,Medical Faculty of the University of Porto, Porto, Portugal
| | - Patrícia Carneiro
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Ana Margarida Moreira
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Medical Faculty of the University of Porto, Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Maria Sofia Fernandes
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.,Institute for Systems and Robotics (ISR/IST), LARSyS, Bioengineering Department, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Ana Sofia Ribeiro
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Parry Guilford
- Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Joana Paredes
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Medical Faculty of the University of Porto, Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Raquel Seruca
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Medical Faculty of the University of Porto, Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
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14
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Zoppino FCM, Guerrero-Gimenez ME, Castro GN, Ciocca DR. Comprehensive transcriptomic analysis of heat shock proteins in the molecular subtypes of human breast cancer. BMC Cancer 2018; 18:700. [PMID: 29954368 PMCID: PMC6022707 DOI: 10.1186/s12885-018-4621-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 06/20/2018] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Heat Shock Proteins (HSPs), a family of genes with key roles in proteostasis, have been extensively associated with cancer behaviour. However, the HSP family is quite large and many of its members have not been investigated in breast cancer (BRCA), particularly in relation with the current molecular BRCA classification. In this work, we performed a comprehensive transcriptomic study of the HSP gene family in BRCA patients from both The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohorts discriminating the BRCA intrinsic molecular subtypes. METHODS We examined gene expression levels of 1097 BRCA tissue samples retrieved from TCGA and 1981 samples of METABRIC, focusing mainly on the HSP family (95 genes). Data were stratified according to the PAM50 gene expression (Luminal A, Luminal B, HER2, Basal, and Normal-like). Transcriptomic analyses include several statistical approaches: differential gene expression, hierarchical clustering and survival analysis. RESULTS Of the 20,531 analysed genes we found that in BRCA almost 30% presented deregulated expression (19% upregulated and 10% downregulated), while of the HSP family 25% appeared deregulated (14% upregulated and 11% downregulated) (|fold change| > 2 comparing BRCA with normal breast tissues). The study revealed the existence of shared HSP genes deregulated in all subtypes of BRCA while other HSPs were deregulated in specific subtypes. Many members of the Chaperonin subfamily were found upregulated while three members (BBS10, BBS12 and CCTB6) were found downregulated. HSPC subfamily had moderate increments of transcripts levels. Various genes of the HSP70 subfamily were upregulated; meanwhile, HSPA12A and HSPA12B appeared strongly downregulated. The strongest downregulation was observed in several HSPB members except for HSPB1. DNAJ members showed heterogeneous expression pattern. We found that 23 HSP genes correlated with overall survival and three HSP-based transcriptional profiles with impact on disease outcome were recognized. CONCLUSIONS We identified shared and specific HSP genes deregulated in BRCA subtypes. This study allowed the recognition of HSP genes not previously associated with BRCA and/or any cancer type, and the identification of three clinically relevant clusters based on HSPs expression patterns with influence on overall survival.
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Affiliation(s)
- Felipe C. M. Zoppino
- Laboratory of Oncology, Institute of Medicine and Experimental Biology of Cuyo (IMBECU), National Scientific and Technical Research Council (CONICET), Av. Dr. Ruiz Leal s/n, Parque General San Martín, 5500 Mendoza, Argentina
| | - Martin E. Guerrero-Gimenez
- Laboratory of Oncology, Institute of Medicine and Experimental Biology of Cuyo (IMBECU), National Scientific and Technical Research Council (CONICET), Av. Dr. Ruiz Leal s/n, Parque General San Martín, 5500 Mendoza, Argentina
| | - Gisela N. Castro
- Laboratory of Oncology, Institute of Medicine and Experimental Biology of Cuyo (IMBECU), National Scientific and Technical Research Council (CONICET), Av. Dr. Ruiz Leal s/n, Parque General San Martín, 5500 Mendoza, Argentina
| | - Daniel R. Ciocca
- Laboratory of Oncology, Institute of Medicine and Experimental Biology of Cuyo (IMBECU), National Scientific and Technical Research Council (CONICET), Av. Dr. Ruiz Leal s/n, Parque General San Martín, 5500 Mendoza, Argentina
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15
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Acun T, Doberstein N, Habermann JK, Gemoll T, Thorns C, Oztas E, Ried T. HLJ1 (DNAJB4) Gene Is a Novel Biomarker Candidate in Breast Cancer. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2018; 21:257-265. [PMID: 28481734 DOI: 10.1089/omi.2017.0016] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Breast cancer is the most common cancer type and cause of cancer-related mortality among women worldwide. New biomarker discovery is crucial for diagnostic innovation and personalized medicine in breast cancer. Heat shock proteins (HSPs) have been increasingly reported as biomarkers and potential drug targets for cancers. HLJ1 (DNAJB4) belongs to the DNAJ (HSP40) family of HSPs and is regarded as a tumor suppressor gene in lung, colon, and gastric cancers. However, the role of the HLJ1 gene in breast cancer is currently unknown. We evaluated the role of the HLJ1 gene in breast cancer progression by analyzing its in vitro and in vivo expression and its genetic/epigenetic alterations. HLJ1 expression was found to be reduced or lost in breast cancer cell lines (SK-BR-3, MDA-MB-231, ZR-75-1) compared with the nontumorigenic mammary epithelial cell line (MCF 10A). In a clinical context for breast cancer progression, the HLJ1 expression was significantly less frequent in invasive breast carcinoma samples (n = 230) compared with normal breast tissue (n = 100), benign neoplasia (n = 53), and ductal carcinoma in situ (n = 21). In methylation analyses by the combined bisulfite restriction analysis assay, the CpG island located in the 5'-flanking region of the HLJ1 gene was found to be methylated in breast cancer cell lines. HLJ1 expression was restored in the ZR-75-1 cell line by DNA demethylating agent 5-Aza-2'-deoxycytidine (5-AzadC) and histone deacetylase inhibitor trichostatin A. These new observations support the idea that HLJ1 is a tumor suppressor candidate and potential biomarker for breast cancer. Epigenomic mechanisms such as CpG methylation and histone deacetylation might contribute to downregulation of HLJ1 expression. We call for future functional, epigenomic, and clinical studies to ascertain the contribution of HLJ1 to breast cancer pathogenesis and, importantly, evaluate its potential for biomarker development in support of personalized medicine diagnostic innovation in clinical oncology.
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Affiliation(s)
- Tolga Acun
- 1 Department of Molecular Biology and Genetics, Bülent Ecevit University , Zonguldak, Turkey
| | - Natalie Doberstein
- 2 Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Medical Center Schleswig-Holstein , Lübeck, Germany
| | - Jens K Habermann
- 2 Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Medical Center Schleswig-Holstein , Lübeck, Germany
| | - Timo Gemoll
- 2 Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Medical Center Schleswig-Holstein , Lübeck, Germany
| | - Christoph Thorns
- 3 Institute of Pathology, University of Lübeck and University Medical Center Schleswig-Holstein , Lübeck, Germany
| | - Emin Oztas
- 4 Department of Medical Histology and Embryology, Gülhane Military Medical Academy , Ankara, Turkey
| | - Thomas Ried
- 5 Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland
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16
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Predicting the Functional Impact of CDH1 Missense Mutations in Hereditary Diffuse Gastric Cancer. Int J Mol Sci 2017; 18:ijms18122687. [PMID: 29231860 PMCID: PMC5751289 DOI: 10.3390/ijms18122687] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 11/28/2017] [Accepted: 11/30/2017] [Indexed: 12/20/2022] Open
Abstract
The role of E-cadherin in Hereditary Diffuse Gastric Cancer (HDGC) is unequivocal. Germline alterations in its encoding gene (CDH1) are causative of HDGC and occur in about 40% of patients. Importantly, while in most cases CDH1 alterations result in the complete loss of E-cadherin associated with a well-established clinical impact, in about 20% of cases the mutations are of the missense type. The latter are of particular concern in terms of genetic counselling and clinical management, as the effect of the sequence variants in E-cadherin function is not predictable. If a deleterious variant is identified, prophylactic surgery could be recommended. Therefore, over the last few years, intensive research has focused on evaluating the functional consequences of CDH1 missense variants and in assessing E-cadherin pathogenicity. In that context, our group has contributed to better characterize CDH1 germline missense variants and is now considered a worldwide reference centre. In this review, we highlight the state of the art methodologies to categorize CDH1 variants, as neutral or deleterious. This information is subsequently integrated with clinical data for genetic counseling and management of CDH1 variant carriers.
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17
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Miller M, Chen A, Gobert V, Augé B, Beau M, Burlet-Schiltz O, Haenlin M, Waltzer L. Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis. PLoS Genet 2017; 13:e1006932. [PMID: 28742844 PMCID: PMC5549762 DOI: 10.1371/journal.pgen.1006932] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 08/08/2017] [Accepted: 07/18/2017] [Indexed: 12/26/2022] Open
Abstract
A tight regulation of transcription factor activity is critical for proper development. For instance, modifications of RUNX transcription factors dosage are associated with several diseases, including hematopoietic malignancies. In Drosophila, Myeloid Leukemia Factor (MLF) has been shown to control blood cell development by stabilizing the RUNX transcription factor Lozenge (Lz). However, the mechanism of action of this conserved family of proteins involved in leukemia remains largely unknown. Here we further characterized MLF's mode of action in Drosophila blood cells using proteomic, transcriptomic and genetic approaches. Our results show that MLF and the Hsp40 co-chaperone family member DnaJ-1 interact through conserved domains and we demonstrate that both proteins bind and stabilize Lz in cell culture, suggesting that MLF and DnaJ-1 form a chaperone complex that directly regulates Lz activity. Importantly, dnaj-1 loss causes an increase in Lz+ blood cell number and size similarly as in mlf mutant larvae. Moreover we find that dnaj-1 genetically interacts with mlf to control Lz level and Lz+ blood cell development in vivo. In addition, we show that mlf and dnaj-1 loss alters Lz+ cell differentiation and that the increase in Lz+ blood cell number and size observed in these mutants is caused by an overactivation of the Notch signaling pathway. Finally, using different conditions to manipulate Lz activity, we show that high levels of Lz are required to repress Notch transcription and signaling. All together, our data indicate that the MLF/DnaJ-1-dependent increase in Lz level allows the repression of Notch expression and signaling to prevent aberrant blood cell development. Thus our findings establish a functional link between MLF and the co-chaperone DnaJ-1 to control RUNX transcription factor activity and Notch signaling during blood cell development in vivo.
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Affiliation(s)
- Marion Miller
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Aichun Chen
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Vanessa Gobert
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Benoit Augé
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Mathilde Beau
- Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Odile Burlet-Schiltz
- Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Marc Haenlin
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Lucas Waltzer
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
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18
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Zhang K, Wang YW, Ma R. Bioinformatics analysis of dysregulated microRNAs in the nipple discharge of patients with breast cancer. Oncol Lett 2017; 13:3100-3108. [PMID: 28521415 PMCID: PMC5431374 DOI: 10.3892/ol.2017.5801] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Accepted: 01/13/2017] [Indexed: 01/18/2023] Open
Abstract
MicroRNAs (miRNAs/miRs) have been reported to be associated with the tumorigenesis and progression of various types of human cancer; however, the underlying mechanisms of this association remain unclear. The aim of the present study was to explore the potential functions of miRNAs in the development of breast cancer using bioinformatics analysis, based on the miRNA expression profile in nipple discharge. A previous study demonstrated the upregulation of miR-3646 and miR-4484, and the downregulation of miR-4732-5p in the nipple discharge of patients with breast cancer, compared with patients with benign breast lesions. In the present study, the target genes of miR-3646, −4484 and −4732-5p were predicted using TargetScan and the MicroRNA Target Prediction and Functional Study Database. The predicted target genes were further analyzed by Gene Ontology term enrichment analysis, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis and protein-protein interaction analysis. Numerous carcinoma-associated genes, including ADIPOQ, CPEB1, DNAJB4, EIF4E, APP and BCLAF1, were revealed to be putative targets of miR-3646, −4484 and −4732-5p. Bioinformatics analysis associated miR-3646 with the Rap1 and TGF-β signaling pathways, miR-4484 with the ErbB, estrogen and focal adhesion signaling pathways, and miR-4732-5p with the proteoglycan signaling pathway. Notably, protein-protein interaction analysis identified that numerous predicted targets of these miRNAs were associated with one other. In addition, the target genes of the miRNAs were identified to be under the regulation of a number of transcription factors (TFs). The predicted target genes of miR-3646, −4484 and −4732-5p were identified to serve a role in cancer-associated signaling pathways and TF-mRNA networks, indicating that they serve a role in breast carcinogenesis and progression. These results provide a comprehensive view of the functions and molecular mechanisms of miR-3646, −4484 and −4732-5p, and will aid in future studies.
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Affiliation(s)
- Kai Zhang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Ya-Wen Wang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Rong Ma
- Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
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19
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Chen W, Zhang J. Potential molecular characteristics in situ in response to repetitive UVB irradiation. Diagn Pathol 2016; 11:129. [PMID: 27829444 PMCID: PMC5103495 DOI: 10.1186/s13000-016-0579-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 10/21/2016] [Indexed: 02/04/2023] Open
Abstract
Background To identify molecular characteristics in situ in response to repetitive UVB (ultraviolet-B) irradiation. Methods Microarray data from the Gene Expression Omnibus were re-analyzed to identify DEGs (differentially expressed genes) between UVB-irradiated and non-irradiated skin biopsies. Enrichment and annotation analyses were performed respectively using DAVID, and TSGene and TAG databases. PPIs (protein-protein interactions) were analyzed using STRING, and miRNAs (microRNAs) and TFs (transcription factors) were predicted separately by miRNA-related databases and ENCODE. Accordingly, the PPI network and regulatory networks were visualized using Cytoscape, and they were merged together to obtain an integrated network for mining densely connected modules. Results Altogether, 151 up- and 64 down-regulated genes were identified between UVB-irradiated and non-irradiated skin biopsies, among which down-regulated DNAJB4 and SLIT2 were annotated as tumor-suppressors and up-regulated KIT was annotated as an oncogene. The up-regulated DEGs were significantly enriched in biological processes related to pigmentation (DCT, SOX10, TYRP1, TYR, MLPH, KIT and GPR143), while the down-regulated DEGs were dramatically related to haemopoiesis and the immune system (GPR183, INHBA, PTPRC, PLEK, CD8A and IKZF1). Furthermore, many miRNAs were screened for the DEGs, including miR-206 and miR-496 targeting KIT, miR-184 targeting DCT, and highly significant miR-337-5p, miR-21 and miR-16. Additionally, TFs were identified for the DEGs, among which PAX5 and HNF4A targeted MLPH and GPR143, respectively, while BATF, SPI1 and EP300 jointly target GPR183, PTPRC and PLEK. Conclusions The pigmentation and immune system implicated by DEGs, miRNAs and TFs might be important molecular mechanisms in response to UVB irradiation.
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Affiliation(s)
- Wenqi Chen
- Department of Dermatology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu, 210006, China.
| | - Jinhai Zhang
- Department of Epidemiology, Research Institute for Medicine of Nanjing Command, Nanjing, China
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20
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Rhodes CJ, Im H, Cao A, Hennigs JK, Wang L, Sa S, Chen PI, Nickel NP, Miyagawa K, Hopper RK, Tojais NF, Li CG, Gu M, Spiekerkoetter E, Xian Z, Chen R, Zhao M, Kaschwich M, Del Rosario PA, Bernstein D, Zamanian RT, Wu JC, Snyder MP, Rabinovitch M. RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 2015; 192:356-66. [PMID: 26030479 DOI: 10.1164/rccm.201408-1528oc] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
RATIONALE Pulmonary arterial hypertension is characterized by endothelial dysregulation, but global changes in gene expression have not been related to perturbations in function. OBJECTIVES RNA sequencing was used to discriminate changes in transcriptomes of endothelial cells cultured from lungs of patients with idiopathic pulmonary arterial hypertension versus control subjects and to assess the functional significance of major differentially expressed transcripts. METHODS The endothelial transcriptomes from the lungs of seven control subjects and six patients with idiopathic pulmonary arterial hypertension were analyzed. Differentially expressed genes were related to bone morphogenetic protein type 2 receptor (BMPR2) signaling. Those down-regulated were assessed for function in cultured cells and in a transgenic mouse. MEASUREMENTS AND MAIN RESULTS Fold differences in 10 genes were significant (P < 0.05), four increased and six decreased in patients versus control subjects. No patient was mutant for BMPR2. However, knockdown of BMPR2 by siRNA in control pulmonary arterial endothelial cells recapitulated 6 of 10 patient-related gene changes, including decreased collagen IV (COL4A1, COL4A2) and ephrinA1 (EFNA1). Reduction of BMPR2-regulated transcripts was related to decreased β-catenin. Reducing COL4A1, COL4A2, and EFNA1 by siRNA inhibited pulmonary endothelial adhesion, migration, and tube formation. In mice null for the EFNA1 receptor, EphA2, versus control animals, vascular endothelial growth factor receptor blockade and hypoxia caused more severe pulmonary hypertension, judged by elevated right ventricular systolic pressure, right ventricular hypertrophy, and loss of small arteries. CONCLUSIONS The novel relationship between BMPR2 dysfunction and reduced expression of endothelial COL4 and EFNA1 may underlie vulnerability to injury in pulmonary arterial hypertension.
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Affiliation(s)
- Christopher J Rhodes
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,3 Department of Pediatrics
| | - Hogune Im
- 2 Cardiovascular Institute.,4 Department of Genetics, and
| | - Aiqin Cao
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,3 Department of Pediatrics
| | - Jan K Hennigs
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,3 Department of Pediatrics
| | - Lingli Wang
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,3 Department of Pediatrics
| | - Silin Sa
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,3 Department of Pediatrics
| | - Pin-I Chen
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,3 Department of Pediatrics
| | - Nils P Nickel
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,3 Department of Pediatrics
| | - Kazuya Miyagawa
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,3 Department of Pediatrics
| | - Rachel K Hopper
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,3 Department of Pediatrics
| | - Nancy F Tojais
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,3 Department of Pediatrics
| | - Caiyun G Li
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,3 Department of Pediatrics
| | - Mingxia Gu
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,3 Department of Pediatrics
| | - Edda Spiekerkoetter
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,5 Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Zhaoying Xian
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,3 Department of Pediatrics
| | - Rui Chen
- 2 Cardiovascular Institute.,4 Department of Genetics, and
| | - Mingming Zhao
- 2 Cardiovascular Institute.,3 Department of Pediatrics
| | - Mark Kaschwich
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,3 Department of Pediatrics
| | - Patricia A Del Rosario
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,5 Department of Medicine, Stanford University School of Medicine, Stanford, California
| | | | - Roham T Zamanian
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,5 Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Joseph C Wu
- 2 Cardiovascular Institute.,5 Department of Medicine, Stanford University School of Medicine, Stanford, California
| | | | - Marlene Rabinovitch
- 1 Vera Moulton Wall Center for Pulmonary Vascular Diseases.,2 Cardiovascular Institute.,3 Department of Pediatrics
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21
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Caldeira J, Figueiredo J, Brás-Pereira C, Carneiro P, Moreira AM, Pinto MT, Relvas JB, Carneiro F, Barbosa M, Casares F, Janody F, Seruca R. E-cadherin-defective gastric cancer cells depend on Laminin to survive and invade. Hum Mol Genet 2015; 24:5891-900. [PMID: 26246502 DOI: 10.1093/hmg/ddv312] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 07/29/2015] [Indexed: 01/05/2023] Open
Abstract
Epithelial-cadherin (Ecad) deregulation affects cell-cell adhesion and results in increased invasiveness of distinct human carcinomas. In gastric cancer, loss of Ecad expression is a common event and is associated with disease aggressiveness and poor prognosis. However, the molecular mechanisms underlying the invasive process associated to Ecad dysfunction are far from understood. We hypothesized that deregulation of cell-matrix interactions could play an important role during this process. Thus, we focussed on LM-332, which is a major matrix component, and in Ecad/LM-332 crosstalk in the process of Ecad-dependent invasion. To verify whether matrix deregulation was triggered by Ecad loss, we used the Drosophila model. To dissect the key molecules involved and unveil their functional significance, we used gastric cancer cell lines. The relevance of this relationship was then confirmed in human primary tumours. In vivo, Ecad knockdown induced apoptosis; nonetheless, at the invasive front, cells ectopically expressed Laminin A and βPS integrin. In vitro, we demonstrated that, in two different gastric cancer cell models, Ecad-defective cells overexpressed Laminin γ2 (LM-γ2), β1 and β4 integrin, when compared with Ecad-competent ones. We showed that LM-γ2 silencing impaired invasion and enhanced cell death, most likely via pSrc and pAkt reduction, and JNK activation. In human gastric carcinomas, we found a concomitant decrease in Ecad and increase in LM-γ2. This is the first evidence that ectopic Laminin expression depends on Ecad loss and allows Ecad-dysfunctional cells to survive and invade. This opens new avenues for using LM-γ2 signalling regulators as molecular targets to impair gastric cancer progression.
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Affiliation(s)
- Joana Caldeira
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Andalusian Centre for Developmental Biology (CABD), Seville, Spain, Instituto de Engenharia Biomédica (INEB), Instituto de Investigação e Inovação em Saúde (i3S)
| | - Joana Figueiredo
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Instituto de Investigação e Inovação em Saúde (i3S)
| | | | - Patrícia Carneiro
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Instituto de Investigação e Inovação em Saúde (i3S)
| | - Ana M Moreira
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Instituto de Investigação e Inovação em Saúde (i3S)
| | - Marta T Pinto
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Instituto de Investigação e Inovação em Saúde (i3S)
| | - João B Relvas
- Instituto de Investigação e Inovação em Saúde (i3S), Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal
| | - Fátima Carneiro
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Instituto de Investigação e Inovação em Saúde (i3S), Department of Pathology and Oncology, Medical Faculty of the University of Porto, Porto, Portugal, Centro Hospitalar São João, Porto, Portugal and
| | - Mário Barbosa
- Instituto de Engenharia Biomédica (INEB), Instituto de Investigação e Inovação em Saúde (i3S), Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto (ICBAS), Porto, Portugal
| | - Fernando Casares
- Andalusian Centre for Developmental Biology (CABD), Seville, Spain
| | | | - Raquel Seruca
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Instituto de Investigação e Inovação em Saúde (i3S), Department of Pathology and Oncology, Medical Faculty of the University of Porto, Porto, Portugal,
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Tsai MF, Wang CC, Chen JJW. Tumour suppressor HLJ1: A potential diagnostic, preventive and therapeutic target in non-small cell lung cancer. World J Clin Oncol 2014; 5:865-873. [PMID: 25493224 PMCID: PMC4259948 DOI: 10.5306/wjco.v5.i5.865] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 02/10/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related mortality throughout the world. Non-small cell lung cancer (NSCLC) accounts for 85% of all diagnosed lung cancers. Despite considerable progress in the diagnosis and treatment of the disease, the overall 5-year survival rate of NSCLC patients remains lower than 15%. The most common causes of death in lung cancer patients are treatment failure and metastasis. Therefore, developing novel strategies that target both tumour growth and metastasis is an important and urgent mission for the next generation of anticancer therapy research. Heat shock proteins (HSPs), which are involved in the fundamental defence mechanism for maintaining cellular viability, are markedly activated during environmental or pathogenic stress. HSPs facilitate rapid cell division, metastasis, and the evasion of apoptosis in cancer development. These proteins are essential players in the development of cancer and are prime therapeutic targets. In this review, we focus on the current understanding of the molecular mechanisms responsible for HLJ1’s role in lung cancer carcinogenesis and progression. HLJ1, a member of the human HSP 40 family, has been characterised as a tumour suppressor. Research studies have also reported that HLJ1 shows promising dual anticancer effects, inhibiting both tumour growth and metastasis in NSCLC. The accumulated evidence suggests that HLJ1 is a potential biomarker and treatment target for NSCLC.
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