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Gatti PHF, Mangone FRR, Pavanelli AC, Nonogaki S, Osorio CABDT, Capelozzi VL, Nagai MA. Downregulation of DNAJC12 Expression Predicts Worse Survival for ER-Positive Breast Cancer Patients. Biomark Insights 2025; 20:11772719251323095. [PMID: 40008192 PMCID: PMC11851741 DOI: 10.1177/11772719251323095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
Background DNAJC12 (DnaJ heat shock protein family (Hsp40) member C12) encodes a member of the molecular chaperone Hsp40/DnaJ family, which are important protein folding and proteostasis regulators. Its role as a biomarker has been studied for a limited number of cancer types. Objectives: Here, we sought to investigate the potential of DNAJC12 mRNA and protein expression as a prognostic and predictive biomarker for breast cancer (BC). Methods Using in silico analysis and data from immunohistochemistry analysis (IHC) of 292 samples from patients with primary BC, we determined the expression pattern and prognostic value of DNAJC12 mRNA and protein expression. Results From online publicly available data, we were able to identify the transcripts of DNAJC12 as differentially expressed in patients with different clinicopathological characteristics, such as ER status (P < .001), PR status (P < .001), HER2 status (P < .010) and molecular subtype (P ⩽ .001). We also found DNAJC12 to be a potential prognostic predictor for overall survival, disease-free survival, and responsiveness to treatment; a low DNAJC12 mRNA expression is commonly associated with a worse prognosis. Using IHC analysis, we showed that low DNAJC12 protein-level expression is also associated with a worse prognosis in patients with all subtypes of BC and patients with Luminal BC, and its expression is significantly different between patients with different tumor size classifications (T1/T2 vs T3/T4; P = .013) or with different lymph node involvement (N0 vs N+; P = .005). Conclusion Our findings suggested a potential role for DNAJC12 as a prognostic and predictive biomarker for BC.
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Affiliation(s)
- Pedro Henrique Fernandes Gatti
- Laboratory of Molecular Genetics, Centro de Investigação Translacional em Oncologia-CTO, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
- Comprehensive Center for Precision Oncology (C2PO), Universidade de São Paulo, São Paulo, Brazil
| | - Flavia Regina Rotea Mangone
- Laboratory of Molecular Genetics, Centro de Investigação Translacional em Oncologia-CTO, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
- Comprehensive Center for Precision Oncology (C2PO), Universidade de São Paulo, São Paulo, Brazil
| | - Ana Carolina Pavanelli
- Laboratory of Molecular Genetics, Centro de Investigação Translacional em Oncologia-CTO, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
- Comprehensive Center for Precision Oncology (C2PO), Universidade de São Paulo, São Paulo, Brazil
| | - Suely Nonogaki
- Departamento de Patologia, A.C.Camargo Cancer Center, São Paulo, Brazil
| | | | - Vera Luiza Capelozzi
- Department of Pathology, University of São Paulo Medical School, São Paulo, Brazil
| | - Maria Aparecida Nagai
- Laboratory of Molecular Genetics, Centro de Investigação Translacional em Oncologia-CTO, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
- Comprehensive Center for Precision Oncology (C2PO), Universidade de São Paulo, São Paulo, Brazil
- Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo (USP), São Paulo, Brazil
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Nakamura ET, Park A, Pereira MA, Kikawa D, Tustumi F. Prognosis value of heat-shock proteins in esophageal and esophagogastric cancer: A systematic review and meta-analysis. World J Gastrointest Oncol 2024; 16:1578-1595. [PMID: 38660660 PMCID: PMC11037039 DOI: 10.4251/wjgo.v16.i4.1578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 12/24/2023] [Accepted: 01/23/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Heat shock proteins (HSPs) are molecular chaperones that play an important role in cellular protection against stress events and have been reported to be overexpressed in many cancers. The prognostic significance of HSPs and their regulatory factors, such as heat shock factor 1 (HSF1) and CHIP, are poorly understood. AIM To investigate the relationship between HSP expression and prognosis in esophageal and esophagogastric cancer. METHODS A systematic review was conducted in accordance with PRISMA recommendations (PROSPERO: CRD42022370653), on Embase, PubMed, Cochrane, and LILACS. Cohort, case-control, and cross-sectional studies of patients with esophagus or esophagogastric cancer were included. HSP-positive patients were compared with HSP-negative, and the endpoints analyzed were lymph node metastasis, tumor depth, distant metastasis, and overall survival (OS). HSPs were stratified according to the HSP family, and the summary risk difference (RD) was calculated using a random-effect model. RESULTS The final selection comprised 27 studies, including esophageal squamous cell carcinoma (21), esophagogastric adenocarcinoma (5), and mixed neoplasms (1). The pooled sample size was 3465 patients. HSP40 and 60 were associated with a higher 3-year OS [HSP40: RD = 0.22; 95% confidence interval (CI): 0.09-0.35; HSP60: RD = 0.33; 95%CI: 0.17-0.50], while HSF1 was associated with a poor 3-year OS (RD = -0.22; 95%CI: -0.32 to -0.12). The other HSP families were not associated with long-term survival. HSF1 was associated with a higher probability of lymph node metastasis (RD = -0.16; 95%CI: -0.29 to -0.04). HSP40 was associated with a lower probability of lymph node dissemination (RD = 0.18; 95%CI: 0.03-0.33). The expression of other HSP families was not significantly related to tumor depth and lymph node or distant metastasis. CONCLUSION The expression levels of certain families of HSP, such as HSP40 and 60 and HSF1, are associated with long-term survival and lymph node dissemination in patients with esophageal and esophagogastric cancer.
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Affiliation(s)
- Eric Toshiyuki Nakamura
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
- Department of Scientific Initiation, Universidade Mogi das Cruzes, São Paulo 08780911, Brazil
| | - Amanda Park
- Department of Evidence-Based Medicine, Centro Universitário Lusíada, Centre for Evidence-Based Medicine, Centro Universitário Lusíada (UNILUS), Santos, Brazil
| | - Marina Alessandra Pereira
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
| | - Daniel Kikawa
- Department of Scientific Initiation, Universidade Mogi das Cruzes, São Paulo 08780911, Brazil
| | - Francisco Tustumi
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
- Department of Surgery, Hospital Israelita Albert Einstein, São Paulo 05652900, Brazil
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Shen M, Cao S, Long X, Xiao L, Yang L, Zhang P, Li L, Chen F, Lei T, Gao H, Ye F, Bu H. DNAJC12 causes breast cancer chemotherapy resistance by repressing doxorubicin-induced ferroptosis and apoptosis via activation of AKT. Redox Biol 2024; 70:103035. [PMID: 38306757 PMCID: PMC10847378 DOI: 10.1016/j.redox.2024.103035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 01/03/2024] [Accepted: 01/07/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND Chemotherapy is a primary treatment for breast cancer (BC), yet many patients develop resistance over time. This study aims to identify critical factors contributing to chemoresistance and their underlying molecular mechanisms, with a focus on reversing this resistance. METHODS We utilized samples from the Gene Expression Omnibus (GEO) and West China Hospital to identify and validate genes associated with chemoresistance. Functional studies were conducted using MDA-MB-231 and MCF-7 cell lines, involving gain-of-function and loss-of-function approaches. RNA sequencing (RNA-seq) identified potential mechanisms. We examined interactions between DNAJC12, HSP70, and AKT using co-immunoprecipitation (Co-IP) assays and established cell line-derived xenograft (CDX) models for in vivo validations. RESULTS Boruta analysis of four GEO datasets identified DNAJC12 as highly significant. Patients with high DNAJC12 expression showed an 8 % pathological complete response (pCR) rate, compared to 38 % in the low expression group. DNAJC12 inhibited doxorubicin (DOX)-induced cell death through both ferroptosis and apoptosis. Combining apoptosis and ferroptosis inhibitors completely reversed DOX resistance caused by DNAJC12 overexpression. RNA-seq suggested that DNAJC12 overexpression activated the PI3K-AKT pathway. Inhibition of AKT reversed the DOX resistance induced by DNAJC12, including reduced apoptosis and ferroptosis, restoration of cleaved caspase 3, and decreased GPX4 and SLC7A11 levels. Additionally, DNAJC12 was found to increase AKT phosphorylation in an HSP70-dependent manner, and inhibiting HSP70 also reversed the DOX resistance. In vivo studies confirmed that AKT inhibition reversed DNAJC12-induced DOX resistance in the CDX model. CONCLUSION DNAJC12 expression is closely linked to chemoresistance in BC. The DNAJC12-HSP70-AKT signaling axis is crucial in mediating resistance to chemotherapy by suppressing DOX-induced ferroptosis and apoptosis. Our findings suggest that targeting AKT and HSP70 activities may offer new therapeutic strategies to overcome chemoresistance in BC.
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Affiliation(s)
- Mengjia Shen
- Department of Pathology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan, China; Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Shiyu Cao
- Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xinyi Long
- Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Lin Xiao
- Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Libo Yang
- Department of Pathology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan, China; Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Peichuan Zhang
- Institute of Thoracic Oncology and Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Li Li
- Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Fei Chen
- Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Ting Lei
- Department of Pathology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China
| | - Hongwei Gao
- Laboratory Medicine Center, Lanzhou University Second Hospital, The Second Clinical Medical College of Lanzhou University, Lanzhou 730000, China
| | - Feng Ye
- Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Key Lab of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Hong Bu
- Department of Pathology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan, China; Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Key Lab of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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Mazurakova A, Solarova Z, Koklesova L, Caprnda M, Prosecky R, Khakymov A, Baranenko D, Kubatka P, Mirossay L, Kruzliak P, Solar P. Heat shock proteins in cancer - Known but always being rediscovered: Their perspectives in cancer immunotherapy. Adv Med Sci 2023; 68:464-473. [PMID: 37926002 DOI: 10.1016/j.advms.2023.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/14/2023] [Accepted: 10/16/2023] [Indexed: 11/07/2023]
Abstract
Heat shock proteins (HSPs) represent cellular chaperones that are classified into several families, including HSP27, HSP40, HSP60, HSP70, and HSP90. The role of HSPs in the cell includes the facilitation of protein folding and maintaining protein structure. Both processes play crucial roles during stress conditions in the cell such as heat shock, degradation, and hypoxia. Moreover, HSPs are important modulators of cellular proliferation and differentiation, and are strongly associated with the molecular orchestration of carcinogenesis. The expression and/or activity of HSPs in cancer cells is generally abnormally high and is associated with increased metastatic potential and activity of cancer stem cells, more pronounced angiogenesis, downregulated apoptosis, and the resistance to anticancer therapy in many patients. Based on the mentioned reasons, HSPs have strong potential as valid diagnostic, prognostic, and therapeutic biomarkers in clinical oncology. In addition, numerous papers describe the role of HSPs as chaperones in the regulation of immune responses inside and outside the cell. Importantly, highly expressed/activated HSPs may be inhibited via immunotherapeutic targets in various types of cancers. The aim of this work is to provide a comprehensive overview of the relationship between HSPs and the tumor cell with the intention of highlighting the potential use of HSPs in personalized cancer management.
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Affiliation(s)
- Alena Mazurakova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Zuzana Solarova
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Martin Caprnda
- 1st Department of Internal Medicine, Faculty of Medicine, Comenius University and University Hospital, Bratislava, Slovakia
| | - Robert Prosecky
- 2nd Department of Internal Medicine, Faculty of Medicine, Masaryk University and St. Anne's University Hospital, Brno, Czech Republic; International Clinical Research Centre, St. Anne's University Hospital and Masaryk University, Brno, Czech Republic
| | - Artur Khakymov
- International Research Centre "Biotechnologies of the Third Millennium", Faculty of Biotechnologies (BioTech), ITMO University, Saint-Petersburg, Russian Federation
| | - Denis Baranenko
- International Research Centre "Biotechnologies of the Third Millennium", Faculty of Biotechnologies (BioTech), ITMO University, Saint-Petersburg, Russian Federation
| | - Peter Kubatka
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Ladislav Mirossay
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia
| | - Peter Kruzliak
- 2nd Department of Surgery, Faculty of Medicine, Masaryk University and St. Anne's University Hospital, Brno, Czech Republic.
| | - Peter Solar
- Department of Medical Biology, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia.
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Fan YC, Meng ZY, Zhang CS, Wei DW, Wei WS, Xie XD, Huang ML, Jiang LH. DNAJ heat shock protein family member C1 can regulate proliferation and migration in hepatocellular carcinoma. PeerJ 2023; 11:e15700. [PMID: 37520264 PMCID: PMC10386825 DOI: 10.7717/peerj.15700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 06/14/2023] [Indexed: 08/01/2023] Open
Abstract
Background DNAJ heat shock protein family (Hsp40) member C1(DNAJC1) is a member of the DNAJ family. Some members of the DNAJ gene family had oncogenic properties in many cancers. However, the role of DNAJC1 in hepatocellular carcinoma (HCC) was unclear. Methods In this study, expression and prognostic value of DNAJC1 in HCC were analyzed by bioinformatics. Quantitative real-time PCR and Western blotting were used to verify DNAJC1 expression in liver cancer cell lines. Furthermore, immunohistochemical (IHC) was used to detect DNAJC1 expression in liver cancer tissues. Subsequently, the effect of DNAJC1 on the proliferation, migration, invasion and apoptosis of HCC cells was detected by knocking down DNAJC1. Finally, gene set enrichment analysis (GSEA) was used to investigate the potential mechanism of DNAJC1 and was verified by Western blotting. Results DNAJC1 was highly expressed in HCC and was significantly associated with the prognosis of patients with HCC. Importantly, the proliferation, migration and invasion of Huh7 and MHCC97H cells were inhibited by the knockdown of DNAJC1 and the knockdown of DNAJC1 promoted Huh7 and MHCC97H cell apoptosis. Furthermore, compared to the negative control group, DNAJC1 knockdown in Huh7 and MHCC97H cells promoted the expression of p21, p53, p-p53(Ser20), Bax and E-cadherin proteins, while inhibiting the expression of PARP, MMP9, Vimentin, Snai1, Bcl-2 and N-cadherin proteins. Conclusions DNAJC1 had a predictive value for the prognosis of HCC. Knockdown of DNAJC1 may inhibit HCC cell proliferation, migration and invasion and promote the HCC cell apoptosis through p53 and EMT signaling pathways.
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Affiliation(s)
- Yu-Chun Fan
- Medical College, Guangxi University, Nanning, Guangxi, China
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, China
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Zhejiang, China
| | - Zhi-Yong Meng
- First Clinical Medical College, Guangxi Traditional Chinese Medical University, Nanning, China
| | - Chao-Sheng Zhang
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, China
| | - De-Wei Wei
- School of Stomatology, Youjiang Medical University for Nationalities, Baise, China
| | - Wan-Shuo Wei
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, China
| | - Xian-Dong Xie
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, China
| | - Ming-Lu Huang
- School of Stomatology, Youjiang Medical University for Nationalities, Baise, China
| | - Li-He Jiang
- Medical College, Guangxi University, Nanning, Guangxi, China
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, China
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Zhejiang, China
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Shanxi, China
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Ramos INDF, da Silva MF, Lopes JMS, Cruz JN, Alves FS, do Rego JDAR, Costa MLD, Assumpção PPD, Barros Brasil DDS, Khayat AS. Extraction, Characterization, and Evaluation of the Cytotoxic Activity of Piperine in Its Isolated form and in Combination with Chemotherapeutics against Gastric Cancer. Molecules 2023; 28:5587. [PMID: 37513459 PMCID: PMC10385350 DOI: 10.3390/molecules28145587] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 06/30/2023] [Accepted: 07/05/2023] [Indexed: 07/30/2023] Open
Abstract
Gastric cancer is one of the most frequent types of neoplasms worldwide, usually presenting as aggressive and difficult-to-manage tumors. The search for new structures with anticancer potential encompasses a vast research field in which natural products arise as promising alternatives. In this scenario, piperine, an alkaloid of the Piper species, has received attention due to its biological activity, including anticancer attributes. The present work proposes three heating-independent, reliable, low-cost, and selective methods for obtaining piperine from Piper nigrum L. (Black pepper). Electronic (SEM) and optical microscopies, X-ray diffraction, nuclear magnetic resonance spectroscopies (13C and 1H NMR), and optical spectroscopies (UV-Vis, photoluminescence, and FTIR) confirm the obtention of piperine crystals. The MTT assay reveals that the piperine samples exhibit good cytotoxic activity against primary and metastasis models of gastric cancer cell lines from the Brazilian Amazon. The samples showed selective cytotoxicity on the evaluated models, revealing higher effectiveness in cells bearing a higher degree of aggressiveness. Moreover, the investigated piperine crystals demonstrated the ability to act as a good cytotoxicity enhancer when combined with traditional chemotherapeutics (5-FU and GEM), allowing the drugs to achieve the same cytotoxic effect in cells employing lower concentrations. These results establish piperine as a promising molecule for therapy investigations in aggressive gastric cancer, both in its isolated form or as a bioenhancer.
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Affiliation(s)
| | | | | | - Jordy Neves Cruz
- Institute of Technology, Federal University of Pará, Belém 66075-110, PA, Brazil
| | - Fabrine Silva Alves
- Graduate Program in Pharmaceutical Innovation, Federal University of Pará, Belém 66075-110, PA, Brazil
| | | | | | | | - Davi do Socorro Barros Brasil
- Institute of Technology, Federal University of Pará, Belém 66075-110, PA, Brazil
- Graduate Program in Pharmaceutical Innovation, Federal University of Pará, Belém 66075-110, PA, Brazil
- Graduate Program in Science and Environment, Federal University of Pará, Belém 66075-110, PA, Brazil
| | - André Salim Khayat
- Oncology Research Center, Federal University of Pará, Belém 66075-110, PA, Brazil
- Institute of Biological Science, Federal University of Pará, Belém 66075-110, PA, Brazil
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Sun Q, Lv Y, Sun W. Inhibition of DNAJC12 Inhibited Tumorigenesis of Rectal Cancer via Downregulating HSPA4 Expression. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:1027895. [PMID: 36185081 PMCID: PMC9519347 DOI: 10.1155/2022/1027895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/08/2022] [Accepted: 08/20/2022] [Indexed: 11/18/2022]
Abstract
Background Dysregulation of DnaJ heat shock protein family (HSP40) member C12 (DNAJC12) is implicated in the malignancy progression of multiple cancers. The current study aimed to determine the biology function and mechanism of DNAJC12 in rectal cancer (RC). Methods RC tissues, adjacent tissues, RC cell lines, and normal colorectal epithelial cell lines were collected to analyze DNAJC12 expression. The abilities of DNAJC12 on proliferation, migration, and apoptosis of RC cells were detected by CCK-8, wound healing, and flow cytometry assays. Co-IP assays were carried out to confirm the association between DNAJC12 and HSPA4. The effect of DNAJC12 on tumor growth was detected by using the xenograft model of nude mice. Results Elevation of DNAJC12 was uncovered in RC tissues and cell lines. DNAJC12 upregulation facilitated RC cell proliferation and migration and induced apoptosis, while DNAJC12 interference showed the opposite results. Besides, HSAP4 served as a potential binding protein for DNAJC12. Rescue experiments revealed that elevated of HSAP4 restored the impact of DNAJC12 silencing on the cell functions. Finally, DNAJC12 silencing hampered tumor growth of RC in vivo. Conclusion In summary, this study highlighted a key player of DNAJC12 in modulating the malignant biological progression of RC via DNAJC12/HSPA4 axis, displaying a potential therapeutic target for RC.
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Affiliation(s)
- Qi Sun
- Third Ward of Cancer Center, The PLA Navy Anqing Hospital, Anqing 246003, Anhui, China
| | - Yan Lv
- Department of Oncology, Qingdao Municipal Hospital, Qingdao 266071, Shandong, China
| | - Weihua Sun
- Department of Oncology, Qingdao Municipal Hospital, Qingdao 266071, Shandong, China
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8
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Javid H, Hashemian P, Yazdani S, Sharbaf Mashhad A, Karimi-Shahri M. The role of heat shock proteins in metastatic colorectal cancer: A review. J Cell Biochem 2022; 123:1704-1735. [PMID: 36063530 DOI: 10.1002/jcb.30326] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 08/20/2022] [Accepted: 08/24/2022] [Indexed: 01/18/2023]
Abstract
Heat shock proteins (HSPs) are a large molecular chaperone family classified by their molecular weights, including HSP27, HSP40, HSP60, HSP70, HSP90, and HSP110. HSPs are likely to have antiapoptotic properties and participate actively in various processes such as tumor cell proliferation, invasion, metastases, and death. In this review, we discuss comprehensively the functions of HSPs associated with the progression of colorectal cancer (CRC) and metastasis and resistance to cancer therapy. Taken together, HSPs have numerous clinical applications as biomarkers for cancer diagnosis and prognosis and potential therapeutic targets for CRC and its related metastases.
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Affiliation(s)
- Hossein Javid
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran
| | - Pedram Hashemian
- Jahad Daneshgahi Research Committee, Jahad Daneshgahi Institute, Mashhad, Iran
| | - Shaghayegh Yazdani
- Department of Medical Laboratory Sciences, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Laboratory Sciences, Ilam University of Medical Sciences, Ilam, Iran
| | - Alireza Sharbaf Mashhad
- Department of Medical Laboratory Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehdi Karimi-Shahri
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pathology, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
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Smith JL, Wilson ML, Nilson SM, Rowan TN, Schnabel RD, Decker JE, Seabury CM. Genome-wide association and genotype by environment interactions for growth traits in U.S. Red Angus cattle. BMC Genomics 2022; 23:517. [PMID: 35842584 PMCID: PMC9287884 DOI: 10.1186/s12864-022-08667-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 05/27/2022] [Indexed: 11/10/2022] Open
Abstract
Background Genotypic information produced from single nucleotide polymorphism (SNP) arrays has routinely been used to identify genomic regions associated with complex traits in beef and dairy cattle. Herein, we assembled a dataset consisting of 15,815 Red Angus beef cattle distributed across the continental U.S. and a union set of 836,118 imputed SNPs to conduct genome-wide association analyses (GWAA) for growth traits using univariate linear mixed models (LMM); including birth weight, weaning weight, and yearling weight. Genomic relationship matrix heritability estimates were produced for all growth traits, and genotype-by-environment (GxE) interactions were investigated. Results Moderate to high heritabilities with small standard errors were estimated for birth weight (0.51 ± 0.01), weaning weight (0.25 ± 0.01), and yearling weight (0.42 ± 0.01). GWAA revealed 12 pleiotropic QTL (BTA6, BTA14, BTA20) influencing Red Angus birth weight, weaning weight, and yearling weight which met a nominal significance threshold (P ≤ 1e-05) for polygenic traits using 836K imputed SNPs. Moreover, positional candidate genes associated with Red Angus growth traits in this study (i.e., LCORL, LOC782905, NCAPG, HERC6, FAM184B, SLIT2, MMRN1, KCNIP4, CCSER1, GRID2, ARRDC3, PLAG1, IMPAD1, NSMAF, PENK, LOC112449660, MOS, SH3PXD2B, STC2, CPEB4) were also previously associated with feed efficiency, growth, and carcass traits in beef cattle. Collectively, 14 significant GxE interactions were also detected, but were less consistent among the investigated traits at a nominal significance threshold (P ≤ 1e-05); with one pleiotropic GxE interaction detected on BTA28 (24 Mb) for Red Angus weaning weight and yearling weight. Conclusions Sixteen well-supported QTL regions detected from the GWAA and GxE GWAA for growth traits (birth weight, weaning weight, yearling weight) in U.S. Red Angus cattle were found to be pleiotropic. Twelve of these pleiotropic QTL were also identified in previous studies focusing on feed efficiency and growth traits in multiple beef breeds and/or their composites. In agreement with other beef cattle GxE studies our results implicate the role of vasodilation, metabolism, and the nervous system in the genetic sensitivity to environmental stress. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-022-08667-6.
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Affiliation(s)
- Johanna L Smith
- Department of Veterinary Pathobiology, Texas A&M University, College Station, 77843, USA
| | - Miranda L Wilson
- Department of Veterinary Pathobiology, Texas A&M University, College Station, 77843, USA
| | - Sara M Nilson
- Division of Animal Sciences, University of Missouri, Columbia, 65211, USA
| | - Troy N Rowan
- Division of Animal Sciences, University of Missouri, Columbia, 65211, USA.,Genetics Area Program, University of Missouri, Columbia, 65211, USA
| | - Robert D Schnabel
- Division of Animal Sciences, University of Missouri, Columbia, 65211, USA.,Genetics Area Program, University of Missouri, Columbia, 65211, USA.,Informatics Institute, University of Missouri, Columbia, 65211, USA
| | - Jared E Decker
- Division of Animal Sciences, University of Missouri, Columbia, 65211, USA.,Genetics Area Program, University of Missouri, Columbia, 65211, USA.,Informatics Institute, University of Missouri, Columbia, 65211, USA
| | - Christopher M Seabury
- Department of Veterinary Pathobiology, Texas A&M University, College Station, 77843, USA.
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10
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Asgharzadeh F, Moradi-Marjaneh R, Marjaneh MM. The role of heat shock protein 40 in carcinogenesis and biology of colorectal cancer. Curr Pharm Des 2022; 28:1457-1465. [PMID: 35570564 DOI: 10.2174/1381612828666220513124603] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 03/31/2022] [Indexed: 11/22/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. Despite the enormous amount of effort in the diagnosis and treatment of CRC, the overall survival rate of patients remains low. The precise molecular and cellular basis underlying CRC has not been completely understood yet. Over time, new genes and molecular pathways involved in the pathogenesis of the disease are being identified. Accurate discovery of these genes and signaling pathways are important and urgent missions for the next generation of anticancer therapy research. Chaperone DnaJ, also known as Hsp40 (heat shock protein 40), has been of particular interest in CRC pathogenesis, as it is involved in the fundamental cell activities for maintaining cellular homeostasis. Evidence show that protein family members of DnaJ/Hsp40 play both roles; enhancing and reducing the growth of CRC cells. In the present review, we focus on the current knowledge on the molecular mechanisms responsible for the role of DnaJ/Hsp40 in CRC carcinogenesis and biology.
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Affiliation(s)
- Fereshteh Asgharzadeh
- Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reyhaneh Moradi-Marjaneh
- Department of Physiology, School of Paramedical Sciences, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Mahdi Moradi Marjaneh
- Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, United Kingdom
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11
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Li G, Zhang S, Wang H, Liang L, Liu Z, Wang Y, Xu B, Zhao H. Differential Expression Characterisation of the Heat Shock Proteins DnaJB6, DnaJshv, DnaJB13, and DnaJB14 in Apis cerana cerana Under Various Stress Conditions. Front Ecol Evol 2022. [DOI: 10.3389/fevo.2022.873791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
As key pollinators, bees are frequently exposed to multiple environmental stresses and have developed crucial mechanisms by which they adapt to these stressors. However, the molecular bases mediated at the gene level remain to be discovered. Here, we found four heat shock protein DnaJB subfamily genes, DnaJB6, DnaJshv, DnaJB13, and DnaJB14, from Apis cerana cerana, that all have J domains in their protein sequences. The expression levels of DnaJB6 and DnaJshv were upregulated by different degrees of heat stress, and the transcript level of DnaJB14 was gradually upregulated as the degree of heat stress increased, while the mRNA level of DnaJB13 was downregulated at multiple time points during heat stress treatment. The mRNA levels of all four DnaJBs were upregulated by cold and UV stress. In addition, the expression levels of DnaJB6, DnaJshv and DnaJB13 were reduced under abamectin, imidacloprid, cypermethrin, bifenthrin, spirodiclofen, and methomyl stresses. The transcript level of DnaJB14 was decreased by imidacloprid, cypermethrin, spirodiclofen, and methomyl exposure but increased by abamectin and bifenthrin exposure. These results indicate that the demand of A. cerana cerana for these four DnaJBs differs under various stress conditions. To further explore the role of DnaJBs in the stress response, we successfully silenced DnaJshv and DnaJB14. The content of protein carbonyl was increased, while the content of VC, the enzymatic activities of CAT, GST, and SOD, the mRNA levels of many antioxidant-related genes, and the total antioxidant capacity were reduced after knockdown of DnaJshv and DnaJB14 in A. cerana cerana. These results indicate that silencing DnaJshv and DnaJB14 increases oxidative damage and decreases the antioxidant ability of A. cerana cerana. Taken together, our results demonstrate that DnaJB6, DnaJshv, DnaJB13, and DnaJB14 are differentially expressed under stress conditions and play crucial roles in response to various stressors, possibly through the antioxidant signalling pathway. These findings will be conducive to understanding the molecular basis of bee responses to environmental stresses and are beneficial for improving bee protection.
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12
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Li Y, Tian R, Liu J, Ou C, Wu Q, Fu X. A 13-Gene Signature Based on Estrogen Response Pathway for Predicting Survival and Immune Responses of Patients With UCEC. Front Mol Biosci 2022; 9:833910. [PMID: 35558564 PMCID: PMC9087353 DOI: 10.3389/fmolb.2022.833910] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 04/11/2022] [Indexed: 12/11/2022] Open
Abstract
Background: Accumulating evidence suggests that anti-estrogens have been effective against multiple gynecological diseases, especially advanced uterine corpus endometrial carcinoma (UCEC), highlighting the contribution of the estrogen response pathway in UCEC progression. This study aims to identify a reliable prognostic signature for potentially aiding in the comprehensive management of UCEC. Methods: Firstly, univariate Cox and LASSO regression were performed to identify a satisfying UCEC prognostic model quantifying patients' risk, constructed from estrogen-response-related genes and verified to be effective by Kaplan-Meier curves, ROC curves, univariate and multivariate Cox regression. Additionally, a nomogram was constructed integrating the prognostic model and other clinicopathological parameters. Next, UCEC patients from the TCGA dataset were divided into low- and high-risk groups according to the median risk score. To elucidate differences in biological characteristics between the two risk groups, pathway enrichment, immune landscape, genomic alterations, and therapeutic responses were evaluated to satisfy this objective. As for treatment, effective responses to anti-PD-1 therapy in the low-risk patients and sensitivity to six chemotherapy drugs in the high-risk patients were demonstrated. Results: The low-risk group with a relatively favorable prognosis was marked by increased immune cell infiltration, higher expression levels of HLA members and immune checkpoint biomarkers, higher tumor mutation burden, and lower copy number alterations. This UCEC prognostic signature, composed of 13 estrogen-response-related genes, has been identified and verified as effective. Conclusion: Our study provides molecular signatures for further functional and therapeutic investigations of estrogen-response-related genes in UCEC and represents a potential systemic approach to characterize key factors in UCEC pathogenesis and therapeutic responses.
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Affiliation(s)
- Yimin Li
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ruotong Tian
- Department of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jiaxin Liu
- Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Qihui Wu
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
- Department of Obstetrics and Gynecology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaodan Fu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
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13
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Kaida A, Iwakuma T. Regulation of p53 and Cancer Signaling by Heat Shock Protein 40/J-Domain Protein Family Members. Int J Mol Sci 2021; 22:13527. [PMID: 34948322 PMCID: PMC8706882 DOI: 10.3390/ijms222413527] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/13/2021] [Accepted: 12/14/2021] [Indexed: 12/27/2022] Open
Abstract
Heat shock proteins (HSPs) are molecular chaperones that assist diverse cellular activities including protein folding, intracellular transportation, assembly or disassembly of protein complexes, and stabilization or degradation of misfolded or aggregated proteins. HSP40, also known as J-domain proteins (JDPs), is the largest family with over fifty members and contains highly conserved J domains responsible for binding to HSP70 and stimulation of the ATPase activity as a co-chaperone. Tumor suppressor p53 (p53), the most frequently mutated gene in human cancers, is one of the proteins that functionally interact with HSP40/JDPs. The majority of p53 mutations are missense mutations, resulting in acquirement of unexpected oncogenic activities, referred to as gain of function (GOF), in addition to loss of the tumor suppressive function. Moreover, stability and levels of wild-type p53 (wtp53) and mutant p53 (mutp53) are crucial for their tumor suppressive and oncogenic activities, respectively. However, the regulatory mechanisms of wtp53 and mutp53 are not fully understood. Accumulating reports demonstrate regulation of wtp53 and mutp53 levels and/or activities by HSP40/JDPs. Here, we summarize updated knowledge related to the link of HSP40/JDPs with p53 and cancer signaling to improve our understanding of the regulation of tumor suppressive wtp53 and oncogenic mutp53 GOF activities.
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Affiliation(s)
- Atsushi Kaida
- Department of Oral Radiation Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan;
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Tomoo Iwakuma
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Pediatrics, Children’s Mercy Research Institute, Kansas City, MO 64108, USA
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14
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Kaida A, Yamamoto S, Parrales A, Young ED, Ranjan A, Alalem MA, Morita KI, Oikawa Y, Harada H, Ikeda T, Thomas SM, Diaz FJ, Iwakuma T. DNAJA1 promotes cancer metastasis through interaction with mutant p53. Oncogene 2021; 40:5013-5025. [PMID: 34183772 DOI: 10.1038/s41388-021-01921-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 06/10/2021] [Accepted: 06/18/2021] [Indexed: 11/09/2022]
Abstract
Accumulation of mutant p53 (mutp53) is crucial for its oncogenic gain of function activity. DNAJA1, a member of J-domain containing proteins or heat shock protein 40, is shown to prevent unfolded mutp53 from proteasomal degradation. However, the biological function of DNAJA1 remains largely unknown. Here we show that DNAJA1 promotes tumor metastasis by accumulating unfolded mutp53. Levels of DNAJA1 in head and neck squamous cell carcinoma (HNSCC) tissues were higher than those in normal tissues. Knockdown of DNAJA1 in HNSCC cell lines carrying unfolded mutp53 significantly decreased the levels of mutp53, filopodia/lamellipodia formation, migratory potential, and active forms of CDC42/RAC1, which were not observed in HNSCC cells with DNA contact mutp53, wild-type p53, or p53 null. Such mutp53-dependent functions of DNAJA1 were supported by the observation that DNAJA1 selectively bound to unfolded mutp53. Moreover, DNAJA1 knockdown in HNSCC cells carrying unfolded mutp53 inhibited primary tumor growth and metastases to the lymph nodes and lungs. Our study suggests that DNAJA1 promotes HNSCC metastasis mainly in a manner dependent on mutp53 status, suggesting DNAJA1 as a potential therapeutic target for HNSCC harboring unfolded mutp53.
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Affiliation(s)
- Atsushi Kaida
- Department of Cancer Biology, University of Kansas Medical Center, Kansas, KS, USA.,Department of Oral Radiation Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Satomi Yamamoto
- Department of Cancer Biology, University of Kansas Medical Center, Kansas, KS, USA
| | - Alejandro Parrales
- Department of Cancer Biology, University of Kansas Medical Center, Kansas, KS, USA.,Department of Pediatrics, Children's Mercy Research Institute, Kansas, MO, USA
| | - Eric D Young
- Department of Cancer Biology, University of Kansas Medical Center, Kansas, KS, USA
| | - Atul Ranjan
- Department of Cancer Biology, University of Kansas Medical Center, Kansas, KS, USA.,Department of Pediatrics, Children's Mercy Research Institute, Kansas, MO, USA
| | - Mohamed A Alalem
- Department of Pediatrics, Children's Mercy Research Institute, Kansas, MO, USA
| | - Kei-Ichi Morita
- Department of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo, Japan.,Bioresource Research Center, Tokyo, Japan
| | - Yu Oikawa
- Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo, Japan
| | - Hiroyuki Harada
- Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo, Japan
| | - Tohru Ikeda
- Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sufi M Thomas
- Department of Otolaryngology, Head and Neck Surgery, Kansas, KS, USA
| | - Francisco J Diaz
- Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas, KS, USA
| | - Tomoo Iwakuma
- Department of Cancer Biology, University of Kansas Medical Center, Kansas, KS, USA. .,Department of Pediatrics, Children's Mercy Research Institute, Kansas, MO, USA.
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15
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Li Y, Li M, Jin F, Liu J, Chen M, Yin J. DNAJC12 promotes lung cancer growth by regulating the activation of β‑catenin. Int J Mol Med 2021; 47:105. [PMID: 33907820 PMCID: PMC8057298 DOI: 10.3892/ijmm.2021.4938] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 03/24/2021] [Indexed: 01/03/2023] Open
Abstract
Lung cancer has become the leading cause of cancer‑associated mortality worldwide. However, the underlying mechanisms of lung cancer remain poorly understood. DnaJ heat shock protein family (HSP40) member C12 (DNAJC12) is a type III member belonging to the HSP40/DNAJ family. The role of DNAJC12 in numerous types of cancer has been previously reported; however, the effect of DNAJC12 in lung cancer remains unknown. The results of the present study indicated that DNAJC12 may be involved in lung cancer proliferation and migration by regulating the β‑catenin signaling pathway. Data generated in the present study and from The Cancer Genome Atlas revealed that the DNAJC12 expression levels were significantly upregulated in lung cancer tissues compared with non‑cancer lung tissues. The expression of DNAJC12 was subsequently knocked down in A549 and NCI‑H1975 lung cancer cells using lentiviral transfections and further experiments demonstrated that the knockdown of DNAJC12 inhibited the proliferation, colony formation, migration and invasion of lung cancer cells. The results of flow cytometric assays also revealed that the knockdown of DNAJC12 induced the apoptosis of lung cancer cells. In addition, the effects of DNAJC12 knockdown on the in vivo growth of lung cancer cells were observed. Signaling pathway analysis revealed that the knockdown of DNAJC12 expression suppressed the phosphorylation of p65 NF‑κB, downregulated the expression levels and inhibited the subsequent activation of β‑catenin, and downregulated the expression levels of vimentin. Rescue experiments demonstrated that the overexpression of β‑catenin, but not that of NF‑κB or vimentin, reversed the effects of DNAJC12 knockdown on the proliferation and invasion of lung cancer cells. On the whole, the findings of the present study suggest that DNAJC12 may play a crucial role in lung cancer tumorigenesis by regulating the expression and activation of β‑catenin. Therefore, DNAJC12 may represent a novel target for the treatment of lung cancer.
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Affiliation(s)
- Yun Li
- School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
- Department of Thoracic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, P.R. China
| | - Meng Li
- Department of Thoracic Surgery, The First People's Hospital of Taian Affiliated to Shandong First Medical University, Taian, Shandong 271000, P.R. China
| | - Fengqi Jin
- Department of Thoracic Surgery, Jinan Zhangqiu District Hospital of Traditional Chinese Medicine, Jinan, Shandong 250200, P.R. China
| | - Jianbo Liu
- Department of Thoracic Surgery, The Fourth People's Hospital, Heze, Shangdong 274100, P.R. China
| | - Minghui Chen
- Department of Anesthesia Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 271000, P.R. China
| | - Jingjing Yin
- Department of Thoracic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, P.R. China
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16
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Nakamura S, Kanda M, Shimizu D, Sawaki K, Tanaka C, Hattori N, Hayashi M, Yamada S, Nakayama G, Omae K, Koike M, Kodera Y. STRA6 Expression Serves as a Prognostic Biomarker of Gastric Cancer. Cancer Genomics Proteomics 2021; 17:509-516. [PMID: 32859629 DOI: 10.21873/cgp.20207] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/20/2020] [Accepted: 05/29/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Despite advances in our understanding on the pathogenesis of gastric cancer (GC), patients face a poor prognosis. To improve clinical outcomes, effective approaches to diagnosis and treatment employing new diagnostic biomarkers are required to achieve early detection and predict recurrence and prognosis. MATERIALS AND METHODS Transcriptome analysis was conducted using surgically resected gastric tissues from four patients with metastatic GC. A total of 228 pairs of primary GC tissues and corresponding normal adjacent tissues were subjected to mRNA expression analysis. To validate our findings, we accessed an integrated microarray dataset and RNA sequencing data of GC cell lines. RESULTS We identified stimulated by retinoic acid 6 (STRA6) as a differentially overexpressed gene, which encodes a transmembrane protein that mediates the cellular uptake of retinol. To investigate how STRA6 contributes to the malignant phenotype of GC cells, we mined public datasets and found the mRNA encoding retinol binding protein 1 (RBP1), which is associated with retinoid metabolism, was co-expressed with STRA6. Furthermore, STRA6 mRNA levels were significantly higher in GC tissues compared to the corresponding noncancerous adjacent tissues of 228 surgically resected gastric tissue samples. Moreover, patients with high levels of STRA6 mRNA experienced significantly shorter disease-free survival and overall survival. Multivariate analysis revealed that high levels of STRA6 served as a significant risk factor. CONCLUSION Patients with high levels of STRA6 mRNA experienced significantly worse clinical outcomes, indicating that STRA6 may serve as a diagnostic and prognostic biomarker of GC.
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Affiliation(s)
- Shunsuke Nakamura
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Dai Shimizu
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kouichi Sawaki
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Norifumi Hattori
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenji Omae
- Department of Innovative Research and Education for Clinicians and Trainees (DiRECT), Fukushima Medical University Hospital, Fukushima, Japan
| | | | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
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17
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Lin M, Wang YN, Ye Y, Xiong Z, Guo F, Chen H. DNAJC12 as a Mediator Between ESR1 and ERBB4 in Breast Carcinoma Cells. Front Oncol 2021; 11:582277. [PMID: 33718139 PMCID: PMC7943744 DOI: 10.3389/fonc.2021.582277] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 01/05/2021] [Indexed: 02/05/2023] Open
Abstract
Mutation of the DNAJC12 gene is typically associated with non-progressive Parkinsonism, but is also detectable in breast carcinoma where its contribution and mechanisms are unexplored. In breast carcinoma, ESR1 was positively correlated with DNAJC12 and ERBB4, and DNAJC12 was positively correlated with ERBB4. We used the GEO2R tool to compare differential gene expression of MCF-7 cells, following ESR1 knockdown (GEO database, E-GEOD-27473 array), and found decreased expression of DNAJC12 and ERBB4 in ESR1-silenced MCF-7 cells. The number of identical genes having correlativity with ESR1, DNAJC12, or ERBB4 was 12,165 (66.41%). These results suggest that ESR1 can promote the expression of DNAJC12 and ERBB4, and DNAJC12 can enhance the expression of ERBB4 in MCF-7 cells, implying that there may be a regulatory network among these three genes.
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Affiliation(s)
- Mianjie Lin
- Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou University Medical College, Shantou, China
| | - Ya-Nan Wang
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
| | - Yixin Ye
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
| | - Zhelei Xiong
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
| | - Fengbiao Guo
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
| | - Haibin Chen
- Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou University Medical College, Shantou, China
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
- *Correspondence: Haibin Chen,
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18
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Guo Y, Liu J, Luo J, You X, Weng H, Wang M, Ouyang T, Li X, Liao X, Wang M, Lan Z, Shi Y, Chen S. Molecular Profiling Reveals Common and Specific Development Processes in Different Types of Gynecologic Cancers. Front Oncol 2020; 10:584793. [PMID: 33194730 PMCID: PMC7658613 DOI: 10.3389/fonc.2020.584793] [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: 07/30/2020] [Accepted: 09/21/2020] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Gynecologic cancers have become a major threat to women's health. The molecular biology of gynecologic cancers is not as well understood as that of breast cancer, and precision targeting is still new. Although viewed collectively as a group of cancers within the female reproductive system, they are more often studied separately. A comprehensive within-group comparison on molecular profiles is lacking. METHODS We conducted a whole-exome sequencing study of cervical/endometrial/ovarian cancer samples from 209 Chinese patients. We combined our data with genomic and transcriptomic data from relevant TCGA cohorts to identify and verify common/exclusive molecular changes in cervical/endometrial/ovarian cancer. RESULTS We identified shared molecular features including a COSMIC signature of deficient mismatch repair (dMMR), four recurrent copy-number variation (CNV) events, and extensive alterations in PI3K-Akt-mTOR signaling and cilium component genes; we also identified transcription factors and pathways that are exclusively altered in cervical/endometrial/ovarian cancer. The functions of the commonly/exclusively altered genomic circuits suggest (1) a common reprogramming process during early tumor initiation, which involves PI3K activation, defects in mismatch repair and cilium organization, as well as disruption in interferon signaling and immune recognition; (2) a cell-type specific program at late-stage tumor development that eventually lead to tumor proliferation and migration. CONCLUSION This study describes, from a molecular point of view, how similar and how different gynecologic cancers are, and it provides a hypothesis about the causes of the observed similarities and differences.
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Affiliation(s)
- Yuanli Guo
- Department of Gynaecology and Obstetrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Junfeng Liu
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiaqi Luo
- Department of Research, Top Gene Tech (Guangzhou) Co., Ltd., Guangzhou, China
| | - Xiaobin You
- Department of Research, Top Gene Tech (Guangzhou) Co., Ltd., Guangzhou, China
| | - Hui Weng
- Department of Research, Top Gene Tech (Guangzhou) Co., Ltd., Guangzhou, China
| | - Minyi Wang
- Department of Research, Top Gene Tech (Guangzhou) Co., Ltd., Guangzhou, China
| | - Ting Ouyang
- Department of Research, Top Gene Tech (Guangzhou) Co., Ltd., Guangzhou, China
| | - Xiao Li
- Department of Gynaecology and Obstetrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoming Liao
- Department of Research, Top Gene Tech (Guangzhou) Co., Ltd., Guangzhou, China
| | - Maocai Wang
- Department of Gynaecology and Obstetrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhaoji Lan
- Department of Research, Top Gene Tech (Guangzhou) Co., Ltd., Guangzhou, China
| | - Yujian Shi
- Department of Research, Top Gene Tech (Guangzhou) Co., Ltd., Guangzhou, China
| | - Shan Chen
- Department of Gynaecology and Obstetrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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19
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Yun CW, Kim HJ, Lim JH, Lee SH. Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy. Cells 2019; 9:cells9010060. [PMID: 31878360 PMCID: PMC7017199 DOI: 10.3390/cells9010060] [Citation(s) in RCA: 180] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/06/2019] [Accepted: 12/21/2019] [Indexed: 12/24/2022] Open
Abstract
Heat shock proteins (HSPs) constitute a large family of molecular chaperones classified by their molecular weights, and they include HSP27, HSP40, HSP60, HSP70, and HSP90. HSPs function in diverse physiological and protective processes to assist in maintaining cellular homeostasis. In particular, HSPs participate in protein folding and maturation processes under diverse stressors such as heat shock, hypoxia, and degradation. Notably, HSPs also play essential roles across cancers as they are implicated in a variety of cancer-related activities such as cell proliferation, metastasis, and anti-cancer drug resistance. In this review, we comprehensively discuss the functions of HSPs in association with cancer initiation, progression, and metastasis and anti-cancer therapy resistance. Moreover, the potential utilization of HSPs to enhance the effects of chemo-, radio-, and immunotherapy is explored. Taken together, HSPs have multiple clinical usages as biomarkers for cancer diagnosis and prognosis as well as the potential therapeutic targets for anti-cancer treatment.
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Affiliation(s)
- Chul Won Yun
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea; (C.W.Y.); (H.J.K.); (J.H.L.)
| | - Hyung Joo Kim
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea; (C.W.Y.); (H.J.K.); (J.H.L.)
| | - Ji Ho Lim
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea; (C.W.Y.); (H.J.K.); (J.H.L.)
| | - Sang Hun Lee
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea; (C.W.Y.); (H.J.K.); (J.H.L.)
- Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan 31538, Korea
- Correspondence: ; Tel.: +82-02-709-2029
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Nakamura S, Kanda M, Kodera Y. Incorporating molecular biomarkers into clinical practice for gastric cancer. Expert Rev Anticancer Ther 2019; 19:757-771. [PMID: 31437076 DOI: 10.1080/14737140.2019.1659136] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Gastric cancer is one of the most common causes of cancer-related mortality worldwide. To improve clinical outcomes, it is critical to develop appropriate approaches to diagnosis and treatment. Biomarkers have numerous potential clinical applications, including screening, assessing risk, determining prognosis, monitoring recurrence, and predicting response to treatment. Furthermore, biomarkers may contribute to the development of effective therapies. Areas covered: Here we review recent progress in exploiting GC-specific biomarkers such as protein-coding genes, microRNAs, long noncoding RNAs, and methylated gene promoters. Expert opinion: The development of biomarkers for diagnosing and monitoring gastric cancer and for individualizing therapeutic targets shows great promise for improving gastric cancer management.
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Affiliation(s)
- Shunsuke Nakamura
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine , Nagoya , Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine , Nagoya , Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine , Nagoya , Japan
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21
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Uno Y, Kanda M. ASO Author Reflections: Increased Expression of DNAJC12 is Associated with Aggressive Phenotype of Gastric Cancer. Ann Surg Oncol 2019; 26:592-593. [PMID: 31020503 DOI: 10.1245/s10434-019-07404-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Indexed: 11/18/2022]
Affiliation(s)
- Yasuo Uno
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
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