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Boka HJ, Engel RM, Georges C, McMurrick PJ, Abud HE. Does side matter? Deciphering mechanisms that underpin side-dependent pathogenesis and therapy response in colorectal cancer. Mol Cancer 2025; 24:130. [PMID: 40312719 PMCID: PMC12046799 DOI: 10.1186/s12943-025-02327-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Accepted: 04/08/2025] [Indexed: 05/03/2025] Open
Abstract
Colorectal cancer (CRC) is stratified by heterogeneity between disease sites, with proximal right-sided CRC (RCRC) multifactorial in its distinction from distal left-sided CRC (LCRC). Notably, right-sided tumors are associated with aggressive disease characteristics which culminate in poor clinical outcomes for these patients. While factors such as mutational profile and patterns of metastasis have been suggested to contribute to differences in therapy response, the exact mechanisms through which RCRC resists effective treatment have yet to be elucidated. In response, recent analyzes, including those utilizing whole genome sequencing, transcriptional profiling, and single-cell analyses, have demonstrated that key molecular differences exist between disease sites, with differentially expressed genes spanning a diverse range of cellular functions. Here, we review and contextualize the most recent data on molecular biomarkers found to exhibit discordance between RCRC and LCRC, and highlight candidates for further investigation, including those which present promise for future clinical application. Given the present disparity in survival outcomes for RCRC patients, we expect the prognostic biomarkers presented in our review to be useful in establishing future directions for the side-specific treatment of CRC.
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Affiliation(s)
- Harrison J Boka
- Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Department of Surgery, Cabrini Monash University, Cabrini Hospital, Malvern, VIC, 3144, Australia
| | - Rebekah M Engel
- Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Department of Surgery, Cabrini Monash University, Cabrini Hospital, Malvern, VIC, 3144, Australia
| | - Christine Georges
- Department of Surgery, Cabrini Monash University, Cabrini Hospital, Malvern, VIC, 3144, Australia
| | - Paul J McMurrick
- Department of Surgery, Cabrini Monash University, Cabrini Hospital, Malvern, VIC, 3144, Australia
| | - Helen E Abud
- Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia.
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
- Department of Surgery, Cabrini Monash University, Cabrini Hospital, Malvern, VIC, 3144, Australia.
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2
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Lv K, Li Q, Jiang N, Chen Q. Role of TRIM29 in disease: What is and is not known. Int Immunopharmacol 2025; 147:113983. [PMID: 39755113 DOI: 10.1016/j.intimp.2024.113983] [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: 08/10/2024] [Revised: 12/17/2024] [Accepted: 12/28/2024] [Indexed: 01/06/2025]
Abstract
Tripartite motif-containing proteins (TRIMs), comprising the greatest subfamily of E3 ubiquitin ligases with approximately 80 members of this family, are widely distributed in mammalian cells. TRIMs actively participate in ubiquitination of target proteins, a type of post-translational modification associated with protein degradation and other functions. Tripartite motif-containing protein 29 (TRIM29), a member of the TRIM family, differs from other members of this family in that it lacks the RING finger structural domain containing cysteine and histidine residues that mediates DNA binding, protein-protein interactions, and ubiquitin ligase, at its N-terminus. The expression of TRIM29 was initially found to be associated with cancer and diabetic nephropathy progression, and antiviral immunity which is triggered by virus-derived nucleic acids binding to pattern recognition receptors (PRRs) on immune cells. Recently, TRIM29 has also been explored as a diagnostic biomarker and therapeutic target for some immune-related diseases. Here, we review the functions of TRIM29 in the progression of diseases and the inherent mechanisms, as well as the remaining gaps in the literature. A thorough understanding of the detailed regulatory mechanisms of TRIM29 will ultimately facilitate the development of different therapeutic strategies for various diseases.
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Affiliation(s)
- Kunying Lv
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, 120 Dongling Road, Shenyang 110866, China; The Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, 120 Dongling Road, Shenyang 110866, China
| | - Qilong Li
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, 120 Dongling Road, Shenyang 110866, China; The Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, 120 Dongling Road, Shenyang 110866, China
| | - Ning Jiang
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, 120 Dongling Road, Shenyang 110866, China; The Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, 120 Dongling Road, Shenyang 110866, China
| | - Qijun Chen
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, 120 Dongling Road, Shenyang 110866, China; The Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, 120 Dongling Road, Shenyang 110866, China.
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3
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Wu Q, Nandi D, Sharma D. TRIM-endous functional network of tripartite motif 29 (TRIM29) in cancer progression and beyond. Cancer Metastasis Rev 2024; 44:16. [PMID: 39644332 PMCID: PMC11625080 DOI: 10.1007/s10555-024-10226-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 10/16/2024] [Indexed: 12/09/2024]
Abstract
While most Tripartite motif (TRIM) family proteins are E3 ubiquitin ligases, some members have functions beyond the regulation of ubiquitination, impacting normal physiological processes and disease progression. TRIM29, an important member of the TRIM family, exerts a predominant influence on cancer growth, epithelial-to-mesenchymal transition, stemness and metastatic progression by directly potentiating multiple canonical oncogenic pathways. The cancer-promoting effect of TRIM29 is also evident in metabolic interventions and interference with the efficacy of cancer therapeutics. As expected for any key node in cancer, the expression of TRIM29 is tightly regulated by non-coding RNAs, epigenetic modulation, and post-translational regulation. A systematic discussion of how TRIM29 is regulated in cancer, its influences on cancer progression, and its impact on cancer therapeutics is presented in this review. We also explore the context-dependent alterations between TRIM29 function from oncogenic to tumor suppression. As TRIM29 is involved in multiple aspects of cancer progression, a better understanding of its biological impact in cancer may help improve prognosis and develop novel therapeutic combinations, leading to improved personalized cancer care.
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Affiliation(s)
- Qitong Wu
- Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Deeptashree Nandi
- Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Dipali Sharma
- Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB 1, Rm 145, Baltimore, MD, 21231, USA.
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4
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Weng C, Jin R, Jin X, Yang Z, He C, Zhang Q, Xu J, Lv B. Exploring the Mechanisms, Biomarkers, and Therapeutic Targets of TRIM Family in Gastrointestinal Cancer. Drug Des Devel Ther 2024; 18:5615-5639. [PMID: 39654601 PMCID: PMC11626976 DOI: 10.2147/dddt.s482340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 11/23/2024] [Indexed: 12/12/2024] Open
Abstract
Gastrointestinal region (GI) cancers are closely linked to the ubiquitination system, with the E3 ubiquitin ligase playing a crucial role by targeting various substrates. As E3 ubiquitin ligases, proteins of tripartite motif (TRIM) family play a role in cancer signaling, development, apoptosis, and formation. These proteins regulate diverse biological activities and signaling pathways. This study comprehensively outlines the functions of TRIM proteins in gastrointestinal physiology, contributing to our knowledge of the molecular pathways involved in gastrointestinal tumors. Gastrointestinal region (GI) cancers are closely linked to the ubiquitination system, with the E3 ubiquitin ligase playing a crucial role by targeting various substrates.
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Affiliation(s)
- Chunyan Weng
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China
| | - Rijuan Jin
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China
| | - Xiaoliang Jin
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China
| | - Zimei Yang
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China
| | - Chenghai He
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China
- Department of Gastroenterology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang Province, People’s Republic of China
| | - Qiuhua Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China
| | - Jingli Xu
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, People’s Republic of China
| | - Bin Lv
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China
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Zhao FY, Chen X, Wang JM, Yuan Y, Li C, Sun J, Wang HQ. O-GlcNAcylation of TRIM29 and OGT translation forms a feedback loop to promote adaptive response of PDAC cells to glucose deficiency. Cell Oncol (Dordr) 2024; 47:1025-1041. [PMID: 38345749 DOI: 10.1007/s13402-023-00915-5] [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] [Accepted: 12/29/2023] [Indexed: 07/04/2024] Open
Abstract
PURPOSE Glucose not only provides energy for tumor cells, but also provides various biomolecules that are essential for their survival, proliferation and invasion. Therefore, it is of great clinical significance to understand the mechanism of how tumor cells adapt to metabolic stress and maintain their survival. The aim of this research was to study the critical role of OGT and TRIM29 O-GlcNAc modification driven adaptability of PDAC cells to low glucose stress, which might have important medical implications for PDAC therapy. METHODS Western blotting, mass spectrometry and WGA-immunoprecipitation were used to examined the levels of OGT and O-GlcNAc glycosylated proteins in BxPC3 and SW1990 cells in normal culture and under glucose deprivation conditions. Crystal violet assay, flow cytometry, RIP, RT-qPCR, protein stability assay, biotin pull down were used to investigate the mechanism of OGT and TRIM29-mediated adaptive response to glucose deficiency in PDAC cells. RESULTS The current study found that under the condition of low glucose culture, the levels of OGT and O-GlcNAc glycosylation in PDAC cells were significantly higher than those in normal culture. Moreover, the high expression of OGT has a protective effect on PDAC cells under low glucose stress. This study confirmed that there was no significant change in mRNA level and protein degradation of OGT under low glucose stress, which was mainly reflected in the increase of protein synthesis. In addition, O-GlcNAc modification at T120 site plays a critical role in the metabolic adaptive responses mediated by TRIM29. CONCLUSIONS Taken together, our study indicated that O-GlcNAcylation of TRIM29 at T120 site and OGT translation forms a loop feedback to facilitate survival of PDAC under glucose deficiency.
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Affiliation(s)
- Fu-Ying Zhao
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, 110122, China
| | - Xue Chen
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, 110122, China
| | - Jia-Mei Wang
- Department of Laboratory Medicine, The 1st Affiliated Hospital, China Medical University, Shenyang, 110001, China
| | - Ye Yuan
- Central Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, 110042, China
| | - Chao Li
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, 110122, China
| | - Jia Sun
- Department of Biochemistry and Molecular Biology, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Hua-Qin Wang
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, 110122, China.
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Huang W, Hu X, He X, Pan D, Huang Z, Gu Z, Huang G, Wang P, Cui C, Fan Y. TRIM29 facilitates gemcitabine resistance via MEK/ERK pathway and is modulated by circRPS29/miR-770-5p axis in PDAC. Drug Resist Updat 2024; 74:101079. [PMID: 38518727 DOI: 10.1016/j.drup.2024.101079] [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: 01/26/2024] [Revised: 03/05/2024] [Accepted: 03/11/2024] [Indexed: 03/24/2024]
Abstract
AIMS Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. Chemotherapy based on gemcitabine (GEM) remains the first-line drug for patients with advanced PDAC. However, GEM resistance impairs its therapeutic effectiveness. Therefore, identifying effective therapeutic targets are urgently needed to overcome GEM resistance. METHODS The clinical significance of Tripartite Motif Containing 29 (TRIM29) was identified by exploring GEO datasets and TCGA database and its potential biological functions were predicted by GSEA analysis. The regulatory axis was established by bioinformatics analysis and validated by mechanical experiments. Then, in vitro and in vivo assays were performed to validate the roles of TRIM29 in PDAC GEM resistance. RESULTS High TRIM29 expression was associated with poor prognosis of PDAC and functional experiments demonstrated that TRIM29 promoted GEM resistance in PDAC GEM-resistant (GR) cells. Furthermore, we revealed that circRPS29 promoted TRIM29 expression via competitive interaction with miR-770-5p and then activated MEK/ERK signaling pathway. Additionally, both in vitro and in vivo functional experiments demonstrated that circRPS29/miR-770-5p/TRIM29 axis promoted PDAC GEM resistance via activating MEK/ERK signaling pathway. CONCLUSION Our results identify the significance of the signaling axis, circRPS29/miR-770-5p/TRIM29-MEK/ERK, in PDAC GEM resistance, which will provide novel therapeutic targets for PDAC treatment.
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MESH Headings
- Animals
- Humans
- Mice
- Antimetabolites, Antineoplastic/pharmacology
- Antimetabolites, Antineoplastic/therapeutic use
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/pathology
- Cell Line, Tumor
- Deoxycytidine/analogs & derivatives
- Deoxycytidine/pharmacology
- Deoxycytidine/therapeutic use
- DNA-Binding Proteins/metabolism
- DNA-Binding Proteins/genetics
- Drug Resistance, Neoplasm/genetics
- Gemcitabine
- Gene Expression Regulation, Neoplastic/drug effects
- MAP Kinase Signaling System/drug effects
- Mice, Nude
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/pathology
- Prognosis
- RNA, Circular/genetics
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Wenjie Huang
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510280, China; Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong Province 510630, China
| | - Xiaojun Hu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong Province 510630, China
| | - Xiang He
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong Province 510630, China
| | - Dongyue Pan
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong Province 510630, China
| | - Zhaorong Huang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong Province 510630, China
| | - Zhanfeng Gu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong Province 510630, China
| | - Guobing Huang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong Province 510630, China
| | - Ping Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province 510120, China.
| | - Chunhui Cui
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510280, China.
| | - Yingfang Fan
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong Province 510630, China.
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Sultanov R, Mulyukina A, Zubkova O, Fedoseeva A, Bogomazova A, Klimina K, Larin A, Zatsepin T, Prikazchikova T, Lukina M, Bogomiakova M, Sharova E, Generozov E, Lagarkova M, Arapidi G. TP63-TRIM29 axis regulates enhancer methylation and chromosomal instability in prostate cancer. Epigenetics Chromatin 2024; 17:6. [PMID: 38481282 PMCID: PMC10938740 DOI: 10.1186/s13072-024-00529-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 02/09/2024] [Indexed: 03/17/2024] Open
Abstract
BACKGROUND Prostate adenocarcinoma (PRAD) is the second leading cause of cancer-related deaths in men. High variability in DNA methylation and a high rate of large genomic rearrangements are often observed in PRAD. RESULTS To investigate the reasons for such high variance, we integrated DNA methylation, RNA-seq, and copy number alterations datasets from The Cancer Genome Atlas (TCGA), focusing on PRAD, and employed weighted gene co-expression network analysis (WGCNA). Our results show that only single cluster of co-expressed genes is associated with genomic and epigenomic instability. Within this cluster, TP63 and TRIM29 are key transcription regulators and are downregulated in PRAD. We discovered that TP63 regulates the level of enhancer methylation in prostate basal epithelial cells. TRIM29 forms a complex with TP63 and together regulates the expression of genes specific to the prostate basal epithelium. In addition, TRIM29 binds DNA repair proteins and prevents the formation of the TMPRSS2:ERG gene fusion typically observed in PRAD. CONCLUSION Our study demonstrates that TRIM29 and TP63 are important regulators in maintaining the identity of the basal epithelium under physiological conditions. Furthermore, we uncover the role of TRIM29 in PRAD development.
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Affiliation(s)
- R Sultanov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia.
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia.
| | - A Mulyukina
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - O Zubkova
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - A Fedoseeva
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - A Bogomazova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - K Klimina
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - A Larin
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - T Zatsepin
- Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia
| | - T Prikazchikova
- Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia
| | - M Lukina
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - M Bogomiakova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - E Sharova
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - E Generozov
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - M Lagarkova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - G Arapidi
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
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Yin YT, Shi L, Wu C, Zhang MY, Li JX, Zhou YF, Wang SC, Wang HY, Mai SJ. TRIM29 modulates proteins involved in PTEN/AKT/mTOR and JAK2/STAT3 signaling pathway and suppresses the progression of hepatocellular carcinoma. Med Oncol 2024; 41:79. [PMID: 38393440 DOI: 10.1007/s12032-024-02307-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 01/17/2024] [Indexed: 02/25/2024]
Abstract
Tripartite motif-containing 29 (TRIM29), also known as the ataxia telangiectasia group D-complementing (ATDC) gene, has been reported to play an oncogenic or tumor suppressive role in developing different tumors. So far, its expression and biological functions in hepatocellular carcinoma (HCC) remain unclear. We investigated TRIM29 expression pattern in human HCC samples using quantitative RT-PCR and immunohistochemistry. Relationships between TRIM29 expression level, clinical prognostic indicators, overall survival (OS), and disease-free survival (DFS) were evaluated by Kaplan-Meier analysis and Cox proportional hazards model. A series of in vitro experiments and a xenograft tumor model were conducted to detect the functions of TRIM29 in HCC cells. RNA sequencing, western blotting, and immunochemical staining were performed to assess the molecular regulation of TRIM29 in HCC. We found that the mRNA and protein levels of TRIM29 were significantly reduced in HCC samples, compared with adjacent noncancerous tissues, and were negatively correlated with poor differentiation of HCC tissues. Survival analysis confirmed that lower TRIM29 expression significantly correlated with shorter OS and DFS of HCC patients. TRIM29 overexpression remarkably inhibited cell proliferation, migration, and EMT in HCC cells, whereas knockdown of TRIM29 reversed these effects. Moreover, deactivation of the PTEN/AKT/mTOR and JAK2/STAT3 pathways might be involved in the tumor suppressive role of TRIM29 in HCC. Our findings indicate that TRIM29 in HCC exerts its tumor suppressive effects through inhibition of the PTEN/AKT/mTOR and JAK2/STAT3 signaling pathways and may be used as a potential biomarker for survival in patients with HCC.
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Affiliation(s)
- Yu-Ting Yin
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Lu Shi
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Chun Wu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Mei-Yin Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Jia-Xin Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Yu-Feng Zhou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Shuo-Cheng Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Hui-Yun Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China.
| | - Shi-Juan Mai
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China.
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9
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Wu M, Jin MM, Cao XH, Zhao L, Li YH. Silencing TRIM29 Sensitizes Non-small Cell Lung Cancer Cells to Anlotinib by Promoting Apoptosis via Binding RAD50. Curr Cancer Drug Targets 2024; 24:445-454. [PMID: 37644752 DOI: 10.2174/1568009623666230829143148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 06/13/2023] [Accepted: 07/25/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND Previous studies have proposed that the transcriptional regulatory factor tripartite motif containing 29 (TRIM29) is involved in carcinogenesis via binding with nucleic acid. TRIM29 is confirmed to be highly expressed when the cancer cells acquire therapy-resistant properties. We noticed that TRIM29 levels were significantly increased in anlotinib-resistant NCIH1975 (NCI-H1975/AR) cells via mining data information from gene expression omnibus (GEO) gene microarray (GSE142031; log2 fold change > 1, p < 0.05). OBJECTIVE Our study aimed to investigate the function of TRIM29 on the resistance to anlotinib in non-small cell lung cancer (NSCLC) cells, including NCI-H1975 and A549 cells. METHODS Real-time RT-PCR and western blot were used to detect TRIM29 expression in anlotinib- resistant NSCLC (NSCLC/AR) cells. Apoptosis were determined through flow cytometry, acridine orange/ethidium bromide staining as well as western blot. ELISA was used to measure the content of C-X3-C motif chemokine ligand 1. Co-Immunoprecipitation assay was performed to verify the interaction between TRIM29 and RAD50 double-strand break repair protein (RAD50). RESULTS TRIM29 expression was shown to be elevated in the cytoplasm and nucleus of NSCLC/ AR cells compared to normal NSCLC cells. Next, we demonstrated that TRIM29 knockdown facilitated apoptosis and enhanced the sensitivity to anlotinib in NSCLC/AR cells. Based on the refined results citing from the database BioGRID, it was proved that TRIM29 interacted with RAD50. Herein, RAD50 overexpression diminished the pro-apoptotic effect induced by silencing TRIM29 in anlotinib-resistant A549 (A549/AR) cells. CONCLUSION Finally, we concluded that the increased sensitivity to anlotinib in NSCLC/AR cells was achieved by knocking down TRIM29, besides, the positive effects of TRIM29 knockdown were attributed to the promotion of apoptosis via binding to RAD50 in NSCLC/AR cell nucleus. Therefore, TRIM29 might become a potential target for overcoming anlotinib resistance in NSCLC treatment.
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Affiliation(s)
- Min Wu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, No. 100, Huaihai Avenue, Hefei, Anhui, People's Republic of China
- Department of Respiratory and Critical Care Medicine, Anhui Public Health Clinical Center, No. 100, Huaihai Avenue, Hefei, Anhui, People's Republic of China
| | - Meng-Meng Jin
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, No. 100, Huaihai Avenue, Hefei, Anhui, People's Republic of China
- Department of Respiratory and Critical Care Medicine, Anhui Public Health Clinical Center, No. 100, Huaihai Avenue, Hefei, Anhui, People's Republic of China
| | - Xiao-Hui Cao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, No. 100, Huaihai Avenue, Hefei, Anhui, People's Republic of China
- Department of Respiratory and Critical Care Medicine, Anhui Public Health Clinical Center, No. 100, Huaihai Avenue, Hefei, Anhui, People's Republic of China
| | - Lei Zhao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, No. 100, Huaihai Avenue, Hefei, Anhui, People's Republic of China
- Department of Respiratory and Critical Care Medicine, Anhui Public Health Clinical Center, No. 100, Huaihai Avenue, Hefei, Anhui, People's Republic of China
| | - Yong-Huai Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, No. 100, Huaihai Avenue, Hefei, Anhui, People's Republic of China
- Department of Respiratory and Critical Care Medicine, Anhui Public Health Clinical Center, No. 100, Huaihai Avenue, Hefei, Anhui, People's Republic of China
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10
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Palmbos P, Wang Y, Jerome N, Kelleher A, Henderson M, Day M, Coulombe P. TRIM29 promotes bladder cancer invasion by regulating the intermediate filament network and focal adhesion. RESEARCH SQUARE 2023:rs.3.rs-3697712. [PMID: 38168254 PMCID: PMC10760242 DOI: 10.21203/rs.3.rs-3697712/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Bladder cancer is a common malignancy whose lethality is determined by invasive potential. We have previously shown that TRIM29, also known as ATDC, is transcriptionally regulated by TP63 in basal bladder cancers where it promotes invasive progression and metastasis, but the molecular events which promote invasion and metastasis downstream of TRIM29 remained poorly understood. Here we identify stimulation of bladder cancer migration as the specific role of TRIM29 during invasion. We show that TRIM29 physically interacts with K14 + intermediate filaments which in turn regulates focal adhesion stability. Further, we find that both K14 and the focal adhesion protein, ZYX are required for bladder cancer migration and invasion. Taken together, these results establish a role for TRIM29 in the regulation of cytoskeleton and focal adhesions during invasion and identify a pathway with therapeutic potential.
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11
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Gu J, Chen J, Xiang S, Zhou X, Li J. Intricate confrontation: Research progress and application potential of TRIM family proteins in tumor immune escape. J Adv Res 2023; 54:147-179. [PMID: 36736694 DOI: 10.1016/j.jare.2023.01.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 01/06/2023] [Accepted: 01/12/2023] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Tripartite motif (TRIM) family proteins have more than 80 members and are widely found in various eukaryotic cells. Most TRIM family proteins participate in the ubiquitin-proteasome degradation system as E3-ubiquitin ligases; therefore, they play pivotal regulatory roles in the occurrence and development of tumors, including tumor immune escape. Due to the diversity of functional domains of TRIM family proteins, they can extensively participate in multiple signaling pathways of tumor immune escape through different substrates. In current research and clinical contexts, immune escape has become an urgent problem. The extensive participation of TRIM family proteins in curing tumors or preventing postoperative recurrence and metastasis makes them promising targets. AIM OF REVIEW The aim of the review is to make up for the gap in the current research on TRIM family proteins and tumor immune escape and propose future development directions according to the current progress and problems. KEY SCIENTIFIC CONCEPTS OF REVIEW This up-to-date review summarizes the characteristics and biological functions of TRIM family proteins, discusses the mechanisms of TRIM family proteins involved in tumor immune escape, and highlights the specific mechanism from the level of structure-function-molecule-pathway-phenotype, including mechanisms at the level of protein domains and functions, at the level of molecules and signaling pathways, and at the level of cells and microenvironments. We also discuss the application potential of TRIM family proteins in tumor immunotherapy, such as possible treatment strategies for combination targeting TRIM family protein drugs and checkpoint inhibitors for improving cancer treatment.
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Affiliation(s)
- Junjie Gu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jingyi Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Shuaixi Xiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xikun Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
| | - Jing Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
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12
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Bahreyni-Toossi MT, Zafari N, Azimian H, Mehrad-Majd H, Farhadi J, Vaziri Nezamdoust F. Alteration in Expression of Trim29, TRIM37, TRIM44, and β-Catenin Genes After Irradiation in Human Cells with Different Radiosensitivity. Cancer Biother Radiopharm 2023; 38:506-511. [PMID: 32833505 DOI: 10.1089/cbr.2020.3915] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Introduction: Radiotherapy is a crucial component of treatment for ∼70% of all cancer patients. The identification of effective biomarkers of radiosensitivity (RS) is a fundamental goal of radiobiology. The authors hypothesize that the RS of human normal and tumoral cells is correlated by the level of expression of TRIM29, TRIM37, TRIM44, and β-catenin genes. Materials and Methods: Clonogenic assay was performed and RS of four cell lines was determined by survival fraction at 2 Gy. To determine the level of gene expression 6 and 24 h after irradiation, RNA was extracted from each cell line, and expression of the above-mentioned genes in cell lines with different RS was determined by real-time polymerase chain reaction (PCR). Results: The clonogenic assay showed that human dermal fibroblasts (fibroblast) and HT-29 (colorectal) cells are radioresistant, while human foreskin fibroblasts (fibroblast) and QU-DB (lung) cells are radiosensitive. Analysis of the real-time PCR data, 6 h after irradiation, showed that the increase and decrease of the expression of TRIM29 and TRIM37 genes were directly correlated with the RS of normal and tumor cells. At 24 h postirradiation, a considerable difference was only observed in the expression of the β-catenin gene. Conclusion: This study showed that the TRIM29 and TRIM37 genes are involved in the cell response to radiation and proposed that these genes may be biomarkers for predicting RS in normal and tumoral cell lines.
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Affiliation(s)
| | - Navid Zafari
- Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hosein Azimian
- Medical Physics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hassan Mehrad-Majd
- Cancer Molecular Pathology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Javad Farhadi
- Department of Biochemistry and Molecular Biology, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran
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Sun L, Wang D, Chen Z, Zhu X. TRIM29 knockdown prevented the colon cancer progression through decreasing the ubiquitination levels of KRT5. Open Life Sci 2023; 18:20220711. [PMID: 37671092 PMCID: PMC10476480 DOI: 10.1515/biol-2022-0711] [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: 01/30/2023] [Revised: 08/01/2023] [Accepted: 08/06/2023] [Indexed: 09/07/2023] Open
Abstract
To investigate the specific role of TRIM29 in colon cancer progression, bioinformatic analysis was performed on TRIM29. Colon cancer tissues were collected and colon cancer cells were cultured for further experiments. Cell viability and proliferation were determined using CCK-8, colony formation, and EDU staining assays. The mRNA and protein levels of TRIM29 and KRT5 were determined using quantitative real-time PCR and western blotting, respectively. The interaction between TRIM29 and KRT5 was detected using a co-immunoprecipitation (CO-IP) assay. Cycloheximide treatment was performed to analyse the stability of KRT5. TRIM29 was upregulated in colon cancer tissues and cells. TRIM29 knockdown decreased the cell viability and proliferation and ubiquitination levels of KRT5 and enhanced the protein stability and expression of KRT5. The CO-IP assay confirmed that TRIM29 and KRT5 binded to each other. KRT5 knockdown neutralises the inhibitory effect of sh-TRIM29 on colon cancer cell growth and TRIM29 knockdown prevented the proliferation of colon cancer cells by decreasing ubiquitination of KRT5, which enhanced the protein stability and expression of KRT5 in cancer cells. Thus, targeting TRIM29-mediated ubiquitination levels of KRT5 might be a new direction for colon cancer therapy.
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Affiliation(s)
- Lihui Sun
- The Fifth Department of General Surgery, The Third Affiliated Hospital of Jinzhou Medical University, No. 2, Section 5, Heping Road, Jinzhou, Liaoning 121000, China
| | - Dawei Wang
- The Second Department of General Surgery, Dalian Fifth People’s Hospital, Dalian, Liaoning 116081, China
| | - Zhenyu Chen
- The Fifth Department of General Surgery, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121000, China
| | - Xu Zhu
- The Fifth Department of General Surgery, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121000, China
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14
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Yi Q, Zhao Y, Xia R, Wei Q, Chao F, Zhang R, Bian P, Lv L. TRIM29 hypermethylation drives esophageal cancer progression via suppression of ZNF750. Cell Death Discov 2023; 9:191. [PMID: 37365152 DOI: 10.1038/s41420-023-01491-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 06/06/2023] [Accepted: 06/15/2023] [Indexed: 06/28/2023] Open
Abstract
Esophageal cancer (ESCA) is the seventh most frequent and deadly neoplasm. Due to the lack of early diagnosis and high invasion/metastasis, the prognosis of ESCA remains very poor. Herein, we identify skin-related signatures as the most deficient signatures in invasive ESCA, which are regulated by the transcription factor ZNF750. Of note, we find that TRIM29 level strongly correlated with the expression of many genes in the skin-related signatures, including ZNF750. TRIM29 is significantly down-regulated due to hypermethylation of its promoter in both ESCA and precancerous lesions compared to normal tissues. Low TRIM29 expression and high methylation levels of its promoter are associated with malignant progression and poor clinical outcomes in ESCA patients. Functionally, TRIM29 overexpression markedly hinders proliferation, migration, invasion, and epithelial-mesenchymal transition of esophageal cancer cells, whereas opposing results are observed when TRIM29 is silenced in vitro. In addition, TRIM29 inhibits metastasis in vivo. Mechanistically, TRIM29 downregulation suppresses the expression of the tumor suppressor ZNF750 by activating the STAT3 signaling pathway. Overall, our study demonstrates that TRIM29 expression and its promoter methylation status could be potential early diagnostic and prognostic markers. It highlights the role of the TRIM29-ZNF750 signaling axis in modulating tumorigenesis and metastasis of esophageal cancer.
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Affiliation(s)
- Qiyi Yi
- School of Basic Medical Sciences, Anhui Medical University, 230032, Hefei, Anhui, China
| | - Yujia Zhao
- School of Basic Medical Sciences, Anhui Medical University, 230032, Hefei, Anhui, China
- Department of education training, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Ran Xia
- Department of Cancer Epigenetics Program, Anhui Cancer Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 230031, Hefei, Anhui, China
| | - Qinqin Wei
- School of Basic Medical Sciences, Anhui Medical University, 230032, Hefei, Anhui, China
| | - Fengmei Chao
- Department of Cancer Epigenetics Program, Anhui Cancer Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 230031, Hefei, Anhui, China
| | - Rui Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui University of Chinese Medicine, 230031, Hefei, Anhui, China
| | - Po Bian
- School of Basic Medical Sciences, Anhui Medical University, 230032, Hefei, Anhui, China.
| | - Lei Lv
- Department of Cancer Epigenetics Program, Anhui Cancer Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 230031, Hefei, Anhui, China.
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15
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Yue C, Qian Y, Wang C, Chen J, Wang J, Wang Z, Wan X, Cao S, Zhu J, Tao Q, Yan M, Liu Q. TRIM29 acts as a potential senescence suppressor with epigenetic activation in nasopharyngeal carcinoma. Cancer Sci 2023. [PMID: 37248790 PMCID: PMC10394149 DOI: 10.1111/cas.15852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 05/03/2023] [Accepted: 05/06/2023] [Indexed: 05/31/2023] Open
Abstract
Epigenetic alterations marked by DNA methylation are frequent events during the early development of nasopharyngeal carcinoma (NPC). We identified that TRIM29 is hypomethylated and overexpressed in NPC cell lines and tissues. TRIM29 silencing not only limited the growth of NPC cells in vitro and in vivo, but also induced cellular senescence, along with reactive oxygen species (ROS) accumulation. Mechanistically, we found that TRIM29 interacted with voltage-dependent anion-selective channel 1 (VDAC1) to activate mitophagy clearing up damaged mitochondria, which are the major source of ROS. In patients with NPC, high levels of TRIM29 expression are associated with an advanced clinical stage. Moreover, we detected hypomethylation of TRIM29 in patient nasopharyngeal swab DNA. Our findings indicate that TRIM29 depends on VDAC1 to induce mitophagy and prevents cellular senescence by decreasing ROS. Detection of aberrantly methylated TRIM29 in the nasopharyngeal swab DNA could be a promising strategy for the early detection of NPC.
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Affiliation(s)
- Caifeng Yue
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
- Department of Laboratory Medicine, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, China
| | - Yuanmin Qian
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Chang Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
- Institute of Anatomy, University of Bern, Bern, Switzerland
| | - Jiewei Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Jing Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Zifeng Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Xiangbo Wan
- Gastrointestinal Institute, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Sumei Cao
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Jingde Zhu
- Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, China
| | - Qian Tao
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong, China
| | - Min Yan
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Quentin Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
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16
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Xu X, Qin Z, Zhang C, Mi X, Zhang C, Zhou F, Wang J, Zhang L, Hua F. TRIM29 promotes podocyte pyroptosis in diabetic nephropathy through the NF-kB/NLRP3 inflammasome pathway. Cell Biol Int 2023; 47:1126-1135. [PMID: 36841942 DOI: 10.1002/cbin.12006] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 09/09/2022] [Accepted: 02/20/2023] [Indexed: 02/27/2023]
Abstract
Diabetic nephropathy (DN) is one of the most common complications of diabetes. Gradual loss of podocytes is a sign of DN and pyroptosis mechanistically correlates with podocyte injury in DN; however, the mechanism(s) involved remain unknown. Here we reveal that TRIM29 is overexpressed in high glucose (HG)-treated murine podocytes cells and that TRIM29 silencing significantly inhibits podocyte damage due to HG treatment, as evidenced by lower desmin expression and greater nephrin expression. Additionally, flow cytometry analysis showed that TRIM29 silencing significantly inhibited HG treatment-induced pyroptosis, which was confirmed by immunoblotting for NLRP3, active Caspase-1, GSDMD-N, and phosphorylated NF-κB-p65. Conversely, overexpression of TRIM29 could trigger pyroptosis that was attenuated by NF-κB inhibition, indicating that TRIM29 promotes pyroptosis through the NF-κB pathway. Mechanistic studies revealed that TRIM29 interacts with IκBα to mediate its ubiquitination-dependent degradation, which in turn leads to NF-κB activation. Taken together, our data demonstrate that TRIM29 can promote podocyte pyroptosis by activating the NF-κB/NLRP3 pathway. Thus, TRIM29 represents a potentially novel therapeutic target that may also be clinically relevant in the management of DN.
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Affiliation(s)
- Xiaohong Xu
- Department of Nephrology, Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, China.,Department of Nephrology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Zihan Qin
- Department of Endocrinology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Ce Zhang
- Department of Nephrology, Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, China
| | - Xia Mi
- Department of Nephrology, Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, China
| | - Chi Zhang
- Department of Nephrology, Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, China
| | - Feihong Zhou
- Department of Nephrology, Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, China
| | - Junsheng Wang
- Department of Nephrology, Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, China
| | - Liexiang Zhang
- Department of Neurosurgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, China.,Department of Neurosurgery, Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, China
| | - Fei Hua
- Department of Endocrinology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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Li W, Song Y, Du Y, Huang Z, Zhang M, Chen Z, He Z, Ding Y, Zhang J, Zhao L, Sun H, Jiao P. Duck TRIM29 negatively regulates type I IFN production by targeting MAVS. Front Immunol 2023; 13:1016214. [PMID: 36685538 PMCID: PMC9853200 DOI: 10.3389/fimmu.2022.1016214] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 12/19/2022] [Indexed: 01/09/2023] Open
Abstract
The innate immune response is a host defense mechanism that induces type I interferon and proinflammatory cytokines. Tripartite motif (TRIM) family proteins have recently emerged as pivotal regulators of type I interferon production in mammals. Here, we first identified duck TRIM29, which encodes 571 amino acids and shows high sequence homology with other bird TRIM29 proteins. DuTRIM29 inhibited IFN-β and IRF7 promoter activation in a dose-dependent manner and downregulated the mRNA expression of IFN-β, IRF7, Mx and IL-6 mediated by duRIG-I. Moreover, duTRIM29 interacted and colocalized with duMAVS in the cytoplasm. DuTRIM29 interacted with duMAVS via its C-terminal domains. In addition, duTRIM29 inhibited IFN-β and IRF7 promoter activation and significantly downregulated IFN-β and immune-related gene expression mediated by duMAVS in ducks. Furthermore, duTRIM29 induced K29-linked polyubiquitination and degradation of duMAVS to suppress the expression of IFN-β. Overall, our results demonstrate that duTRIM29 negatively regulates type I IFN production by targeting duMAVS in ducks. This study will contribute to a better understanding of the molecular mechanism regulating the innate immune response by TRIM proteins in ducks.
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Affiliation(s)
- Weiqiang Li
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Yating Song
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Yuqing Du
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Zhanhong Huang
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Meng Zhang
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Zuxian Chen
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Zhuoliang He
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Yangbao Ding
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Junsheng Zhang
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Luxiang Zhao
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Hailiang Sun
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Peirong Jiao
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
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Ray SK, Mukherjee S. Altered Expression of TRIM Proteins - Inimical Outcome and Inimitable Oncogenic Function in Breast Cancer with Diverse Carcinogenic Hallmarks. Curr Mol Med 2023; 23:44-53. [PMID: 35021972 DOI: 10.2174/1566524022666220111122450] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 11/25/2021] [Accepted: 11/30/2021] [Indexed: 12/16/2022]
Abstract
Deregulation of ubiquitin-mediated degradation of oncogene products or tumor suppressors appears to be implicated in the genesis of carcinomas, according to new clinical findings. Conferring to recent research, some members of the tripartite motif (TRIM) proteins (a subfamily of the RING type E3 ubiquitin ligases) act as significant carcinogenesis regulators. Intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy, and carcinogenesis are all regulated by TRIM family proteins, the majority of which have E3 ubiquitin ligase activity. The expression of TRIMs in tumors is likely to be related to the formation and/or progression of the disease, and TRIM expression could be used to predict cancer prognosis. Breast cancer is the most common malignancy in women and also the leading cause of death. TRIM family proteins have unique, vital activities, and their dysregulation, such as TRIM 21, promotes breast cancer, according to growing evidence. Many TRIM proteins have been identified as important cancer biomarkers, with decreased or elevated levels of expression. TRIM29 functions as a hypoxia-induced tumor suppressor gene, revealing a new molecular mechanism for ATM-dependent breast cancer suppression. In breast cancer cells, the TRIM28-TWIST1-EMT axis exists, and TRIM28 enhances breast cancer metastasis by stabilizing TWIST1, and thereby increasing epithelial-tomesenchymal transition. Interestingly, many TRIM proteins are involved in the control of p53, and many TRIM proteins are likewise regulated by p53, according to current research. Furthermore, TRIMs linked to specific tumors may aid in the creation of innovative TRIM-targeted cancer treatments. This review focuses on TRIM proteins that are involved in tumor development, progression, and are of clinical significance in breast cancer.
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Affiliation(s)
| | - Sukhes Mukherjee
- Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh-462020, India
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19
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Huang N, Sun X, Li P, Liu X, Zhang X, Chen Q, Xin H. TRIM family contribute to tumorigenesis, cancer development, and drug resistance. Exp Hematol Oncol 2022; 11:75. [PMID: 36261847 PMCID: PMC9583506 DOI: 10.1186/s40164-022-00322-w] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 09/16/2022] [Indexed: 11/26/2022] Open
Abstract
The tripartite-motif (TRIM) family represents one of the largest classes of putative single protein RING-finger E3 ubiquitin ligases. TRIM family is involved in a variety of cellular signaling transductions and biological processes. TRIM family also contributes to cancer initiation, progress, and therapy resistance, exhibiting oncogenic and tumor-suppressive functions in different human cancer types. Moreover, TRIM family members have great potential to serve as biomarkers for cancer diagnosis and prognosis. In this review, we focus on the specific mechanisms of the participation of TRIM family members in tumorigenesis, and cancer development including interacting with dysregulated signaling pathways such as JAK/STAT, PI3K/AKT, TGF-β, NF-κB, Wnt/β-catenin, and p53 hub. In addition, many studies have demonstrated that the TRIM family are related to tumor resistance; modulate the epithelial–mesenchymal transition (EMT) process, and guarantee the acquisition of cancer stem cells (CSCs) phenotype. In the end, we havediscussed the potential of TRIM family members for cancer therapeutic targets.
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Affiliation(s)
- Ning Huang
- Department of Pharmacology, School of Pharmacy & General Surgery of Minhang Hospital, Fudan University, Shanghai, 201203, China.,PharmaLegacy Laboratories Co.,Ltd, Shengrong Road No.388, Zhangjiang High-tech Park, Pudong New Area, Shanghai, China
| | - Xiaolin Sun
- Department of Pharmacology, School of Pharmacy & General Surgery of Minhang Hospital, Fudan University, Shanghai, 201203, China
| | - Peng Li
- Department of Pharmacology, School of Pharmacy & General Surgery of Minhang Hospital, Fudan University, Shanghai, 201203, China
| | - Xin Liu
- Department of Pharmacology, School of Pharmacy & General Surgery of Minhang Hospital, Fudan University, Shanghai, 201203, China.,PharmaLegacy Laboratories Co.,Ltd, Shengrong Road No.388, Zhangjiang High-tech Park, Pudong New Area, Shanghai, China
| | - Xuemei Zhang
- Department of Pharmacology, School of Pharmacy & General Surgery of Minhang Hospital, Fudan University, Shanghai, 201203, China.
| | - Qian Chen
- Department of Pharmacology, School of Pharmacy & General Surgery of Minhang Hospital, Fudan University, Shanghai, 201203, China.
| | - Hong Xin
- Department of Pharmacology, School of Pharmacy & General Surgery of Minhang Hospital, Fudan University, Shanghai, 201203, China.
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20
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Zhang Y, Zhang W, Zheng L, Guo Q. The roles and targeting options of TRIM family proteins in tumor. Front Pharmacol 2022; 13:999380. [PMID: 36249749 PMCID: PMC9561884 DOI: 10.3389/fphar.2022.999380] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Tripartite motif (TRIM) containing proteins are a class of E3 ubiquitin ligases, which are critically implicated in the occurrence and development of tumors. They can function through regulating various aspects of tumors, such as tumor proliferation, metastasis, apoptosis and the development of drug resistance during tumor therapy. Some members of TRIM family proteins can mediate protein ubiquitination and chromosome translocation via modulating several signaling pathways, like p53, NF-κB, AKT, MAPK, Wnt/β-catenin and other molecular regulatory mechanisms. The multi-domain nature/multi-functional biological role of TRIMs implies that blocking just one function or one domain might not be sufficient to obtain the desired therapeutic outcome, therefore, a detailed and systematic understanding of the biological functions of the individual domains of TRIMs is required. This review mainly described their roles and underlying mechanisms in tumorigenesis and progression, and it might shade light on a potential targeting strategy for TRIMs in tumor treatment, especially using PROTACs.
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Affiliation(s)
- Yuxin Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Wenzhou Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Qianqian Guo
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
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21
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Roshanazadeh MR, Adelipour M, Sanaei A, Chenane H, Rashidi M. TRIM3 and TRIM16 as potential tumor suppressors in breast cancer patients. BMC Res Notes 2022; 15:312. [PMID: 36180926 PMCID: PMC9523982 DOI: 10.1186/s13104-022-06193-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/07/2022] [Indexed: 11/10/2022] Open
Abstract
Objective Breast cancer is the leading cause of death among women in many countries. Numerous factors serve as oncogenes or tumor suppressors in breast cancer. The large family of Tripartite-motif (TRIM) proteins with ~ 80 members has drawn attention for their role in cancer. TRIM3 and TRIM16 have shown suppressive activity in different cancers. This study aimed to evaluate the expression of TRIM3 and TRIM16 in cancerous and normal breast samples and to investigate their association with different clinical and pathological parameters. Results qRT-PCR was utilized to determine the gene expression of TRIM3 and TRIM16. The expression of TRIM3 and TRIM16 genes in tumor samples were significantly reduced to 0.45 and 0.29 fold, respectively. TRIM3 and TRIM16 genes expression were both positively correlated with the invasion of breast cancer. TRIM3 gene expression was associated with tumors’ histological grade. However, no significant association was found between the expression of the genes and tumor size, stage and necrosis. The expression of TRIM3 and TRIM16 are significantly reduced in breast cancer tissues. Besides, the expression of both TRIM3 and TRIM16 genes significantly plummet in lymphatic/vascular and perineural invasive samples. Hence, we suggest a potential tumor suppressor role for TRIM3 and TRIM16 in breast cancer.
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Affiliation(s)
- Mohammad Reza Roshanazadeh
- Cancer Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of clinical biochemistry, Faculty of medicine, jundishapour University of medical sciences, Ahvaz, Iran
| | - Maryam Adelipour
- Department of clinical biochemistry, Faculty of medicine, jundishapour University of medical sciences, Ahvaz, Iran
| | - Arash Sanaei
- Department of clinical biochemistry, Faculty of medicine, jundishapour University of medical sciences, Ahvaz, Iran
| | - Hadi Chenane
- Department of clinical biochemistry, Faculty of medicine, jundishapour University of medical sciences, Ahvaz, Iran
| | - Mojtaba Rashidi
- Cancer Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. .,Department of clinical biochemistry, Faculty of medicine, jundishapour University of medical sciences, Ahvaz, Iran.
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22
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Xiao S, Yu J, Yuan X, Chen Q. Identification of a tripartite motif family gene signature for predicting the prognosis of patients with glioma. Am J Transl Res 2022; 14:1535-1550. [PMID: 35422900 PMCID: PMC8991143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 01/20/2022] [Indexed: 06/14/2023]
Abstract
UNLABELLED Objectiove: The tripartite motif (TRIM) family genes, which encode a protein subfamily of the RING type E3 ubiquitin ligases, function as important regulators of oncogenesis and development. It is thus of great importance to investigate the potential value of the TRIM family genes for prognostic prediction in glioma. METHODS The gene expression RNA-Seq data and corresponding clinical information of glioma patients were obtained from The Cancer Genome Atlas (TCGA) dataset and the Chinese Glioma Genome Atlas (CGGA) dataset. LASSO regression and multivariate Cox regression analyses were performed to construct a risk signature of the TRIM family genes. The accuracy of the risk signature in predicting the prognosis of glioma patients was evaluated. The effects of TRIM17 on glioma cell proliferation were further explored. RESULTS We constructed a prognostic signature based on eight TRIMs for the prediction of overall survival of glioma patients. Internal and external cohorts confirmed the satisfactory accuracy and generalizability of the signature in predicting the prognosis of glioma patients. Of the eight TRIMs, TRIM17 was significantly downregulated in glioma, and decreased with an increase in the tumor grade. Moreover, low expression of TRIM17 predicted poor prognosis in glioma. CCK-8 and colony formation assays indicated that TRIM17 overexpression significantly inhibited cell proliferation. Conversely, silencing of TRIM17 had the opposite effects. CONCLUSION Our eight-gene signature based on the TRIM gene family is a novel and clinically useful biomarker, which may be helpful for clinical decision-making. Additionally, TRIM17 might be a therapeutic target for glioma.
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Affiliation(s)
- Sheng Xiao
- Department of Neurosurgery, Renmin Hospital of Wuhan UniversityWuhan 430060, Hubei Province, China
- Department of Neurosurgery, Ezhou Central HospitalEzhou 436000, Hubei Province, China
| | - Junhua Yu
- Department of Neurosurgery, Ezhou Central HospitalEzhou 436000, Hubei Province, China
| | - Xuegang Yuan
- Department of Neurosurgery, Ezhou Central HospitalEzhou 436000, Hubei Province, China
| | - Qianxue Chen
- Department of Neurosurgery, Renmin Hospital of Wuhan UniversityWuhan 430060, Hubei Province, China
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23
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Nagasawa S, Ikeda K, Shintani D, Yang C, Takeda S, Hasegawa K, Horie K, Inoue S. Identification of a Novel Oncogenic Fusion Gene SPON1-TRIM29 in Clinical Ovarian Cancer That Promotes Cell and Tumor Growth and Enhances Chemoresistance in A2780 Cells. Int J Mol Sci 2022; 23:689. [PMID: 35054873 PMCID: PMC8776205 DOI: 10.3390/ijms23020689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/04/2022] [Accepted: 01/06/2022] [Indexed: 02/04/2023] Open
Abstract
Gene structure alterations, such as chromosomal rearrangements that develop fusion genes, often contribute to tumorigenesis. It has been shown that the fusion genes identified in public RNA-sequencing datasets are mainly derived from intrachromosomal rearrangements. In this study, we explored fusion transcripts in clinical ovarian cancer specimens based on our RNA-sequencing data. We successfully identified an in-frame fusion transcript SPON1-TRIM29 in chromosome 11 from a recurrent tumor specimen of high-grade serous carcinoma (HGSC), which was not detected in the corresponding primary carcinoma, and validated the expression of the identical fusion transcript in another tumor from a distinct HGSC patient. Ovarian cancer A2780 cells stably expressing SPON1-TRIM29 exhibited an increase in cell growth, whereas a decrease in apoptosis was observed, even in the presence of anticancer drugs. The siRNA-mediated silencing of SPON1-TRIM29 fusion transcript substantially impaired the enhanced growth of A2780 cells expressing the chimeric gene treated with anticancer drugs. Moreover, a subcutaneous xenograft model using athymic mice indicated that SPON1-TRIM29-expressing A2780 cells rapidly generated tumors in vivo compared to control cells, whose growth was significantly repressed by the fusion-specific siRNA administration. Overall, the SPON1-TRIM29 fusion gene could be involved in carcinogenesis and chemotherapy resistance in ovarian cancer, and offers potential use as a diagnostic and therapeutic target for the disease with the fusion transcript.
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Affiliation(s)
- Saya Nagasawa
- Division of Systems Medicine & Gene Therapy, Saitama Medical University, Hidaka, Saitama 350-1241, Japan; (S.N.); (K.I.); (C.Y.)
- Department of Obstetrics and Gynecology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan;
| | - Kazuhiro Ikeda
- Division of Systems Medicine & Gene Therapy, Saitama Medical University, Hidaka, Saitama 350-1241, Japan; (S.N.); (K.I.); (C.Y.)
| | - Daisuke Shintani
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama 350-1298, Japan; (D.S.); (K.H.)
| | - Chiujung Yang
- Division of Systems Medicine & Gene Therapy, Saitama Medical University, Hidaka, Saitama 350-1241, Japan; (S.N.); (K.I.); (C.Y.)
- Department of Obstetrics and Gynecology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan;
| | - Satoru Takeda
- Department of Obstetrics and Gynecology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan;
| | - Kosei Hasegawa
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama 350-1298, Japan; (D.S.); (K.H.)
| | - Kuniko Horie
- Division of Systems Medicine & Gene Therapy, Saitama Medical University, Hidaka, Saitama 350-1241, Japan; (S.N.); (K.I.); (C.Y.)
| | - Satoshi Inoue
- Division of Systems Medicine & Gene Therapy, Saitama Medical University, Hidaka, Saitama 350-1241, Japan; (S.N.); (K.I.); (C.Y.)
- Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan
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24
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Hsu CY, Yanagi T, Ujiie H. TRIM29 in Cutaneous Squamous Cell Carcinoma. Front Med (Lausanne) 2022; 8:804166. [PMID: 34988104 PMCID: PMC8720877 DOI: 10.3389/fmed.2021.804166] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/02/2021] [Indexed: 12/13/2022] Open
Abstract
Tripartite motif (TRIM) proteins play important roles in a wide range of cell physiological processes, such as signal transduction, transcriptional regulation, innate immunity, and programmed cell death. TRIM29 protein, encoded by the ATDC gene, belongs to the RING-less group of TRIM protein family members. It consists of four zinc finger motifs in a B-box domain and a coiled-coil domain, and makes use of the B-box domain as E3 ubiquitin ligase in place of the RING. TRIM29 was found to be involved in the formation of homodimers and heterodimers in relation to DNA binding; additional studies have also demonstrated its role in carcinogenesis, DNA damage signaling, and the suppression of radiosensitivity. Recently, we reported that TRIM29 interacts with keratins and FAM83H to regulate keratin distribution. Further, in cutaneous SCC, the expression of TRIM29 is silenced by DNA methylation, leading to the loss of TRIM29 and promotion of keratinocyte migration. This paper reviews the role of TRIM family proteins in malignant tumors, especially the role of TRIM29 in cutaneous SCC.
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Affiliation(s)
- Che-Yuan Hsu
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Teruki Yanagi
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hideyuki Ujiie
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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25
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Targeting Post-Translational Regulation of p53 in Colorectal Cancer by Exploiting Vulnerabilities in the p53-MDM2 Axis. Cancers (Basel) 2022; 14:cancers14010219. [PMID: 35008383 PMCID: PMC8750794 DOI: 10.3390/cancers14010219] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/23/2021] [Accepted: 12/30/2021] [Indexed: 02/05/2023] Open
Abstract
The role played by the key tumor suppressor gene p53 and the implications of p53 mutations for the development and progression of neoplasia continue to expand. This review focuses on colorectal cancer and the regulators of p53 expression and activity identified over the past decade. These newly recognized regulatory mechanisms include (1) direct regulation of mouse double minute 2 homolog (MDM2), an E3 ubiquitin-protein ligase; (2) modulation of the MDM2-p53 interaction; (3) MDM2-independent p53 degradation; and (4) inhibition of p53 nuclear translocation. We positioned these regulatory mechanisms in the context of p53 missense mutations, which not only evade canonical p53 degradation machinery but also exhibit gain-of-function phenotypes that enhance tumor survival and metastasis. Lastly, we discuss current and potential therapeutic strategies directed against p53 mutant-bearing tumors.
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26
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Abstract
Replicative senescence occurs due to an inability to repair DNA damage and activation of p53/p21 and p16INK4 pathways. It is considered a preventive mechanism for arresting proliferation of DNA-damaged cells. Stably senescent cells are characterized by a senescence-associated secretory phenotype (SASP), which produces and secretes cytokines, chemokines, and/or matrix metalloproteinases depending on the cell type. SASP proteins may increase cell proliferation, facilitating conversion of premalignant to malignant tumor cells, triggering DNA damage, and altering the tissue microenvironment. Further, senescent cells accumulate with age, thereby aggravating age-related tissue damage. Here, we review a heretofore unappreciated role for growth hormone (GH) as a SASP component, acting in an autocrine and paracrine fashion. In senescent cells, GH is activated by DNA-damage-induced p53 and inhibits phosphorylation of DNA repair proteins ATM, Chk2, p53, and H2AX. Somatotroph adenomas containing abundant intracellular GH exhibit increased somatic copy number alterations, indicative of DNA damage, and are associated with induced p53/p21. As this pathway restrains proliferation of DNA-damaged cells, these mechanisms may underlie the senescent phenotype and benign nature of slowly proliferating pituitary somatotroph adenomas. In highly proliferative cells, such as colon epithelial cells, GH induced in response to DNA damage suppresses p53, thereby triggering senescent cell proliferation. As senescent cells harbor unrepaired DNA damage, GH may enable senescent cells to evade senescence and reenter the cell cycle, resulting in acquisition of harmful mutations. These mechanisms, at least in part, may underlie pro-aging effects of GH observed in animal models and in patients with chronically elevated GH levels.
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Affiliation(s)
- Vera Chesnokova
- Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Shlomo Melmed
- Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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27
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Lei G, Liu S, Yang X, He C. TRIM29 Reverses Oxaliplatin Resistance of P53 Mutant Colon Cancer Cell. Can J Gastroenterol Hepatol 2021; 2021:8870907. [PMID: 33824865 PMCID: PMC8007381 DOI: 10.1155/2021/8870907] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 02/25/2021] [Accepted: 03/09/2021] [Indexed: 02/08/2023] Open
Abstract
Background Oxaliplatin is the first-choice chemotherapy method for patients with advanced colon cancer. However, its resistance leads to treatment failure for many patients. In our experiments, we aim to elucidate the associations among TRIM29 protein, mutant P53, and the resistance of colon cancer cells to oxaliplatin. Methods HCT116 and HT-29 cells were cultured and transfected with plasmids pIRES2-ZsGreen1-TRIM29-flag. Western blot and real-time qRT-PCR were utilized to examine the protein and mRNA expressions of TRIM29 and other related markers, respectively. MTT assay was utilized to determine the cell growth rate and generate the inhibition curve. Continuous culture in low-concentration oxaliplatin was conducted to construct oxaliplatin-resistant cell lines. The coimmunoprecipitation method and immunofluorescence detection were used to examine the interaction between TRIM29 and mutant P53 protein in HT29 cells. Results We successfully transfected pIRES2-ZsGreen1-TRIM29-flag into HCT116 and HT29 cells, which were utilized in the whole experiments. TRIM29 significantly increased the sensitivity of P53 mutant colon cancer cell HT29 to oxaliplatin. The oxaliplatin-resistant model of P53 mutant colon cancer cell HT29 was successfully constructed. TRIM29 physically bound with mutant P53 and retained it in the cytoplasm from the nucleus, which inhibited its transcription function of downstream genes such as MDR1. In addition, TRIM29 successfully reversed the resistance of HT29-OX resistant cell model to oxaliplatin. Conclusion In mutant P53 colon cancer cell HT29, TRIM29 greatly increased the sensitivity of HT29 to oxaliplatin and reverse oxaliplatin resistance. The underlying mechanism is TRIM29 may increase the sensitivity of HT29 to oxaliplatin by blocking the transcriptional function of mutant P53, which inhibits the transcription function of its downstream gene such as MDR1.
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Affiliation(s)
- Guoqiong Lei
- Department of Neurosurgery, The Second People's Hospital of Hunan Province, Changsha, Hunan 410007, China
| | - Sushun Liu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Xin Yang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Chao He
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
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28
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Marzano F, Caratozzolo MF, Pesole G, Sbisà E, Tullo A. TRIM Proteins in Colorectal Cancer: TRIM8 as a Promising Therapeutic Target in Chemo Resistance. Biomedicines 2021; 9:biomedicines9030241. [PMID: 33673719 PMCID: PMC7997459 DOI: 10.3390/biomedicines9030241] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/16/2021] [Accepted: 02/23/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) represents one of the most widespread forms of cancer in the population and, as all malignant tumors, often develops resistance to chemotherapies with consequent tumor growth and spreading leading to the patient’s premature death. For this reason, a great challenge is to identify new therapeutic targets, able to restore the drugs sensitivity of cancer cells. In this review, we discuss the role of TRIpartite Motifs (TRIM) proteins in cancers and in CRC chemoresistance, focusing on the tumor-suppressor role of TRIM8 protein in the reactivation of the CRC cells sensitivity to drugs currently used in the clinical practice. Since the restoration of TRIM8 protein levels in CRC cells recovers chemotherapy response, it may represent a new promising therapeutic target in the treatment of CRC.
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Affiliation(s)
- Flaviana Marzano
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, CNR, 70126 Bari, Italy; (F.M.); (M.F.C.); (G.P.)
| | - Mariano Francesco Caratozzolo
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, CNR, 70126 Bari, Italy; (F.M.); (M.F.C.); (G.P.)
| | - Graziano Pesole
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, CNR, 70126 Bari, Italy; (F.M.); (M.F.C.); (G.P.)
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, “Aldo Moro”, 70125 Bari, Italy
| | - Elisabetta Sbisà
- Institute for Biomedical Technologies, National Research Council, CNR, 70126 Bari, Italy;
| | - Apollonia Tullo
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, CNR, 70126 Bari, Italy; (F.M.); (M.F.C.); (G.P.)
- Correspondence:
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29
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Purohit V, Wang L, Yang H, Li J, Ney GM, Gumkowski ER, Vaidya AJ, Wang A, Bhardwaj A, Zhao E, Dolgalev I, Zamperone A, Abel EV, Magliano MPD, Crawford HC, Diolaiti D, Papagiannakopoulos TY, Lyssiotis CA, Simeone DM. ATDC binds to KEAP1 to drive NRF2-mediated tumorigenesis and chemoresistance in pancreatic cancer. Genes Dev 2021; 35:218-233. [PMID: 33446568 PMCID: PMC7849366 DOI: 10.1101/gad.344184.120] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 11/25/2020] [Indexed: 01/04/2023]
Abstract
Pancreatic ductal adenocarcinoma is a lethal disease characterized by late diagnosis, propensity for early metastasis and resistance to chemotherapy. Little is known about the mechanisms that drive innate therapeutic resistance in pancreatic cancer. The ataxia-telangiectasia group D-associated gene (ATDC) is overexpressed in pancreatic cancer and promotes tumor growth and metastasis. Our study reveals that increased ATDC levels protect cancer cells from reactive oxygen species (ROS) via stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Mechanistically, ATDC binds to Kelch-like ECH-associated protein 1 (KEAP1), the principal regulator of NRF2 degradation, and thereby prevents degradation of NRF2 resulting in activation of a NRF2-dependent transcriptional program, reduced intracellular ROS and enhanced chemoresistance. Our findings define a novel role of ATDC in regulating redox balance and chemotherapeutic resistance by modulating NRF2 activity.
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Affiliation(s)
- Vinee Purohit
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
| | - Lidong Wang
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
| | - Huibin Yang
- Department of Radiation Oncology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
| | - Jiufeng Li
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
| | - Gina M Ney
- Department of Pediatric Oncology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
| | - Erica R Gumkowski
- Department of Molecular and Integrative Physiology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
| | - Akash J Vaidya
- Department of Molecular and Integrative Physiology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
| | - Annie Wang
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
- Department of Surgery, New York University, New York, New York 10016, USA
| | - Amit Bhardwaj
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
| | - Ende Zhao
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
| | - Igor Dolgalev
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
| | - Andrea Zamperone
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
| | - Ethan V Abel
- Department of Molecular and Integrative Physiology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
| | - Marina Pasca Di Magliano
- Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
| | - Howard C Crawford
- Department of Molecular and Integrative Physiology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
- Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
| | - Daniel Diolaiti
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
| | - Thales Y Papagiannakopoulos
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
- Department of Pathology, New York University, New York, New York 10016, USA
| | - Costas A Lyssiotis
- Department of Molecular and Integrative Physiology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
- Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
| | - Diane M Simeone
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
- Department of Surgery, New York University, New York, New York 10016, USA
- Department of Pathology, New York University, New York, New York 10016, USA
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Zhan W, Zhang S. TRIM proteins in lung cancer: Mechanisms, biomarkers and therapeutic targets. Life Sci 2021; 268:118985. [PMID: 33412211 DOI: 10.1016/j.lfs.2020.118985] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 12/13/2020] [Accepted: 12/22/2020] [Indexed: 12/24/2022]
Abstract
The tripartite motif (TRIM) family is defined by the presence of a Really Interesting New Gene (RING) domain, one or two B-box motifs and a coiled-coil region. TRIM proteins play key roles in many biological processes, including innate immunity, tumorigenesis, cell differentiation and ontogenetic development. Alterations in TRIM gene and protein levels frequently emerge in a wide range of tumors and affect tumor progression. As canonical E3 ubiquitin ligases, TRIM proteins participate in ubiquitin-dependent proteolysis of prominent components of the p53, NF-κB and PI3K/AKT signaling pathways. The occurrence of ubiquitylation events induced by TRIM proteins sustains internal balance between tumor suppressive and tumor promoting genes. In this review, we summarized the diverse mechanism of TRIM proteins responsible for the most common malignancy, lung cancer. Furthermore, we also discussed recent progress in both the diagnosis and therapeutics of tumors contributed by TRIM proteins.
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Affiliation(s)
- Weihua Zhan
- Ecology and Health Institute, Hangzhou Vocational & Technical College, Hangzhou 310018, China.
| | - Song Zhang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
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Suppression of long noncoding RNA LINC00324 restricts cell proliferation and invasion of papillary thyroid carcinoma through downregulation of TRIM29 via upregulating microRNA-195-5p. Aging (Albany NY) 2020; 12:26000-26011. [PMID: 33318312 PMCID: PMC7803523 DOI: 10.18632/aging.202219] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 10/23/2020] [Indexed: 12/13/2022]
Abstract
Long noncoding RNAs (lncRNAs) are identified as novel regulators of carcinogenesis. To date, the precise functions of lncRNAs in papillary thyroid carcinoma (PTC) remains poorly understood. The purposes of this work were to explore the potential relevance of lncRNA 00324 (LINC00324) in PTC. Levels of LINC00324 were markedly up-regulated in PTC. Silencing of LINC00324 significantly repressed the proliferation and invasion of PTC cells. LINC00324 was documented as a sponge of microRNA-195-5p (miR-195-5p). Decreased levels of miR-195-5p were detected in PTC. The up-regulation of miR-195-5p suppressed PTC cellular proliferation and invasion. Suppression of miR-195-5p partially reversed the LINC00324-knockdown-mediated effects in PTC cells. We identified tripartite motif-containing 29 (TRIM29) as a target gene of miR-195-5p. TRIM29 overexpression partially reversed the LINC00324-knockdown- or miR-195-5p-overexpression-mediated effects in PTC cells. In short, this work demonstrates that LINC00324 knockdown inhibits the proliferation and invasion of PTC cells by decreasing TRIM29 expression via up-regulating miR-195-5p expression.
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32
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Song Z, Guo Q, Wang H, Gao L, Wang S, Liu D, Liu J, Qi Y, Lin B. miR-5193, regulated by FUT1, suppresses proliferation and migration of ovarian cancer cells by targeting TRIM11. Pathol Res Pract 2020; 216:153148. [PMID: 32823233 DOI: 10.1016/j.prp.2020.153148] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 07/14/2020] [Accepted: 07/24/2020] [Indexed: 12/24/2022]
Abstract
Ovarian cancer is the most lethal gynecological malignancy worldwide. A better understanding of the pathogenesis of ovarian cancer may help to improve the overall survival. Our previous studies have demonstrated that alpha-(1,2)-fucosyltransferase 1 (FUT1) is an oncogenic glycogene in ovarian cancer. However, the underlying mechanism is not fully clarified. In this study, we identified a microRNA as an important downstream regulator for the carcinogenic effect of FUT1 in ovarian cancer. miR-5193 was found down-regulated in ovarian cancer cells, FUT1-overexpression ovarian cancer cells and ovarian tumor samples. MTT, flow cytometry and Transwell assays demonstrated that miR-5193 inhibited the proliferation and migration, and induced the cell cycle arrest and apoptosis of ovarian cancer cells. Real-time PCR and western blot assays showed that miR-5193 downregulated the expression of TRIM11 and upregulated the expression of p53 and p21. Dual luciferase reporter assay indicated that TRIM11 was a direct target of miR‑5193. Rescue experiments confirmed that miR-5193 functioned in ovarian cancer cells by directly targeting TRIM11. Moreover, transfection with miR-5193 mimic in FUT1-overexpression ovarian cancer cells reversed the carcinogenic effect of FUT1. Taken together, our results suggest that miR-5193 is an essential suppressor of human ovarian cancer development, and is an important downstream regulator regarding the carcinogenesis of FUT1 in ovarian cancer.
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Affiliation(s)
- Zuofei Song
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China; Department of Obstetrics and Gynecology, General Hospital of Northern Theater Command, Shenyang, 110016, People's Republic of China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Benxi 117004, People's Republic of China
| | - Qian Guo
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Benxi 117004, People's Republic of China
| | - Huimin Wang
- Department of Obstetrics and Gynecology, Liaoning Cancer Hospital and Institute, Shenyang, 110042, People's Republic of China
| | - Lingling Gao
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Benxi 117004, People's Republic of China
| | - Shuang Wang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Benxi 117004, People's Republic of China
| | - Dawo Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Benxi 117004, People's Republic of China
| | - Juanjuan Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Benxi 117004, People's Republic of China
| | - Yue Qi
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Benxi 117004, People's Republic of China
| | - Bei Lin
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Benxi 117004, People's Republic of China.
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Eberhardt W, Haeussler K, Nasrullah U, Pfeilschifter J. Multifaceted Roles of TRIM Proteins in Colorectal Carcinoma. Int J Mol Sci 2020; 21:ijms21207532. [PMID: 33066016 PMCID: PMC7590211 DOI: 10.3390/ijms21207532] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/06/2020] [Accepted: 10/07/2020] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most frequently diagnosed tumor in humans and one of the most common causes of cancer-related death worldwide. The pathogenesis of CRC follows a multistage process which together with somatic gene mutations is mainly attributed to the dysregulation of signaling pathways critically involved in the maintenance of homeostasis of epithelial integrity in the intestine. A growing number of studies has highlighted the critical impact of members of the tripartite motif (TRIM) protein family on most types of human malignancies including CRC. In accordance, abundant expression of many TRIM proteins has been observed in CRC tissues and is frequently correlating with poor survival of patients. Notably, some TRIM members can act as tumor suppressors depending on the context and the type of cancer which has been assessed. Mechanistically, most cancer-related TRIMs have a critical impact on cell cycle control, apoptosis, epithelial–mesenchymal transition (EMT), metastasis, and inflammation mainly through directly interfering with diverse oncogenic signaling pathways. In addition, some recent publications have emphasized the emerging role of some TRIM members to act as transcription factors and RNA-stabilizing factors thus adding a further level of complexity to the pleiotropic biological activities of TRIM proteins. The current review focuses on oncogenic signaling processes targeted by different TRIMs and their particular role in the development of CRC. A better understanding of the crosstalk of TRIMs with these signaling pathways relevant for CRC development is an important prerequisite for the validation of TRIM proteins as novel biomarkers and as potential targets of future therapies for CRC.
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Wikiniyadhanee R, Lerksuthirat T, Stitchantrakul W, Chitphuk S, Sura T, Dejsuphong D. TRIM29 is required for efficient recruitment of 53BP1 in response to DNA double-strand breaks in vertebrate cells. FEBS Open Bio 2020; 10:2055-2071. [PMID: 33017104 PMCID: PMC7530400 DOI: 10.1002/2211-5463.12954] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 07/18/2020] [Accepted: 08/14/2020] [Indexed: 12/17/2022] Open
Abstract
Tripartite motif‐containing protein 29 (TRIM29) is involved in DNA double‐strand break (DSB) repair. However, the specific roles of TRIM29 in DNA repair are not clearly understood. To investigate the involvement of TRIM29 in DNA DSB repair, we disrupted TRIM29 in DT40 cells by gene targeting with homologous recombination (HR). The roles of TRIM29 were investigated by clonogenic survival assays and immunofluorescence analyses. TRIM29 triallelic knockout (TRIM29−/−/−/+) cells were sensitive to etoposide, but resistant to camptothecin. Foci formation assays to assess DNA repair activities showed that the dissociation of etoposide‐induced phosphorylated H2A histone family member X (ɣ‐H2AX) foci was retained in TRIM29−/−/−/+ cells, and the formation of etoposide‐induced tumor suppressor p53‐binding protein 1 (53BP1) foci in TRIM29−/−/−/+ cells was slower compared with wild‐type (WT) cells. Interestingly, the kinetics of camptothecin‐induced RAD51 foci formation of TRIM29−/−/−/+ cells was higher than that of WT cells. These results indicate that TRIM29 is required for efficient recruitment of 53BP1 to facilitate the nonhomologous end‐joining (NHEJ) pathway and thereby suppress the HR pathway in response to DNA DSBs. TRIM29 regulates the choice of DNA DSB repair pathway by facilitating 53BP1 accumulation to promote NHEJ and may have potential for development into a therapeutic target to sensitize refractory cancers or as biomarker of personalized therapies.
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Affiliation(s)
- Rakkreat Wikiniyadhanee
- Section for Translational Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Tassanee Lerksuthirat
- Research Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Wasana Stitchantrakul
- Research Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Sermsiri Chitphuk
- Research Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Thanyachai Sura
- Department of Internal Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Donniphat Dejsuphong
- Section for Translational Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Wu T, Zhang DL, Wang JM, Jiang JY, Du X, Zeng XY, Du ZX. TRIM29 inhibits miR-873-5P biogenesis via CYTOR to upregulate fibronectin 1 and promotes invasion of papillary thyroid cancer cells. Cell Death Dis 2020; 11:813. [PMID: 32994394 PMCID: PMC7525524 DOI: 10.1038/s41419-020-03018-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 08/02/2020] [Accepted: 08/03/2020] [Indexed: 02/08/2023]
Abstract
Papillary thyroid cancer (PTC) is the most common endocrine tumor with an increasing incidence, has a strong propensity for neck lymph node metastasis. Limited treatment options are available for patients with advanced or recurrent metastatic disease, resulting in a poor prognosis. Tripartite motif protein 29 (TRIM29) is dysregulated in various cancer and functions as oncogene or tumor suppressor in discrete cancers. In this study, we found that both TRIM29 and fibronectin 1 (FN1) were upregulated with positive correlation in PTC tissues. Neither overexpression nor downregulation of TRIM29 altered the proliferation of PTC cells significantly. Overexpression of TRIM29 significantly promotes, while knockdown of TRIM29 significantly decreases migration and invasion by regulating FN1 expression in PTC cells. In terms of mechanism, we found that TRIM29 altered the stability of FN1 mRNA via regulation of miR-873-5p expression. The current study also demonstrated that long non-coding RNA (LncRNA) CYTOR suppressed maturation of miR-873-5p via interaction with premiR-873, and TRIM29 decreased miR-873-5p via upregulation of CYTOR. This study suggests that involvement of TRIM29 in migration and invasion in PTC cells may reveal potential metastatic mechanism of PTC and represent a novel therapeutic target and strategy.
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Affiliation(s)
- Tong Wu
- Department of Endocrinology & Metabolism, the 1st affiliated Hospital, China Medical University, 110001, Shenyang, China
| | - Da-Lin Zhang
- Department of Thyroid Surgery, the 1st affiliated Hospital, China Medical University, 110001, Shenyang, China
| | - Jia-Mei Wang
- Department of Laboratory Medicine, the 1st affiliated hospital, China Medical University, 110001, Shenyang, China
| | - Jing-Yi Jiang
- Department of Biochemistry & Molecular Biology, China Medical University, 110122, Shenyang, China
| | - Xin Du
- Department of Endocrinology & Metabolism, the 1st affiliated Hospital, China Medical University, 110001, Shenyang, China
| | - Xiao-Yan Zeng
- Department of Endocrinology & Metabolism, the 1st affiliated Hospital, China Medical University, 110001, Shenyang, China
| | - Zhen-Xian Du
- Department of Endocrinology & Metabolism, the 1st affiliated Hospital, China Medical University, 110001, Shenyang, China.
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Liu J, Zhang C, Wang X, Hu W, Feng Z. Tumor suppressor p53 cross-talks with TRIM family proteins. Genes Dis 2020; 8:463-474. [PMID: 34179310 PMCID: PMC8209353 DOI: 10.1016/j.gendis.2020.07.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/06/2020] [Accepted: 07/07/2020] [Indexed: 12/11/2022] Open
Abstract
p53 is a key tumor suppressor. As a transcription factor, p53 accumulates in cells in response to various stress signals and selectively transcribes its target genes to regulate a wide variety of cellular stress responses to exert its function in tumor suppression. In addition to tumor suppression, p53 is also involved in many other physiological and pathological processes, e.g. anti-infection, immune response, development, reproduction, neurodegeneration and aging. To maintain its proper function, p53 is under tight and delicate regulation through different mechanisms, particularly the posttranslational modifications. The tripartite motif (TRIM) family proteins are a large group of proteins characterized by the RING, B-Box and coiled-coil (RBCC) domains at the N-terminus. TRIM proteins play important roles in regulation of many fundamental biological processes, including cell proliferation and death, DNA repair, transcription, and immune response. Alterations of TRIM proteins have been linked to many diseases including cancer, infectious diseases, developmental disorders, and neurodegeneration. Interestingly, recent studies have revealed that many TRIM proteins are involved in the regulation of p53, and at the same time, many TRIM proteins are also regulated by p53. Here, we review the cross-talk between p53 and TRIM proteins, and its impact upon cellular biological processes as well as cancer and other diseases.
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Affiliation(s)
- Juan Liu
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA
| | - Cen Zhang
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA
| | - Xue Wang
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA
| | - Wenwei Hu
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA
| | - Zhaohui Feng
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA
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Hao Q, Chen Y, Zhou X. The Janus Face of p53-Targeting Ubiquitin Ligases. Cells 2020; 9:cells9071656. [PMID: 32660118 PMCID: PMC7407405 DOI: 10.3390/cells9071656] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/03/2020] [Accepted: 07/06/2020] [Indexed: 12/11/2022] Open
Abstract
The tumor suppressor p53 prevents tumorigenesis and cancer progression by maintaining genomic stability and inducing cell growth arrest and apoptosis. Because of the extremely detrimental nature of wild-type p53, cancer cells usually mutate the TP53 gene in favor of their survival and propagation. Some of the mutant p53 proteins not only lose the wild-type activity, but also acquire oncogenic function, namely “gain-of-function”, to promote cancer development. Growing evidence has revealed that various E3 ubiquitin ligases are able to target both wild-type and mutant p53 for degradation or inactivation, and thus play divergent roles leading to cancer cell survival or death in the context of different p53 status. In this essay, we reviewed the recent progress in our understanding of the p53-targeting E3 ubiquitin ligases, and discussed the potential clinical implications of these E3 ubiquitin ligases in cancer therapy.
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Affiliation(s)
- Qian Hao
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;
| | - Yajie Chen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China;
| | - Xiang Zhou
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;
- Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
- Correspondence: ; Tel.: +86-21-54237325
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Xu W, Chen B, Ke D, Chen X. TRIM29 mediates lung squamous cell carcinoma cell metastasis by regulating autophagic degradation of E-cadherin. Aging (Albany NY) 2020; 12:13488-13501. [PMID: 32640423 PMCID: PMC7377877 DOI: 10.18632/aging.103451] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 05/01/2020] [Indexed: 01/09/2023]
Abstract
Lung squamous cell carcinoma (LSCC) is the most common histological type of primary lung cancer. In this study, we had tested the biological role of TRIM29 in LSCC cells. TRIM29 abundance, the relationships between TRIM29 and E-cadherin and autophagy degradation related proteins in clinical tissues and six cell lines were studied with quantitative real-time PCR test (qRT-PCR) and western blot. TRIM29 overexpression treated HTB-182 cells and knockdown treated NCL-H1915 cells was used for studying cell proliferation, colony formation, migration, invasion, and the expression of epithelial mesenchymal transformation (EMT) associated biomarkers. The relationships between TRIM29 and BECN1 were investigated with western blot. TRIM29 was profoundly overexpressed in LSCC tissues and cells compared with human normal bronchial epithelial cells (HNBE). High TRIM29 expression was closely related to overall survival (OS). TRIM29 overexpression and knockdown affected LSCC activity and the expression of EMT associated biomarkers. TRIM29 can regulate the degradation of E-cadherin and autophagy of LSCC through BECN1 gene, and promote autophagy in HTB-182 and NCL-H1915 cells. Our results revealed that TRIM29 could promote the proliferation, migration, and invasion of LSCC via E-cadherin autophagy degradation. The results are useful for further study in LSCC.
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Affiliation(s)
- Weifeng Xu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan, P.R. China
| | - Beibei Chen
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan, P.R. China
| | - Dianshan Ke
- Department of Cell Biology, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Xiaobing Chen
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan, P.R. China
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39
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Han Y, Tan Y, Zhao Y, Zhang Y, He X, Yu L, Jiang H, Lu H, Tian H. TRIM23 overexpression is a poor prognostic factor and contributes to carcinogenesis in colorectal cancer. J Cell Mol Med 2020; 24:5491-5500. [PMID: 32227572 PMCID: PMC7214184 DOI: 10.1111/jcmm.15203] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Revised: 11/02/2019] [Accepted: 03/06/2020] [Indexed: 01/20/2023] Open
Abstract
The tripartite motif (TRIM) family proteins play a great role in carcinogenesis. However, the expression pattern, prognostic value and biological functions of tripartite motif containing 23 (TRIM23) in colorectal cancer (CRC) are poorly understood. Here, we found that TRIM23 is up‐regulated and associated with tumour size, lymph node metastasis, American Joint Committee on Cancer (AJCC) stage and poor prognosis in CRC. Multivariate Cox regression analyses revealed that TRIM23 overexpression could be identified as an independent prognostic factor for CRC. TRIM23 could promote the proliferation of CRC cell in vitro and in vivo; additionally, TRIM23 depletion induced G1phase arrest. Gene set enrichment analysis (GSEA) revealed that P53 and cell cycle signalling pathway‐related genes were enriched in patients with high TRIM23 expression levels. We show in this study that TRIM23 physically binds to P53 and enhances the ubiquitination of P53, thereby promoting tumour proliferation. Thus, our data indicated that TRIM23 acts as an oncogene in colorectal carcinogenesis and may provide a novel therapeutic target for CRC management.
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Affiliation(s)
- Yudong Han
- Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ye Tan
- Department of Radiation Oncology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yuanyuan Zhao
- Department of Radiation Oncology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yongchun Zhang
- Department of Radiation Oncology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xinjia He
- Department of Radiation Oncology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Li Yu
- Department of Radiation Oncology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Haiping Jiang
- Department of Radiation Oncology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Haijun Lu
- Department of Radiation Oncology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Haiying Tian
- Department of Radiation Oncology, Affiliated Hospital of Qingdao University, Qingdao, China
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40
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Garranzo-Asensio M, San Segundo-Acosta P, Povés C, Fernández-Aceñero MJ, Martínez-Useros J, Montero-Calle A, Solís-Fernández G, Sanchez-Martinez M, Rodríguez N, Cerón MÁ, Fernandez-Diez S, Domínguez G, de Los Ríos V, Peláez-García A, Guzmán-Aránguez A, Barderas R. Identification of tumor-associated antigens with diagnostic ability of colorectal cancer by in-depth immunomic and seroproteomic analysis. J Proteomics 2020; 214:103635. [PMID: 31918032 DOI: 10.1016/j.jprot.2020.103635] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 01/02/2020] [Accepted: 01/05/2020] [Indexed: 12/18/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer related death worldwide. Its diagnosis at early stages would significantly improve the survival of CRC patients. The humoral immune response has been demonstrated useful for cancer diagnosis, predating clinical symptoms up to 3 years. Here, we employed an in-depth seroproteomic approach to identify proteins that elicit a humoral immune response in CRC patients. The seroproteomic approach relied on the immunoprecipitation with patient-derived autoantibodies of proteins from CRC cell lines with different metastatic properties followed by LC-MS/MS. After bioinformatics, we focused on 31 targets of CRC autoantibodies. After WB and IHC validation, ERP44 and TALDO1 showed potential to discriminate disease-free and metastatic CRC patients, and time to recurrence of CRC patients in stage II. Using plasma samples of 30 healthy individuals, 28 premalignant individuals, and 32 CRC patients, nine out of 13 selected targets for seroreactive analysis showed significant diagnostic ability to discriminate either CRC patients or premalignant subjects from controls. Our results suggest that the here defined panel of CRC autoantibodies and their target proteins should be included in CRC blood-based biomarker panels to get a clinically useful blood-based diagnostic signature for CRC detection. SIGNIFICANCE: Colorectal cancer is one of the deadliest cancer types mainly due to its late diagnosis. Its early diagnosis, therefore, is of great importance since it would significantly improve the survival of CRC patients. In our work, the in-depth seroproteomic analysis of colorectal cancer using isolated IgGs from colorectal cancer patients and controls and protein extract of colorectal cancer cells provide the identification of valuable biomarkers with diagnostic and prognostic ability of the disease.
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Affiliation(s)
- María Garranzo-Asensio
- Chronic Disease Programme, UFIEC, Instituto de Salud Carlos III, Majadahonda E-28220, Madrid, Spain
| | - Pablo San Segundo-Acosta
- Chronic Disease Programme, UFIEC, Instituto de Salud Carlos III, Majadahonda E-28220, Madrid, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain
| | - Carmen Povés
- Gastroenterology Unit, Hospital Universitario Clínico San Carlos, E-28040 Madrid, Spain
| | | | - Javier Martínez-Useros
- Translational Oncology Division, OncoHealth Institute, Fundacion Jimenez Diaz University Hospital, E-28040 Madrid, Spain
| | - Ana Montero-Calle
- Chronic Disease Programme, UFIEC, Instituto de Salud Carlos III, Majadahonda E-28220, Madrid, Spain
| | | | | | - Nuria Rodríguez
- Medical Oncology Department, Hospital Universitario La Paz, E-28046 Madrid, Spain
| | - María Ángeles Cerón
- Surgical Pathology Department, Hospital Universitario Clínico San Carlos, E-28040 Madrid, Spain
| | | | - Gemma Domínguez
- Departamento de Medicina, Facultad de Medicina, Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, E-28029 Madrid, Spain
| | | | | | - Ana Guzmán-Aránguez
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain
| | - Rodrigo Barderas
- Chronic Disease Programme, UFIEC, Instituto de Salud Carlos III, Majadahonda E-28220, Madrid, Spain.
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Bang S, Kaur S, Kurokawa M. Regulation of the p53 Family Proteins by the Ubiquitin Proteasomal Pathway. Int J Mol Sci 2019; 21:E261. [PMID: 31905981 PMCID: PMC6981958 DOI: 10.3390/ijms21010261] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 12/24/2019] [Indexed: 12/25/2022] Open
Abstract
The tumor suppressor p53 and its homologues, p63 and p73, play a pivotal role in the regulation of the DNA damage response, cellular homeostasis, development, aging, and metabolism. A number of mouse studies have shown that a genetic defect in the p53 family could lead to spontaneous tumor development, embryonic lethality, or severe tissue abnormality, indicating that the activity of the p53 family must be tightly regulated to maintain normal cellular functions. While the p53 family members are regulated at the level of gene expression as well as post-translational modification, they are also controlled at the level of protein stability through the ubiquitin proteasomal pathway. Over the last 20 years, many ubiquitin E3 ligases have been discovered that directly promote protein degradation of p53, p63, and p73 in vitro and in vivo. Here, we provide an overview of such E3 ligases and discuss their roles and functions.
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Affiliation(s)
| | | | - Manabu Kurokawa
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA; (S.B.); (S.K.)
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Loss of TRIM29 suppresses cancer stem cell-like characteristics of PDACs via accelerating ISG15 degradation. Oncogene 2019; 39:546-559. [DOI: 10.1038/s41388-019-0992-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 06/13/2019] [Accepted: 06/15/2019] [Indexed: 12/30/2022]
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Li W, Xue H, Li Y, Li P, Ma F, Liu M, Kong S. ATDC promotes the growth and invasion of hepatocellular carcinoma cells by modulating GSK-3β/Wnt/β-catenin signalling. Clin Exp Pharmacol Physiol 2019; 46:845-853. [PMID: 31168819 DOI: 10.1111/1440-1681.13119] [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] [Received: 03/13/2019] [Revised: 05/26/2019] [Accepted: 06/03/2019] [Indexed: 12/26/2022]
Abstract
Accumulating evidence has suggested that the ataxia telangiectasia group D complementing (ATDC) gene is an emerging cancer-related gene in multiple human cancer types. However, little is known about the role of ATDC in hepatocellular carcinoma (HCC). In this study, we aimed to investigate the expression level, biological function and underlying mechanism of ATDC in HCC. The expression of ATDC in HCC cells was detected by quantitative real-time polymerase chain reaction and western blot analysis. Cell growth was determined by cell counting kit-8 assay and colony formation assay. Cell invasion was assessed by Transwell invasion assay. The activation status of Wnt/β-catenin signalling was evaluated by the luciferase reporter assay. Functional experiments showed that the silencing of ATDC expression significantly suppressed the growth and invasion of HCC cells, whereas the overexpression of ATDC promoted the growth and invasion of HCC cells in vitro. Moreover, we showed that ATDC overexpression promoted the phosphorylation of glycogen synthase kinase (GSK)-3β and resulted in the activation of Wnt/β-catenin signalling. Notably, the inhibition of GSK-3β activity significantly abrogated the tumour suppressive effect of ATDC silencing, while the silencing of β-catenin partially reversed the oncogenic effect of ATDC overexpression. Taken together, these findings reveal an oncogenic role of ATDC in HCC and show that the suppression of ATDC impedes the growth and invasion of HCC cells associated with the inactivation of Wnt/β-catenin signalling. Our study suggests that ATDC may serve as a potential therapeutic target for HCC.
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Affiliation(s)
- Weizhi Li
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Hui Xue
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yingchao Li
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Peijie Li
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Fuquan Ma
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Mengying Liu
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shuzhen Kong
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Cao Y, Shi L, Wang M, Hou J, Wei Y, Du C. ATDC contributes to sustaining the growth and invasion of glioma cells through regulating Wnt/β-catenin signaling. Chem Biol Interact 2019; 305:148-155. [DOI: 10.1016/j.cbi.2019.03.033] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 03/07/2019] [Accepted: 03/26/2019] [Indexed: 02/09/2023]
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45
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Sun J, Zhang T, Cheng M, Hong L, Zhang C, Xie M, Sun P, Fan R, Wang Z, Wang L, Zhong J. TRIM29 facilitates the epithelial-to-mesenchymal transition and the progression of colorectal cancer via the activation of the Wnt/β-catenin signaling pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:104. [PMID: 30813948 PMCID: PMC6391790 DOI: 10.1186/s13046-019-1098-y] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 02/08/2019] [Indexed: 12/11/2022]
Abstract
Background Tripartite Motif 29 (TRIM29) has been newly identified as being implicated in cancer progression. However, the biological role and molecular mechanism of TRIM29 in the invasion and metastasis of colorectal cancer (CRC) remain to be determined. Methods The expression levels of TRIM29 and β-catenin in CRC patient specimens were detected by immunohistochemistry. Recombinant lentivirus vectors containing the TRIM29 gene and its small hairpin interfering RNAs were constructed and transduced into CRC cells. Wound-healing and Transwell assays were performed to evaluate the migration and invasion abilities of CRC cells in vitro. Hepatic metastasis models in nude mice were established to validate the function of TRIM29 in vivo. Moreover, the expressions of epithelial-to-mesenchymal transition (EMT)-associated proteins were detected by qRT-PCR and Western blotting in CRC cells. Finally, Western blotting, qRT-PCR, luciferase reporter assays, and immunofluorescence assays were used to explore the molecular mechanisms of TRIM29 in CRC progression. Results Increased TRIM29 expression positively correlated with lymph node metastasis and β-catenin expression in patient CRC tissues. Overexpression of TRIM29 promoted invasion and metastasis of CRC cells in vitro and in vivo by regulating EMT, whereas the knockdown of TRIM29 had the opposite effect. Further mechanistic studies suggest that TRIM29 can activate the Wnt/β-catenin signaling pathway via up-regulating CD44 expression in colorectal cancer. Conclusions TRIM29 induces EMT through activating the Wnt/β-catenin signaling pathway via up-regulating CD44 expression, thus promoting invasion and metastasis of CRC.
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Affiliation(s)
- Juntao Sun
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Tianyu Zhang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Mengmeng Cheng
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Liwen Hong
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chen Zhang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Mengfan Xie
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Peijun Sun
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Rong Fan
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhengting Wang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Lei Wang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Jie Zhong
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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46
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ATDC mediates a TP63-regulated basal cancer invasive program. Oncogene 2019; 38:3340-3354. [PMID: 30643195 PMCID: PMC6499660 DOI: 10.1038/s41388-018-0646-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 12/03/2018] [Accepted: 12/03/2018] [Indexed: 12/20/2022]
Abstract
Basal subtype cancers are deadly malignancies but the molecular events driving tumor lethality are not completely understood. Ataxia-Telangiectasia Group D Complementing gene (ATDC, also known as TRIM29), is highly expressed and drives tumor formation and invasion in human bladder cancers but the factor(s) regulating its expression in bladder cancer are unknown. Molecular subtyping of bladder cancer has identified an aggressive basal subtype which shares molecular features of basal/squamous tumors arising in other organs and is defined by activation of a TP63-driven gene program. Here we demonstrate that ATDC is linked with expression of TP63 and highly expressed in basal bladder cancers. We find that TP63 binds to transcriptional regulatory regions of ATDC and KRT14 directly, increasing their expression, and that ATDC and KRT14 execute a TP63-driven invasive program. In vivo, ATDC is required for TP63-induced bladder tumor invasion and metastasis. These results link TP63 and the basal gene expression program to ATDC and to aggressive tumor behavior. Defining ATDC as a molecular determinant of aggressive, basal cancers may lead to improved biomarkers and therapeutic approaches.
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47
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Lee HJ. The Role of Tripartite Motif Family Proteins in TGF-β Signaling Pathway and Cancer. J Cancer Prev 2018; 23:162-169. [PMID: 30671398 PMCID: PMC6330992 DOI: 10.15430/jcp.2018.23.4.162] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 12/18/2018] [Accepted: 12/18/2018] [Indexed: 12/15/2022] Open
Abstract
TGF-β signaling plays a tumor suppressive role in normal and premalignant cells but promotes tumor progression during the late stages of tumor development. The TGF-β signaling pathway is tightly regulated at various levels, including transcriptional and post-translational mechanisms. Ubiquitination of signaling components, such as receptors and Smad proteins is one of the key regulatory mechanisms of TGF-β signaling. Tripartite motif (TRIM) family of proteins is a highly conserved group of E3 ubiquitin ligase proteins that have been implicated in a variety of cellular functions, including cell growth, differentiation, immune response, and carcinogenesis. Recent emerging studies have shown that some TRIM family proteins function as important regulators in tumor initiation and progression. This review summarizes current knowledge of TRIM family proteins regulating the TGF-β signaling pathway with relevance to cancer.
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Affiliation(s)
- Ho-Jae Lee
- Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine, Incheon, Korea
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48
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Wang K, Chen Z, Long L, Tao Y, Wu Q, Xiang M, Liang Y, Xie X, Jiang Y, Xiao Z, Yan Y, Qiu S, Yi B. iTRAQ-based quantitative proteomic analysis of differentially expressed proteins in chemoresistant nasopharyngeal carcinoma. Cancer Biol Ther 2018; 19:809-824. [PMID: 30067426 DOI: 10.1080/15384047.2018.1472192] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a highly prevalent disease in Southeast Asia. The disease is typically diagnosed in the later stages, and chemotherapy resistance often causes treatment failure. To investigate the underlying mechanisms of drug resistance, we searched for chemoresistant-associated proteins in NPC and drug-resistant NPC cell lines using isobaric tags for relative and absolute quantitation combined with nano liquid chromatography-tandem mass spectrometry. The chemoresistant NPC cell lines CNE1DDP and CNE2DDP were resistant to 1 mg/L cisplatin, had resistant indexes of 4.58 and 2.63, respectively, and clearly grew more slowly than the NPC cell lines CNE1 and CNE2. Using three technical replicates, we identified 690 nonredundant proteins, 56 of which were differentially expressed in both groups of cell lines (CNE1 vs. CNE1DDP and CNE2 vs. CNE2DDP). Gene Ontology, KEGG pathway, and miRNA analyses and protein-protein interactions of differentially expressed proteins showed that proteins TRIM29, HSPB1, CLIC1, ANXA1, and STMN1, among others, may play a role in the mechanisms of chemoresistance in clinical therapy. The chemotherapy-resistant proteomic profiles obtained may allow the identification of novel biomarkers for early detection of chemoresistance in NPC and other cancers.
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Affiliation(s)
- Kun Wang
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Zhen Chen
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Lu Long
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Ya Tao
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Qiong Wu
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Manlin Xiang
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Yunlai Liang
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Xulin Xie
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Yuan Jiang
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China.,b Department of Clinical Laboratory , Hunan Cancer Hospital , Changsha , Hunan Province , China
| | - Zhiqiang Xiao
- c The Higher Educational Key Laboratory for Cancer Proteomics and Translational Medicine of Hunan Province , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Yahui Yan
- d Department of pathology , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Shiyang Qiu
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Bin Yi
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
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Li F, Liang J, Bai L. MicroRNA-449a functions as a tumor suppressor in pancreatic cancer by the epigenetic regulation of ATDC expression. Biomed Pharmacother 2018; 103:782-789. [DOI: 10.1016/j.biopha.2018.04.101] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 04/13/2018] [Accepted: 04/13/2018] [Indexed: 02/06/2023] Open
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50
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Liang C, Dong H, Miao C, Zhu J, Wang J, Li P, Li J, Wang Z. TRIM29 as a prognostic predictor for multiple human malignant neoplasms: a systematic review and meta-analysis. Oncotarget 2017; 9:12323-12332. [PMID: 29552313 PMCID: PMC5844749 DOI: 10.18632/oncotarget.23617] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 10/28/2017] [Indexed: 12/20/2022] Open
Abstract
Recent studies have shown that tripartite motif-containing protein 29 (TRIM29) had prognostic values in several cancers. However, different studies have been inconsistent. We conducted a meta-analysis to elucidate the precise predictive value of TRIM29 in various human malignant disease. Eleven eligible studies with 2046 patients were ultimately enrolled in this meta-analysis. Heterogeneity between studies was assessed using I2 statistics. Pooled Hazard ratios (HRs) with 95% confidence intervals (CIs) for patient survival and disease recurrence were calculated to investigate the correlation between TRIM29 expression and cancer prognosis. The results identified an important link between upregulated TRIM29 expression and poor prognosis in patients with multiple human malignant neoplasms in terms of recurrence-free survival (RFS)/disease-free survival (DFS) (HR = 1.66, 95% CI 1.36–2.04) but favorable progression-free survival (PFS)/metastasis-free survival (MFS) (HR = 0.37, 95% CI 0.16–0.85). We found that high TRIM29 expression predicted no significant impact on overall survival (OS) (HR = 1.32, 95% CI 0.90–1.93). Subgroup analyses showed that high TRIM29 expression predicted poor OS in Asians (HR = 2.21, 95% CI 1.78–2.74) but favorable OS in Caucasian (HR = 0.47, 95% CI 0.25–0.89). TRIM29 might play an essential role in carcinogenesis of multiple human malignant neoplasms and could serve as a biomarker for the prediction of patients’ prognosis.
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Affiliation(s)
- Chao Liang
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Huiyu Dong
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chenkui Miao
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jundong Zhu
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jie Wang
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Pu Li
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jie Li
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zengjun Wang
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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