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Zhou G, Liu A, Bai J, Zhu Y, Zou X, Luo Y, Reyimjan Y, Ma Y, Huang S, Hou Y, Li J, Fu X. Identification of the hub genes involved in ATF5 mediated stress response in vitrified mouse oocytes based on WGCNA. Cryobiology 2025; 119:105258. [PMID: 40409046 DOI: 10.1016/j.cryobiol.2025.105258] [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: 12/20/2024] [Revised: 05/02/2025] [Accepted: 05/09/2025] [Indexed: 05/25/2025]
Abstract
Activating transcription factor 5 (ATF5) is a key regulator in the stress response and plays a crucial role in cellular adaptation to the nonphysical environment. Our previous study indicated that a homeostatic state of ATF5 level could improve mitochondrial function in vitrified oocytes. However, the molecular mechanisms underlying the ATF5-mediated gene network in response to oocyte vitrification remain largely unknown. In this study, specific ATF5 siRNA was microinjected into oocytes to suppress ATF5 expression, and oocytes with ATF5 deficiency under normal and vitrification stress conditions were collected for Smart RNA-seq analysis. Weighted gene co-expression network analysis (WGCNA) was used to characterize oocyte co-expression modules involved in the ATF5 mediated response. Our results identified three key gene modules related to ATF5 knockdownRed, Green and, Yellow-using the screening criteria of |R| ≥0.5 and P ≤ 0.05 with WGCNA. Functional enrichment analysis of key gene modules showed that genes in the modules were mainly enriched in apoptosis, ubiquitin mediated proteolysis, the PI3K-Akt signaling pathway, and protein digestion and absorption. STEM and KEGG functional enrichment analysis showed that most genes were involved in protein digestion and absorption, the AMPK signaling pathway, the JAK-STAT signaling pathway, and the apoptosis signaling pathway. Importantly, Diablo, Map3k1, Spta1, and Ubqln4, obtained by sequential scanning of WGCNA and combined functional enrichment analysis, were identified as candidate genes under ATF5 regulation in response to vitrification. These findings demonstrate that the ATF5 mediated gene network exerts regulatory roles in various cellular events and provide novel insights for a deeper understanding of stress response associated impairments in vitrified oocytes.
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Affiliation(s)
- Guizhen Zhou
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the MARA, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Aiju Liu
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the MARA, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Jiachen Bai
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the MARA, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Yixiao Zhu
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the MARA, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Xinhua Zou
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the MARA, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Yuwen Luo
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the MARA, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Yizaitiguli Reyimjan
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the MARA, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Yan Ma
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the MARA, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Shuaixiang Huang
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the MARA, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Yunpeng Hou
- State Key Laboratories of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Jun Li
- Department of Reproductive Medicine, Reproductive Medical Center, The First Hospital of Hebei Medical University, Shijiazhuang, China.
| | - Xiangwei Fu
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the MARA, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China.
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Deng H, Wang Y, Xiao L, Feng M, Dou W, Pan Y. SHMT inhibitor synergizes with 5-Fu to suppress gastric cancer via cell cycle arrest and chemoresistance alleviation. NPJ Precis Oncol 2025; 9:135. [PMID: 40346149 PMCID: PMC12064653 DOI: 10.1038/s41698-025-00926-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 04/24/2025] [Indexed: 05/11/2025] Open
Abstract
Advanced gastric cancer (GC) represents a malignancy tumor with poor prognosis, which requires urgent exploration into its molecular drivers and innovative therapeutic strategies. This study investigates the oncogenic role of serine hydroxymethyltransferase isoforms (SHMT1/SHMT2), key regulators of serine-glycine-one-carbon metabolism, in GC progression and chemoresistanc. Bioinformatics analysis and cytological experiments preliminary identified the important role of SHMTs in GC. Drug synergistic screening assays were used to build the therapeutic model in the study. The transcriptomic analysis was performed to clarify the underlying mechanism of combination treatment. Our investigations demonstrate that SHMT1 and SHMT2 functionally drive malignant progression and confer 5-fluorouracil (5-Fu) resistance in GC, while their selective inhibitor SHIN1 emerges as a novel therapeutic candidate for GC treatment. The synergistic screening analysis showed that SHIN1 was an efficient synergist for 5-Fu, and the combinative therapy amplified their anticancer effects. Mechanistically, the combination treatment induced cell cycle arrest, DNA damage and cellular senescence by regulating the P53 signaling pathway. These unique characteristics of cell cycle arrest through interfering nucleotide synthesis were validated by substantial in vitro and in vivo assays. The present study revealed SHMT isforms as the potential promoter for malignant progression and chemoresistance in GC. The inhibitor SHIN1 alleviates chemoresistance of 5-Fu and augments both therapeutic effects on GC. In conclusion, the combination of SHIN1 with 5-Fu represents a promising preclinical model for GC treatment, offering a novel strategy to overcome drug resistance and improve therapeutic efficacy.
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Affiliation(s)
- Huan Deng
- Department of Gastrointestinal surgery, Peking University First Hospital, 100034, Beijing, China
| | - Yajie Wang
- Department of Gastrointestinal surgery, Peking University First Hospital, 100034, Beijing, China
| | - Lin Xiao
- Department of Gastrointestinal surgery, Peking University First Hospital, 100034, Beijing, China
| | - Mei Feng
- Department of Gastrointestinal surgery, Peking University First Hospital, 100034, Beijing, China
| | - Weidong Dou
- Department of Gastrointestinal surgery, Peking University First Hospital, 100034, Beijing, China
| | - Yisheng Pan
- Department of Gastrointestinal surgery, Peking University First Hospital, 100034, Beijing, China.
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You L, Wu Q. Cellular senescence in tumor immune escape: Mechanisms, implications, and therapeutic potential. Crit Rev Oncol Hematol 2025; 208:104628. [PMID: 39864532 DOI: 10.1016/j.critrevonc.2025.104628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/12/2025] [Accepted: 01/21/2025] [Indexed: 01/28/2025] Open
Abstract
Cellular senescence, a hallmark of aging, has emerged as a captivating area of research in tumor immunology with profound implications for cancer prevention and treatment. In the tumor microenvironment, senescent cells exhibit a dual role, simultaneously hindering tumor development through collaboration with immune cells and evading immune cell attacks by upregulating immunoinhibitory proteins. However, the intricate immune escape mechanism of cellular senescence in the tumor microenvironment remains a subject of intense investigation. Chronic inflammation is exacerbated by cellular senescence through the upregulation of pro-inflammatory factors such as interleukin-1β, thereby augmenting the risk of tumorigenesis. Additionally, the interplay between autophagy and cellular senescence adds another layer of complexity. Autophagy, known to slow down the aging process by reducing p53/p21 levels, may be downregulated by cellular senescence. To harness the therapeutic potential of cellular senescence, targeting its immunological aspects has gained significant attention. Strategies such as immune checkpoint inhibitors and T-cell senescence inhibition are being explored in the context of cellular senescence immunotherapy. In this comprehensive review, we provide a compelling overview of the regulation of cellular senescence and delve into the influencing factors, including chronic inflammation, autophagy, and circadian rhythms, associated with senescence in the tumor microenvironment. We specifically focus on unraveling the enigmatic dual role of cellular senescence in tumor immune escape. By deciphering the intricate nature of cellular senescence in the tumor microenvironment, this review aims to advance our understanding and pave the way for leveraging senescence as a promising target for tumor immunotherapy applications.
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Affiliation(s)
- Li You
- College of Physical Education and Health, Chongqing College of International Business and Economics, Chongqing 401520, China; College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Qinghua Wu
- College of Life Science, Yangtze University, Jingzhou 434025, China.
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Zhu Y, Song Y, Lu Y, Jiang W, Zhang J, Yin L, Lin X, Tao D, Ma Y. RNF114 Interacts with EWSR1 to Regulate VEGFR2 in HER2-positive Breast Cancer. J Cancer 2025; 16:1888-1904. [PMID: 40092691 PMCID: PMC11905403 DOI: 10.7150/jca.106001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 02/07/2025] [Indexed: 03/19/2025] Open
Abstract
RNF114, a member of the E3 ubiquitin ligase family, was first identified as a zinc-binding protein that exhibits frequent genomic amplification across various cancers. Previous studies have shown that inhibition of RNF114 E3 ligase activity by Nimbolide treatment can result in trapping of PARP1 and synthetic lethality in BRCA-mutated cancers, suggesting its E3 ligase role in tumor progress. However, it's important to reveal novel functions and interacting molecules of RNF114. Here, we first described that RNF114 promotes tumor proliferation and autophagy by interacting with EWSR1 and regulating VEGFR2 expression in HER2-positive breast cancer (BC). Our results also showed that RNF114 is significantly overexpressed in BC and is associated with TNM stage and poor prognosis in BC patients. And knockdown of RNF114 suppresses proliferation, migration, invasion, and autophagy of HER2-positive BC cells. Our findings highlight the transcriptional regulatory function of RNF114 in BC, offering new insights into its oncogenic role and contribution to HER2-positive BC progression.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Yongxin Ma
- Department of Medical Genetics, Frontiers Science Center for Disease-related Molecular Networks, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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He L, Chen H, Ruan B, He L, Luo M, Fu Y, Zou R. UBQLN4 promotes the proliferation and invasion of non-small cell lung cancer cell by regulating PI3K/AKT pathway. J Cancer Res Clin Oncol 2024; 150:335. [PMID: 38969831 PMCID: PMC11226510 DOI: 10.1007/s00432-024-05862-8] [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: 05/06/2024] [Accepted: 06/19/2024] [Indexed: 07/07/2024]
Abstract
BACKGROUND Ubiquilin-4 (UBQLN4), a member of the ubiquilin family, has received limited attention in cancer research to date. Here, we investigated for the first time the functional role and mechanism of UBQLN4 in non-small cell lung cancer (NSCLC). METHODS The Cancer Genome Atlas (TCGA) database was employed to validate UBQLN4 as a differentially expressed gene. Expression differences of UBQLN4 in NSCLC cells and tissues were assessed using immunohistochemistry (IHC) experiment and western blotting (WB) experiment. Kaplan-Meier analysis was conducted to examine the association between UBQLN4 expression and NSCLC prognosis. Functional analyses of UBQLN4 were performed through cell counting kit-8 (CCK-8), colony formation, and transwell invasion assays. The impact of UBQLN4 on tumor-associated signaling pathways was assessed using the path scan intracellular signaling array. In vivo tumorigenesis experiments were conducted to further investigate the influence of UBQLN4 on tumor formation. RESULTS UBQLN4 exhibited up-regulation in both NSCLC tissues and cells. Additionally, over-expression of UBQLN4 was associated with an unfavorable prognosis in NSCLC patients. Functional loss analyses demonstrated that inhibiting UBQLN4 could suppress the proliferation and invasion of NSCLC cells in both in vitro and in vivo settings. Conversely, functional gain experiments yielded opposite results. Path scan intracellular signaling array results suggested that the role of UBQLN4 is associated with the PI3K/AKT pathway, a correlation substantiated by in vitro and in vivo tumorigenesis experiments. CONCLUSION We validated that UBQLN4 promotes proliferation and invasion of NSCLC cells by activating the PI3K/AKT pathway, thereby facilitating the progression of NSCLC. These findings underscore the potential of targeting UBQLN4 as a therapeutic strategy for NSCLC.
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Affiliation(s)
- Li He
- Department of Oncology, The People's Hospital of Xinyu City, Xinyu, Jiangxi, 338099, People's Republic of China
| | - Heng Chen
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical Collge, Nanchang University, 17 Yongwai Street, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Bin Ruan
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical Collge, Nanchang University, 17 Yongwai Street, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Li He
- Department of Pathology, Jingdezhen First People's Hospital, Jingdezhen, Jiangxi, 333000, People's Republic of China
| | - Ming Luo
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical Collge, Nanchang University, 17 Yongwai Street, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Yulun Fu
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical Collge, Nanchang University, 17 Yongwai Street, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Rui Zou
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical Collge, Nanchang University, 17 Yongwai Street, Nanchang, Jiangxi, 330006, People's Republic of China.
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Li F, He HY, Fan ZH, Li CM, Gong Y, Wang XJ, Xiong HJ, Xie CM, Bie P. Silencing of FAM111B inhibited proliferation, migration and invasion of hepatoma cells through activating p53 pathway. Dig Liver Dis 2023; 55:1679-1689. [PMID: 37270349 DOI: 10.1016/j.dld.2023.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 04/28/2023] [Accepted: 05/05/2023] [Indexed: 06/05/2023]
Abstract
BACKGROUND The function of Family with sequence similarity 111 member B (FAM111B) has been reported in multiple malignancies, but its involvement in occurrence and development of hepatocellular carcinoma (HCC) is still unclear. PURPOSE To investigate the role of FAM111B in HCC and explore the potential molecular mechanism. METHODS We examined the mRNA level of FAM111B via qPCR and protein level via immunohistochemistry in human HCC tissues. siRNA was used to construct a FAM111B-knockdown model in HCC cell lines. CCK-8, colony formation, transwell, and wound healing assays were performed to investigate the effect of FAM111B on proliferation, migration and invasion of HCC cell. Gene Set Enrichment Analysis, western blotting, and flow cytometry were carried out to find the related molecular mechanism. RESULTS Human HCC tumor tissues exhibited higher expression of FAM111B, and high FAM111B expression was associated with poor prognosis. Vitro assays demonstrated that knockdown of FAM111B greatly repressed proliferation, migration and invasion of HCC cells. Furthermore, silencing of FAM111B significantly resulted in cell cycle arrest at G0/G1 and downregulation of epithelial-mesenchymal transition (EMT)-related proteins MMP7 and MMP9 via activation of p53 pathway. CONCLUSION FAM111B played an essential role in promoting HCC development by regulation of p53 pathway.
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Affiliation(s)
- Feng Li
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, PR China
| | - Hong-Ye He
- Institute of Ultrasound Imaging & Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing 400010, PR China
| | - Zhi-Hao Fan
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, PR China
| | - Chun-Ming Li
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, PR China
| | - Yi Gong
- Department of Hepatobiliary and Pancreatic Surgery, Southwest Hospital, Army Medical University, Chongqing 400038, PR China
| | - Xiao-Jun Wang
- Department of Hepatobiliary and Pancreatic Surgery, Southwest Hospital, Army Medical University, Chongqing 400038, PR China
| | - Hao-Jun Xiong
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing 400038, PR China.
| | - Chuan-Ming Xie
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing 400038, PR China.
| | - Ping Bie
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, PR China.
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Li P, Zhen Y, Kim C, Liu Z, Hao J, Deng H, Deng H, Zhou M, Wang XD, Qin T, Yu Y. Nimbolide targets RNF114 to induce the trapping of PARP1 and synthetic lethality in BRCA-mutated cancer. SCIENCE ADVANCES 2023; 9:eadg7752. [PMID: 37878693 PMCID: PMC10599614 DOI: 10.1126/sciadv.adg7752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 09/22/2023] [Indexed: 10/27/2023]
Abstract
Recent studies have pointed to PARP1 trapping as a key determinant of the anticancer effects of PARP1 inhibitors (PARPi). We identified RNF114, as a PARylation-dependent, E3 ubiquitin ligase involved in DNA damage response. Upon sensing genotoxicity, RNF114 was recruited, in a PAR-dependent manner, to DNA lesions, where it targeted PARP1 for degradation. The blockade of this pathway interfered with the removal of PARP1 from DNA lesions, leading to profound PARP1 trapping. We showed that a natural product, nimbolide, inhibited the E3 ligase activity of RNF114 and thus caused PARP1 trapping. However, unlike conventional PARPi, nimbolide treatment induced the trapping of both PARP1 and PARylation-dependent DNA repair factors. Nimbolide showed synthetic lethality with BRCA mutations, and it overcame intrinsic and acquired resistance to PARPi, both in vitro and in vivo. These results point to the exciting possibility of targeting the RNF114-PARP1 pathway for the treatment of homologous recombination-deficient cancers.
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Affiliation(s)
- Peng Li
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yuanli Zhen
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Chiho Kim
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
| | - Zhengshuai Liu
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
| | - Jianwei Hao
- Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
| | - Heping Deng
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Hejun Deng
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Min Zhou
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xu-Dong Wang
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
| | - Tian Qin
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yonghao Yu
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
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Liu SC, Gong LL, Huang FC, Xu N, Yang KX, Liu XH, Li WL. RNF114 facilitates the proliferation, stemness, and metastasis of colorectal cancer. Pathol Res Pract 2023; 248:154716. [PMID: 37523804 DOI: 10.1016/j.prp.2023.154716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 07/17/2023] [Accepted: 07/25/2023] [Indexed: 08/02/2023]
Abstract
BACKGROUND Colorectal cancer (CRC), the fourth of the world's major common malignancy, poses a serious threat to the physical and mental health of the population. Nevertheless, the prognosis of CRC patients remains unsatisfactory. Consequently, it is still imperative to continuously discover the CRC mechanisms. METHODS The expression profiles of mRNAs were recognized by whole transcriptome sequencing to identity differentially expressed mRNA (DE-mRNA). TCGA COAD cohort, PPOGgene and Kaplan-Meier Plotter databases were utilized to validate RNF114 relevance to CRC prognosis. The effect of RNF114 on the malignant biological behavior of CRC was explored in CRC cells and subcutaneous tumor models and lung metastasis model after exogenous regulation of RNF114. RESULTS A total of 1358 DE-mRNAs were identified, including 617 up-regulated and 741 down-regulated DE-mRNAs, and they were mainly involved in the term of receptor ligand activity, Wnt signaling pathway and pathway in cancer. Notably, RNF114 was hyper-expressed in tissues and cell of CRC, and significantly correlated with tumor invasion depth and TNM stage of CRC patients. RNF114 expression were significantly associated with overall survival, and had superior diagnostic value in CRC. In vitro, knockdown of RNF114 statistically diminished the proliferation, stemness, invasion and wound healing of CRC cells and facilitated their apoptosis, and the opposite result was observed for overexpression of RNF114. In vivo, knockdown of RNF114 effectively diminished the mass and volume of tumors, and lung metastasis in animal model. CONCLUSIONS In summary, we identified DE-mRNAs in CRC, and elucidated that RNF114 facilitates CRC process. The discovery will contribute to theoretical foundation for RNF114 as a potential therapeutic target and biomarker, and offer new perspectives for CRC research.
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Affiliation(s)
- Shi-Cheng Liu
- Department of Colorectal Surgery, the Third Affiliated Hospital of Kunming Medical University (the Tumor Hospital of Yunnan), China
| | - Le-Lan Gong
- Department of Colorectal Surgery, the Third Affiliated Hospital of Kunming Medical University (the Tumor Hospital of Yunnan), China
| | - Feng-Chang Huang
- Department of Oncology, the First Affiliated Hospital of Kunming Medical University, China
| | - Ning Xu
- Department of Oncology, the First Affiliated Hospital of Kunming Medical University, China
| | - Ke-Xin Yang
- Department of Colorectal Surgery, the Third Affiliated Hospital of Kunming Medical University (the Tumor Hospital of Yunnan), China
| | - Xi-Hong Liu
- Department of Oncology, the First Affiliated Hospital of Kunming Medical University, China
| | - Wen-Liang Li
- Department of Colorectal Surgery, the Third Affiliated Hospital of Kunming Medical University (the Tumor Hospital of Yunnan), China.
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Shah PP, Beverly LJ. UBQLN Family Members Regulate MYC in Lung Adenocarcinoma Cells. Cancers (Basel) 2023; 15:3389. [PMID: 37444499 PMCID: PMC10340487 DOI: 10.3390/cancers15133389] [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: 04/18/2023] [Revised: 06/15/2023] [Accepted: 06/16/2023] [Indexed: 07/15/2023] Open
Abstract
The ubiquilin family (UBQLN) of proteins consists of five closely related members (UBQLN1, UBQLN2, UBQLN3, UBQLN4, and UBQLNL) that have a high degree of similarity at the level of both amino acid and domain structure. The role of UBQLN1 and UBQLN2 in regulating processes involved in cancer progression and tumorigenesis is still not completely understood. MYC is an oncogene and is well known to play important roles in cancer progression and metastasis. Herein, we show that the loss of UBQLN1 and UBQLN2 causes increased cell viability, cell proliferation, cell migration, clonogenic potential, and cell cycle progression, which is associated with increased MYC expression. UBQLN1 and UBQLN2 interact with phosphorylated MYC and facilitate its degradation. The overexpression of UBQLN1 reverses the increased expression of MYC following the loss of UBQLN2. Further, we present evidence that decreasing MYC levels back to baseline can reverse phenotypes driven by the loss of UBQLN1 or UBQLN2. Finally, we show that loss of UBQLN1 drives tumorigenesis and lung metastasis in mice which are associated with an increase in the expression of MYC, proteins involved in cell cycle progression, and EMT. Taken together, our results suggest for the first time a novel role of UBQLN1 and UBQLN2 in regulating MYC in lung adenocarcinoma cells.
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Affiliation(s)
- Parag P. Shah
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA;
| | - Levi J. Beverly
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA;
- Department of Medicine, Division of Hematology and Oncology, University of Louisville School of Medicine, Louisville, KY 40202, USA
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Analyses of regulatory network and discovery of potential biomarkers for Korean rockfish (Sebastes schlegelii) in responses to starvation stress through transcriptome and metabolome. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2023; 46:101061. [PMID: 36796184 DOI: 10.1016/j.cbd.2023.101061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 01/29/2023] [Accepted: 01/31/2023] [Indexed: 02/11/2023]
Abstract
Whether in aquaculture or in nature, starvation stress limits the growth of fish. The purpose of the study was to clarify the detailed molecular mechanisms underlying starvation stress in Korean rockfish (Sebastes schlegelii) through liver transcriptome and metabolome analysis. Transcriptome results showed that liver genes associated with cell cycle and fatty acid synthesis were down-regulated, whereas those related to fatty acid decomposition were up-regulated in the experimental group (EG; starved for 72 days) compared to the control group (CG; feeding). Metabolomic results showed that there were significant differences in the levels of metabolites related to nucleotide metabolism and energy metabolism, such as purine metabolism, histidine metabolism and oxidative phosphorylation. Five fatty acids (C22:6n-3; C22:5n-3; C20:5n-3; C20:4n-3; C18:3n-6) were selected as possible biomarkers of starvation stress from the differential metabolites of metabolome. Subsequently, correlation between these differential genes of lipid metabolism and cell cycle and differential metabolites were analyzed, and observed that these five fatty acids were significantly correlated with the differential genes. These results provide new clues for understanding the role of fatty acid metabolism and cell cycle in fish under starvation stress. It also provides a reference for promoting the biomarker identification of starvation stress and stress tolerance breeding research.
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Genomic Amplification of UBQLN4 Is a Prognostic and Treatment Resistance Factor. Cells 2022; 11:cells11203311. [PMID: 36291176 PMCID: PMC9600423 DOI: 10.3390/cells11203311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/20/2022] [Accepted: 10/20/2022] [Indexed: 11/17/2022] Open
Abstract
Ubiquilin-4 (UBQLN4) is a proteasomal shuttle factor that directly binds to ubiquitylated proteins and delivers its cargo to the 26S proteasome for degradation. We previously showed that upregulated UBQLN4 determines the DNA damage response (DDR) through the degradation of MRE11A. However, the regulatory mechanism at DNA level, transcriptionally and post-transcriptional levels that control UBQLN4 mRNA levels remains unknown. In this study, we screened 32 solid tumor types and validated our findings by immunohistochemistry analysis. UBQLN4 is upregulated at both mRNA and protein levels and the most significant values were observed in liver, breast, ovarian, lung, and esophageal cancers. Patients with high UBQLN4 mRNA levels had significantly poor prognoses in 20 of 32 cancer types. DNA amplification was identified as the main mechanism promoting UBQLN4 upregulation in multiple cancers, even in the early phases of tumor development. Using CRISPR screen datasets, UBQLN4 was identified as a common essential gene for tumor cell viability in 81.1% (860/1,060) of the solid tumor derived cell lines. Ovarian cancer cell lines with high UBQLN4 mRNA levels were platinum-based chemotherapy resistant, while they were more sensitive to poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi). Our findings highlight the utilities of UBQLN4 as a significant pan-cancer theranostic factor and a precision oncology biomarker for DDR-related drug resistance.
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Tang X, Liang Y, Sun G, He Q, Hou Z, Jiang X, Gao P, Qu H. Upregulation of CRABP2 by TET1-mediated DNA hydroxymethylation attenuates mitochondrial apoptosis and promotes oxaliplatin resistance in gastric cancer. Cell Death Dis 2022; 13:848. [PMID: 36195596 PMCID: PMC9532395 DOI: 10.1038/s41419-022-05299-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 09/22/2022] [Accepted: 09/26/2022] [Indexed: 11/07/2022]
Abstract
Oxaliplatin is the main chemotherapy drug for gastric cancer (GC), but quite a few patients are resistant to oxaliplatin, which contributes to the poor prognosis of GC patients. There is therefore an urgent need to identify potential targets for reversing chemotherapy resistance in GC patients. In this study, we analyzed the tumor samples of GC patients who received neoadjuvant chemotherapy based on oxaliplatin through quantitative proteomics and identified the potential chemoresistance-related protein cellular retinoic acid binding protein 2 (CRABP2). CRABP2 was significantly upregulated in the tumor tissues of chemoresistant GC patients and was closely related to prognosis. The results of cell function experiments showed that CRABP2 can promote the oxaliplatin resistance of GC cells in vitro. Coimmunoprecipitation and GST pulldown assays showed that CRAPB2 expedited the binding of BAX and PARKIN in GC cells and facilitated the ubiquitination-mediated degradation of BAX. Furthermore, both the in vitro assay and cell-derived xenograft (CDX) in vivo model verified that CRABP2 promoted oxaliplatin resistance by inhibiting BAX-dependent cell apoptosis. Further experiments proved that the abnormally high expression of CRABP2 in oxaliplatin-resistant GC cells was affected by TET1-mediated DNA hydroxymethylation. The patient-derived xenograft (PDX) model suggested that interference with CRABP2 reversed oxaliplatin resistance in GC in vivo. In conclusion, the results of our study show that CRABP2 was a key molecule in oxaliplatin resistance regulation and could be a new target for reversing the chemoresistance of GC.
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Affiliation(s)
- Xiaolong Tang
- grid.452402.50000 0004 1808 3430Department of General Surgery, Qilu Hospital of Shandong University, Jinan, 250012 China
| | - Yahang Liang
- grid.452402.50000 0004 1808 3430Department of General Surgery, Qilu Hospital of Shandong University, Jinan, 250012 China
| | - Guorui Sun
- grid.452402.50000 0004 1808 3430Department of General Surgery, Qilu Hospital of Shandong University, Jinan, 250012 China
| | - Qingsi He
- grid.452402.50000 0004 1808 3430Department of General Surgery, Qilu Hospital of Shandong University, Jinan, 250012 China
| | - Zhenyu Hou
- grid.452402.50000 0004 1808 3430Department of General Surgery, Qilu Hospital of Shandong University, Jinan, 250012 China
| | - Xingzhi Jiang
- grid.452402.50000 0004 1808 3430Department of General Surgery, Qilu Hospital of Shandong University, Jinan, 250012 China
| | - Peng Gao
- grid.452402.50000 0004 1808 3430Department of Pathology, Qilu Hospital of Shandong University, Jinan, 250012 China
| | - Hui Qu
- grid.452402.50000 0004 1808 3430Department of General Surgery, Qilu Hospital of Shandong University, Jinan, 250012 China
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Muniz de Queiroz R, Moon SH, Prives C. O-GlcNAc tranferase regulates p21 protein levels and cell proliferation through the FoxM1-Skp2 axis in a p53-independent manner. J Biol Chem 2022; 298:102289. [PMID: 35868563 PMCID: PMC9418910 DOI: 10.1016/j.jbc.2022.102289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 06/28/2022] [Accepted: 06/30/2022] [Indexed: 11/24/2022] Open
Abstract
The protein product of the CDKN1A gene, p21, has been extensively characterized as a negative regulator of the cell cycle. Nevertheless, it is clear that p21 has manifold complex and context-dependent roles that can be either tumor suppressive or oncogenic. Most well studied as a transcriptional target of the p53 tumor suppressor protein, there are other means by which p21 levels can be regulated. In this study, we show that pharmacological inhibition or siRNA-mediated reduction of O-GlcNAc transferase (OGT), the enzyme responsible for glycosylation of intracellular proteins, increases expression of p21 in both p53-dependent and p53-independent manners in nontransformed and cancer cells. In cells harboring WT p53, we demonstrate that inhibition of OGT leads to p53-mediated transactivation of CDKN1A, while in cells that do not express p53, inhibiting OGT leads to increased p21 protein stabilization. p21 is normally degraded by the ubiquitin-proteasome system following ubiquitination by, among others, the E3 ligase Skp-Cullin-F-box complex; however, in this case, we show that blocking OGT causes impairment of the Skp-Cullin-F-box ubiquitin complex as a result of disruption of the FoxM1 transcription factor–mediated induction of Skp2 expression. In either setting, we conclude that p21 levels induced by OGT inhibition correlate with cell cycle arrest and decreased cancer cell proliferation.
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Affiliation(s)
| | - Sung-Hwan Moon
- Department of Biological Sciences, Columbia University, New York, NY, USA
| | - Carol Prives
- Department of Biological Sciences, Columbia University, New York, NY, USA.
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Wang X, Zhang H, Ye J, Gao M, Jiang Q, Zhao T, Wang S, Mao W, Wang K, Wang Q, Chen X, Hou X, Han D. Genome Instability-Associated Long Non-Coding RNAs Reveal Biomarkers for Glioma Immunotherapy and Prognosis. Front Genet 2022; 13:850888. [PMID: 35571034 PMCID: PMC9094631 DOI: 10.3389/fgene.2022.850888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 04/04/2022] [Indexed: 11/13/2022] Open
Abstract
Genome instability is a hallmark of tumors and is involved in proliferation, invasion, migration, and treatment resistance of many tumors. However, the relationship of genome instability with gliomas remains unclear. Here, we constructed genome instability-derived long non-coding RNA (lncRNA)-based gene signatures (GILncSig) using genome instability-related lncRNAs derived from somatic mutations. Multiple platforms were used to confirm that the GILncSig were closely related to patient prognosis and clinical characteristics. We found that GILncSig, the glioma microenvironment, and glioma cell DNA methylation-based stemness index (mDNAsi) interacted with each other to form a complex regulatory network. In summary, this study confirmed that GILncSig was an independent prognostic indicator for patients, distinguished high-risk and low-risk groups, and affected immune-cell infiltration and tumor-cell stemness indicators (mDNAsi) in the tumor microenvironment, resulting in tumor heterogeneity and immunotherapy resistance. GILncSig are expected to provide new molecular targets for the clinical treatment of patients with gliomas.
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Affiliation(s)
- Xinzhuang Wang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hong Zhang
- Department of Hematology, Liaocheng People's Hospital, Liaocheng, China
| | - Junyi Ye
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ming Gao
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qiuyi Jiang
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tingting Zhao
- Biochip Laboratory, Yantai Yu-Huang-Ding Hospital, Qingdao University, Yantai, China
| | - Shengtao Wang
- The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenbin Mao
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kaili Wang
- The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qi Wang
- The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xin Chen
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xu Hou
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dayong Han
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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15
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Wang LN, Huang KJ, Wang L, Cheng HY. Overexpression of Ubiquilin4 is associated with poor prognosis in patients with cervical cancer. World J Clin Cases 2022; 10:2783-2791. [PMID: 35434088 PMCID: PMC8968826 DOI: 10.12998/wjcc.v10.i9.2783] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 01/26/2022] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Ubiquilins (UBQLNs) are important factors for cell proteostasis maintenance. UBQLNs are involved in the modulation of the cell cycle, as well as in apoptosis, membrane receptors regulation, DNA repair, epithelial-mesenchymal transition, and miRNA activities. They also affect the selection of double-strand break repair pathways. Abnormal UBQLNs expression can lead to many diseases, including cancer. Studies have found that the expression of Ubiquilin4 (UBQLN4) is associated with the development of several tumor types. However, the association between UBQLN4 and cervical cancer has not been examined yet.
AIM To investigate the expression of UBQLN4 in cervical cancer and to evaluate its correlation with disease prognosis.
METHODS Immunohistochemistry was performed to examine the expression of UBQLN4 in 117 cervical cancer tissues and 32 matching pericervical tissues. Paired t-test (two-tailed) was used to compare the differences between groups. We collected patients’ clinical characteristics, including age, histological grade, pathologic type, lymph node metastasis, and FIGO stage (2018) and compared them by chi-square test. All patients were followed for 5.5 to 6.8 years. Kaplan-Meier method and log-rank test were used to compare the differences in the overall survival (OS) and progression-free survival (PFS) among the different groups.
RESULTS Overexpression of UBQLN4 was observed in 70.9% (83/117) of all cervical cancer tissues and in 15.6% (5/32) of the paired parauterine tissues. The expression of UBQLN4 was associated with lymph node metastasis, poor differentiation, and advanced stage, but the difference was not significant. Kaplan-Meier and log-rank test results suggested the high expression of UBQLN4 was associated with short OS and PFS. Regardless of UBQLN4 expression, the patient age and FIGO stage were also associated with disease prognosis. The statistically significant variables obtained from univariate the Kaplan-Meier analysis were subjected to Cox multivariate survival regression analysis, which showed that, in addition to the FIGO stage and age, UBQLN4 was also an independent prognostic marker for OS and PFS (P = 0.011 and P = 0.024, respectively).
CONCLUSION The overexpression of UBQLN4 was associated with poor prognosis in cervical cancer. Our study proposed a novel prognostic factor and improved the existing understanding of the pathogenesis of cervical cancer.
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Affiliation(s)
- Li-Na Wang
- Department of Gynaecology Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Ke-Jin Huang
- Department of Gynaecology Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Le Wang
- Department of Gynaecology Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Hai-Yan Cheng
- Department of Gynaecology Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
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16
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Zhou L, Niu Z, Wang Y, Zheng Y, Zhu Y, Wang C, Gao X, Gao L, Zhang W, Zhang K, Melino G, Huang H, Wang X, Sun Q. Senescence as a dictator of patient outcomes and therapeutic efficacies in human gastric cancer. Cell Death Discov 2022; 8:13. [PMID: 35013121 PMCID: PMC8748965 DOI: 10.1038/s41420-021-00769-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 11/11/2021] [Accepted: 11/22/2021] [Indexed: 12/13/2022] Open
Abstract
Senescence is believed to be a pivotal player in the onset and progression of tumors as well as cancer therapy. However, the guiding roles of senescence in clinical outcomes and therapy selection for patients with cancer remain obscure, largely due to the absence of a feasible senescence signature. Here, by integrative analysis of single cell and bulk transcriptome data from multiple datasets of gastric cancer patients, we uncovered senescence as a veiled tumor feature characterized by senescence gene signature enriched, unexpectedly, in the noncancerous cells, and further identified two distinct senescence-associated subtypes based on the unsupervised clustering. Patients with the senescence subtype had higher tumor mutation loads and better prognosis as compared with the aggressive subtype. By the machine learning, we constructed a scoring system termed as senescore based on six signature genes: ADH1B, IL1A, SERPINE1, SPARC, EZH2, and TNFAIP2. Higher senescore demonstrated robustly predictive capability for longer overall and recurrence-free survival in 2290 gastric cancer samples, which was independently validated by the multiplex staining analysis of gastric cancer samples on the tissue microarray. Remarkably, the senescore signature served as a reliable predictor of chemotherapeutic and immunotherapeutic efficacies, with high-senescore patients benefited from immunotherapy, while low-senescore patients were responsive to chemotherapy. Collectively, we report senescence as a heretofore unrecognized hallmark of gastric cancer that impacts patient outcomes and therapeutic efficacy.
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Affiliation(s)
- Lulin Zhou
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China
- Institute of Biotechnology, Research Unit of Cell Death Mechanism, Chinese Academy of Medical Sciences, 20 Dongda Street, Beijing, 100071, China
| | - Zubiao Niu
- Institute of Biotechnology, Research Unit of Cell Death Mechanism, Chinese Academy of Medical Sciences, 20 Dongda Street, Beijing, 100071, China
| | - Yuqi Wang
- Institute of Biotechnology, Research Unit of Cell Death Mechanism, Chinese Academy of Medical Sciences, 20 Dongda Street, Beijing, 100071, China
| | - You Zheng
- Institute of Biotechnology, Research Unit of Cell Death Mechanism, Chinese Academy of Medical Sciences, 20 Dongda Street, Beijing, 100071, China
| | - Yichao Zhu
- Institute of Biotechnology, Research Unit of Cell Death Mechanism, Chinese Academy of Medical Sciences, 20 Dongda Street, Beijing, 100071, China
| | - Chenxi Wang
- Institute of Biotechnology, Research Unit of Cell Death Mechanism, Chinese Academy of Medical Sciences, 20 Dongda Street, Beijing, 100071, China
| | - Xiaoyan Gao
- Department of Oncology, Beijing Shijitan Hospital of Capital Medical University, 10 TIEYI Road, Beijing, 100038, China
| | - Lihua Gao
- Institute of Biotechnology, Research Unit of Cell Death Mechanism, Chinese Academy of Medical Sciences, 20 Dongda Street, Beijing, 100071, China
| | - Wen Zhang
- Department of Immunology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Kaitai Zhang
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome "Tor Vergata", Rome, 00133, Italy
- DZNE German Center for Neurodegenerative Diseases, 53127, Bonn, Germany
| | - Hongyan Huang
- Department of Oncology, Beijing Shijitan Hospital of Capital Medical University, 10 TIEYI Road, Beijing, 100038, China.
| | - Xiaoning Wang
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
- Institute of Geriatrics, The second Medical Center, Beijing Key Laboratory of Aging and Geriatrics, National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China.
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China.
| | - Qiang Sun
- Institute of Biotechnology, Research Unit of Cell Death Mechanism, Chinese Academy of Medical Sciences, 20 Dongda Street, Beijing, 100071, China.
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Liu F, Pan R, Ding H, Gu L, Yang Y, Li C, Xu Y, Hu R, Chen H, Zhang X, Nie Y. UBQLN4 is an ATM substrate that stabilizes the anti-apoptotic proteins BCL2A1 and BCL2L10 in mesothelioma. Mol Oncol 2021; 15:3738-3752. [PMID: 34245648 PMCID: PMC8637560 DOI: 10.1002/1878-0261.13058] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 05/18/2021] [Accepted: 07/09/2021] [Indexed: 11/15/2022] Open
Abstract
ATM serine/threonine kinase (ATM; previously known as ataxia-telangiectasia mutated) plays a critical role in maintaining genomic stability and regulates multiple downstream pathways, such as DNA repair, cell cycle arrest, and apoptosis. As a serine/threonine kinase, ATM has an array of downstream phosphorylation substrates, including checkpoint effector checkpoint kinase 2 (CHK2). ATM inhibits cell cycle progression by phosphorylating and activating CHK2, which plays an important role in the formation and development of tumors and participates in DNA repair responses after double-stranded DNA breaks. In this study, we used a recently developed mammalian functional genetic screening system to explore a series of ATM substrates and their role in DNA damage to enhance our understanding of the DNA damage response. Ubiquilin 4 (UBQLN4), which belongs to the ubiquilin family characterized by its ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains, was identified as a new substrate for ATM. UBQLN4 is involved in various intracellular processes, such as autophagosome maturation, p21 regulation, and motor axon morphogenesis. However, the biological function of UBQLN4 remains to be elucidated. In this study, we not only identified UBQLN4 as a substrate for ATM, but also found that UBQLN4 interacts with and stabilizes the anti-apoptotic proteins Bcl-2-related protein A1 (BCL2A1) and Bcl-2-like protein 10 (BCL2L10) and prevents mesothelioma cell apoptosis in response to DNA damage. These findings expand our understanding of the role of UBQLN4 in mesothelioma and provide new insights into potential mesothelioma treatments targeting substrates for ATM.
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Affiliation(s)
- Fang Liu
- Medical CollegeGuizhou UniversityGuiyangChina
| | - RunSang Pan
- GuiYang Maternal and Child HospitalGuiyangChina
| | - HongYu Ding
- State Key Laboratory of Systems BiologyCAS Center for Excellence in Molecular Cell ScienceInnovation Center for Cell Signaling NetworkShanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghaiChina
| | - LiLing Gu
- Medical CollegeGuizhou UniversityGuiyangChina
- Department of RehabilitationGuizhou Provincial People’s HospitalGuiyangChina
- NHC Key Laboratory of Pulmonary Immune‐related DiseasesGuizhou Provincial People’s HospitalGuiyangChina
| | - Yun Yang
- Medical CollegeGuizhou UniversityGuiyangChina
| | - ChuanYin Li
- State Key Laboratory of Systems BiologyCAS Center for Excellence in Molecular Cell ScienceInnovation Center for Cell Signaling NetworkShanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghaiChina
| | - YongJie Xu
- NHC Key Laboratory of Pulmonary Immune‐related DiseasesGuizhou Provincial People’s HospitalGuiyangChina
| | - Ronggui Hu
- State Key Laboratory of Systems BiologyCAS Center for Excellence in Molecular Cell ScienceInnovation Center for Cell Signaling NetworkShanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghaiChina
| | - Hui Chen
- NHC Key Laboratory of Pulmonary Immune‐related DiseasesGuizhou Provincial People’s HospitalGuiyangChina
| | - XiangYan Zhang
- NHC Key Laboratory of Pulmonary Immune‐related DiseasesGuizhou Provincial People’s HospitalGuiyangChina
| | - YingJie Nie
- NHC Key Laboratory of Pulmonary Immune‐related DiseasesGuizhou Provincial People’s HospitalGuiyangChina
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18
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Ganini C, Amelio I, Bertolo R, Bove P, Buonomo OC, Candi E, Cipriani C, Di Daniele N, Juhl H, Mauriello A, Marani C, Marshall J, Melino S, Marchetti P, Montanaro M, Natale ME, Novelli F, Palmieri G, Piacentini M, Rendina EA, Roselli M, Sica G, Tesauro M, Rovella V, Tisone G, Shi Y, Wang Y, Melino G. Global mapping of cancers: The Cancer Genome Atlas and beyond. Mol Oncol 2021; 15:2823-2840. [PMID: 34245122 PMCID: PMC8564642 DOI: 10.1002/1878-0261.13056] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/04/2021] [Accepted: 07/09/2021] [Indexed: 12/20/2022] Open
Abstract
Cancer genomes have been explored from the early 2000s through massive exome sequencing efforts, leading to the publication of The Cancer Genome Atlas in 2013. Sequencing techniques have been developed alongside this project and have allowed scientists to bypass the limitation of costs for whole-genome sequencing (WGS) of single specimens by developing more accurate and extensive cancer sequencing projects, such as deep sequencing of whole genomes and transcriptomic analysis. The Pan-Cancer Analysis of Whole Genomes recently published WGS data from more than 2600 human cancers together with almost 1200 related transcriptomes. The application of WGS on a large database allowed, for the first time in history, a global analysis of features such as molecular signatures, large structural variations and noncoding regions of the genome, as well as the evaluation of RNA alterations in the absence of underlying DNA mutations. The vast amount of data generated still needs to be thoroughly deciphered, and the advent of machine-learning approaches will be the next step towards the generation of personalized approaches for cancer medicine. The present manuscript wants to give a broad perspective on some of the biological evidence derived from the largest sequencing attempts on human cancers so far, discussing advantages and limitations of this approach and its power in the era of machine learning.
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Affiliation(s)
- Carlo Ganini
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
- IDI‐IRCCSRomeItaly
| | - Ivano Amelio
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
| | - Riccardo Bertolo
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
- San Carlo di Nancy HospitalRomeItaly
| | - Pierluigi Bove
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
- San Carlo di Nancy HospitalRomeItaly
| | - Oreste Claudio Buonomo
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
| | - Eleonora Candi
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
- IDI‐IRCCSRomeItaly
| | - Chiara Cipriani
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
- San Carlo di Nancy HospitalRomeItaly
| | - Nicola Di Daniele
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
| | | | - Alessandro Mauriello
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
| | - Carla Marani
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
- San Carlo di Nancy HospitalRomeItaly
| | - John Marshall
- Medstar Georgetown University HospitalGeorgetown UniversityWashingtonDCUSA
| | - Sonia Melino
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
| | | | - Manuela Montanaro
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
| | - Maria Emanuela Natale
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
- San Carlo di Nancy HospitalRomeItaly
| | - Flavia Novelli
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
| | - Giampiero Palmieri
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
| | - Mauro Piacentini
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
| | | | - Mario Roselli
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
| | - Giuseppe Sica
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
| | - Manfredi Tesauro
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
| | - Valentina Rovella
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
| | - Giuseppe Tisone
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
| | - Yufang Shi
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
- CAS Key Laboratory of Tissue Microenvironment and TumorShanghai Institute of Nutrition and HealthShanghai Institutes for Biological SciencesUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghaiChina
- The First Affiliated Hospital of Soochow University and State Key Laboratory of Radiation Medicine and ProtectionInstitutes for Translational MedicineSoochow UniversityChina
| | - Ying Wang
- CAS Key Laboratory of Tissue Microenvironment and TumorShanghai Institute of Nutrition and HealthShanghai Institutes for Biological SciencesUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghaiChina
| | - Gerry Melino
- Department of Experimental MedicineTorvergata Oncoscience Research Centre of Excellence, TORUniversity of Rome Tor VergataItaly
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19
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Liu Y, Cheng L, Huang W, Cheng X, Peng W, Shi D. Genome Instability-Related miRNAs Predict Survival, Immune Landscape, and Immunotherapy Responses in Gastric Cancer. J Immunol Res 2021; 2021:2048833. [PMID: 34761007 PMCID: PMC8575650 DOI: 10.1155/2021/2048833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 09/23/2021] [Accepted: 10/16/2021] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Increasing evidence suggests that microRNAs (miRNAs) are involved in genome instability (GI) and drive the occurrence of tumors. However, the role of GI-related miRNAs in gastric cancer (GC) remains largely unknown. Herein, we developed a novel GI-related miRNA signature (GIMiSig) and further investigated its role in prognosis, the immune landscape, and immunotherapy responses in GC patients. METHODS An analysis of somatic mutation data on 434 gastric cancer cases from The Cancer Genome Atlas (TCGA) database was performed, thereby generating genome stability (GS) and GI groups. By detecting differentially expressed miRNAs between the GS and GI groups that were associated with overall survival, 8 miRNAs were identified and used to construct the GIMiSig. RESULTS The GIMiSig showed high accuracy in detecting GC patients. Using GIMiSig to stratify the patients into the high- and low-risk subgroups to predict survival outperformed the use of regular clinical features such as age, gender, or disease stage. Patients with low risk had a more favorable survival time than those with high risk. More importantly, the high-risk patients were associated with decreased UBQLN4 expression, higher accumulation of immune cells, lower Titin (TTN) mutation frequency, worse immunotherapy efficacy, and cancer-associated pathways. Conversely, the low-risk patients were characterized by UBQLN4 overexpression, lower fraction of immune cells, higher TTN mutation frequency, better response to immunotherapy, and GI-related pathways. CONCLUSION In summary, we constructed a novel GIMiSig that could stratify GC patients into distinct risk groups that have different survival outcomes and immunotherapy efficacy. The results may provide new clues for improving GC outcomes.
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Affiliation(s)
- Yaqiong Liu
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
- Regenerative Medicine Institute (REMEDI), CURAM, National University of Ireland Galway, H91TK33, Galway, Ireland
| | - Lin Cheng
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Wei Huang
- Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xin Cheng
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Weijun Peng
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Dazun Shi
- Department of Gynecology and Obstetrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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A Comprehensive Multiomics Analysis Identified Ubiquilin 4 as a Promising Prognostic Biomarker of Immune-Related Therapy in Pan-Cancer. JOURNAL OF ONCOLOGY 2021; 2021:7404927. [PMID: 34539785 PMCID: PMC8443395 DOI: 10.1155/2021/7404927] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 08/28/2021] [Indexed: 01/02/2023]
Abstract
Recently, it was reported that ubiquilin 4 (UBQLN4) alteration was associated with genomic instability in some cancers. However, whether UBQLN4 is a valuable biomarker for the prognosis of immunotherapy in pan-cancer was not identified. We evaluated the biologic and oncologic significance of UBQLN4 in pan-cancer at multiomics level, such as expression, mutation, copy number variation (CNV), methylation, and N6-methyladenosine (m6A) methylation. These omics data were obtained from several public databases, including Oncomine, The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), the Genotype-Tissue Expression (GTEx), the Human Protein Atlas (HPA), Gene Set Cancer Analysis (GSCA), m6A-Atlas, CancerSEA, and RNAactDrug. We found that UBQLN4 mRNA and protein were overexpressed in most cancer types, and the expression, mutation, CNV, and methylation of UBQLN4 were associated with the prognosis of some cancers. Mechanistically, UBQLN4 was involved in angiogenesis, DNA damage, apoptosis, and the pathway of PI3K/AKT and TSC/mTOR. Moreover, UBQLN4 mRNA was significantly correlated with immune checkpoints, tumor mutational burden (TMB), microsatellite instability (MSI), and mismatch repair (MMR). And, the correlation among UBQLN4 mRNA, CNV, and methylation and immune microenvironment was also identified. Furthermore, UBQLN4 was associated with the sensitivity of chemotherapy and targeted drugs at multiomics level. In conclusion, UBQLN4 was a promising prognostic biomarker of immune-related therapy in pan-cancer.
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21
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Sun J, Jiang Q, Chen H, Zhang Q, Zhao J, Li H, Wang X, Fang Y, Ruan Y, Sun Y. Genomic instability-associated lncRNA signature predicts prognosis and distinct immune landscape in gastric cancer. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1326. [PMID: 34532463 PMCID: PMC8422092 DOI: 10.21037/atm-21-3569] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 08/05/2021] [Indexed: 01/27/2023]
Abstract
Background Characterized by multiple features, genomic stability-related markers, such as microsatellite instability (MSI), were regulated as an important predictor of chemotherapy and immunity responses in cancer treatment. The aim of our study was to identify a genomic instability-associated long non-coding RNA (lncRNA) signature to help predict the survival and therapy response of gastric cancers (GCs). Methods We used RNA sequencing and single nucleotide variant (SNV) data from The Cancer Genome Atlas-stomach adenocarcinoma (TCGA-STAD) datasets to explore genomic instability-associated lncRNAs. Hierarchical cluster analyses of 197 differentially expressed genomic instability-associated lncRNAs were performed to separate GC patients into two groups, namely, the genomically unstable (GU)-like group and the genomically stable (GS)-like group. Results Cox regression analysis was conducted to finally identify six lncRNAs (LINC02678, HOXA10-AS, RHOXF1-AS1, AC010789.1, LINC01150, and TGFB2-AS1) with independent prognostic value to establish the genomic instability-associated lncRNA signature (GILncSig). Based on the SNV analysis, GILncSig was correlated with accumulation of gene mutation counts. Further comparisons between different risk score groups were performed to assess chemotherapy drug sensitivity and immune landscape variations. Conclusions Our study not only revealed the genomic instability-associated lncRNAs in GCs, but provided a key method and resource for further studies of the role of these lncRNAs play, and introduced a potential new way to identify genomic instability-associated cancer biomarkers.
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Affiliation(s)
- Jie Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Quan Jiang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Human Phenome Institute, Fudan University, Shanghai, China
| | - Hao Chen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qi Zhang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Junjie Zhao
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Haojie Li
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xuefei Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yong Fang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuanyuan Ruan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yihong Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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22
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Expression of Four Autophagy-Related Genes Accurately Predicts the Prognosis of Gastrointestinal Cancer in Asian Patients. DISEASE MARKERS 2021; 2021:7253633. [PMID: 34484469 PMCID: PMC8413069 DOI: 10.1155/2021/7253633] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 07/07/2021] [Accepted: 08/07/2021] [Indexed: 12/11/2022]
Abstract
Gastrointestinal (GI) cancers are among the most fatal diseases in the world. Numerous studies have demonstrated the relationship between autophagy and development of gastrointestinal cancers. However, whether autophagy-related genes can predict prognosis of GI cancers in individuals of Asian ancestry has not been defined. This study, evaluated the prognostic value of autophagy-related genes in gastrointestinal cancer. Expression profile of autophagy-related genes for 296 gastrointestinal cancer patients of Asian ancestry was downloaded from the TCGA database (TCGA-LIHC, TCGA-STAD, TCGA-ESCA, TCGA-PAAD, TCGA-COAD, TCGA-CHOL, and TCGA-READ). The prognostic value of the autophagy-related genes was evaluated using univariate Cox, LASSO, and multivariate Cox regression analyses. The risk score of the autophagy-related gene signature was calculated to assess its predictive prognostic value for GI cancers. Forty-seven differentially expressed autophagy-related genes, in Asian patients with gastrointestinal cancers, were identified. Of the 47 genes, 4 were associated with prognosis of GI cancer (SQSTM1, BIRC5, NRG3, and CXCR4). A prognostic model for GI cancer, based on the expression of the above 4 genes in the training set, showed that cancer patients were stratified into high-risk and low-risk groups (P < 0.05). The utility of the model for overall survival (OS) of GI cancer patients was consistent across the entire set, training set, and test set (entire set: P = 4.568 × 10−4; train set: P = 5.718 × 10−3; test set: P = 3.516 × 10−2). The sensitivity and specificity of the ROC curve of the above prognostic model in predicting the 5-year prognosis of GI cancer was satisfactory (entire set: 0.728; train set: 0.727; test set: 0.733). Analysis of clinical samples validated the overexpression of the 4 genes (SQSTM1, BIRC5, NRG3, and CXCR4) in tumor tissues relative to paired normal tissues, consistent with bioinformatic findings. Expression of the 4 autophagy-related genes (SQSTM1, BIRC5, NRG3, and CXCR4) can accurately predict the prognosis of gastrointestinal tumors in Asian patients.
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Sun Q, Melino G, Amelio I, Jiang J, Wang Y, Shi Y. Recent advances in cancer immunotherapy. Discov Oncol 2021; 12:27. [PMID: 35201440 PMCID: PMC8777500 DOI: 10.1007/s12672-021-00422-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/05/2021] [Indexed: 12/16/2022] Open
Abstract
Cancer immunotherapy represents a major advance in the cure of cancer following the dramatic advancements in the development and refinement of chemotherapies and radiotherapies. In the recent decades, together with the development of early diagnostic techniques, immunotherapy has significantly contributed to improving the survival of cancer patients. The immune-checkpoint blockade agents have been proven effective in a significant fraction of standard therapy refractory patients. Importantly, recent advances are providing alternative immunotherapeutic tools that could help overcome their limitations. In this mini review, we provide an overview on the main steps of the discovery of classic immune-checkpoint blockade agents and summarise the most recent development of novel immunotherapeutic strategies, such as tumour antigens, bispecific antibodies and TCR-engineered T cells.
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Affiliation(s)
- Qiang Sun
- Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, China
- Research Unit of Cell Death Mechanism, Chinese Academy of Medical Science, Beijing, China
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
- DZNE German Center for Neurodegenerative Diseases, Bonn, Germany
| | - Ivano Amelio
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - Jingting Jiang
- The Third Affiliated Hospital of Soochow University and State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, 199 Renai Road, Suzhou, 215123 Jiangsu China
| | - Ying Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
| | - Yufang Shi
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
- The Third Affiliated Hospital of Soochow University and State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, 199 Renai Road, Suzhou, 215123 Jiangsu China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
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24
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Xiao Z, Zheng YB, Dao WX, Luo JF, Deng WH, Yan RC, Liu JS. MicroRNA-328-3p facilitates the progression of gastric cancer via KEAP1/NRF2 axis. Free Radic Res 2021; 55:720-730. [PMID: 34160338 DOI: 10.1080/10715762.2021.1923705] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Gastric cancer is a common lethal malignancy and causes great cancer-related mortality worldwide. MicroRNA (miR)-328-3p is implicated in the progression of various human cancers; however, its role and mechanism in the progression of gastric cancer remain unclear.Human gastric cancer cells were incubated with miR-328-3p mimic, inhibitor or the matched negative control. Cell viability, colony formation, migrative and invasive capacity, cell apoptosis and oxidative stress were measured. To clarify the involvement of nuclear factor-E2-related factor 2 (NRF2) and kelch-like ECH-associated protein 1 (KEAP1), small interfering RNA was used. miR-328-3p was upregulated in human gastric cancer cells and tissues, and its level positively correlated with the progression of gastric cancer. miR-328-3p promoted cell viability, colony formation, migration and invasion, thereby facilitating the progression of gastric cancer. miR-328-3p mimic reduced, while miR-328-3p inhibitor increased apoptosis and oxidative stress of human gastric cancer cells. Mechanistically, miR-328-3p upregulated NRF2 via targeting KEAP1to attenuate excessive free radical production and cell apoptosis. miR-328-3p functions as an oncogenic gene and inhibiting miR-328-3p may help to develop novel therapeutic strategies of human gastric cancer.
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Affiliation(s)
- Zhe Xiao
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yong-Bin Zheng
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Wen-Xin Dao
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jian-Fei Luo
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Wen-Hong Deng
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Rui-Cheng Yan
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jia-Sheng Liu
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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25
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Electrophilic Natural Products as Drug Discovery Tools. Trends Pharmacol Sci 2021; 42:434-447. [PMID: 33902949 DOI: 10.1016/j.tips.2021.03.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 03/23/2021] [Accepted: 03/24/2021] [Indexed: 12/22/2022]
Abstract
Electrophilic natural products (ENPs) are a rich source of bioactive molecules with tremendous therapeutic potential. While their synthetic complexity may hinder their direct use as therapeutics, they represent tools for elucidation of suitable molecular targets and serve as inspiration for the design of simplified synthetic counterparts. Here, we review the recent use of various activity-based protein profiling methods to uncover molecular targets of ENPs. Beyond target identification, these examples also showcase further development of synthetic ligands from natural product starting points. Two examples demonstrate how ENPs can progress the emerging fields of targeted protein degradation and molecular glues. Though challenges still remain in the synthesis of ENP-based probes, and in their synthetic simplification, their potential for discovery of novel mechanisms of action makes it well worth the effort.
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26
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Isoforms of the p53 Family and Gastric Cancer: A Ménage à Trois for an Unfinished Affair. Cancers (Basel) 2021; 13:cancers13040916. [PMID: 33671606 PMCID: PMC7926742 DOI: 10.3390/cancers13040916] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/06/2021] [Accepted: 02/17/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary The p53 family is a complex family of transcription factors with different cellular functions that are involved in several physiological processes. A massive amount of data has been accumulated on their critical role in the tumorigenesis and the aggressiveness of cancers of different origins. If common features are observed, there are numerous specificities that may reflect particularities of the tissues from which the cancers originated. In this regard, gastric cancer tumorigenesis is rather remarkable, as it is induced by bacterial and viral infections, various chemical carcinogens, and familial genetic alterations, which provide an example of the variety of molecular mechanisms responsible for cell transformation and how they impact the p53 family. This review summarizes the knowledge gathered from over 40 years of research on the role of the p53 family in gastric cancer, which still displays one of the most elevated mortality rates amongst all types of cancers. Abstract Gastric cancer is one of the most aggressive cancers, with a median survival of 12 months. This illustrates its complexity and the lack of therapeutic options, such as personalized therapy, because predictive markers do not exist. Thus, gastric cancer remains mostly treated with cytotoxic chemotherapies. In addition, less than 20% of patients respond to immunotherapy. TP53 mutations are particularly frequent in gastric cancer (±50% and up to 70% in metastatic) and are considered an early event in the tumorigenic process. Alterations in the expression of other members of the p53 family, i.e., p63 and p73, have also been described. In this context, the role of the members of the p53 family and their isoforms have been investigated over the years, resulting in conflicting data. For instance, whether mutations of TP53 or the dysregulation of its homologs may represent biomarkers for aggressivity or response to therapy still remains a matter of debate. This uncertainty illustrates the lack of information on the molecular pathways involving the p53 family in gastric cancer. In this review, we summarize and discuss the most relevant molecular and clinical data on the role of the p53 family in gastric cancer and enumerate potential therapeutic innovative strategies.
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27
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Wang X, Cheng G, Miao Y, Qiu F, Bai L, Gao Z, Huang Y, Dong L, Niu X, Wang X, Li Y, Tang H, Xu Y, Song X. Piezo type mechanosensitive ion channel component 1 facilitates gastric cancer omentum metastasis. J Cell Mol Med 2021; 25:2238-2253. [PMID: 33439514 PMCID: PMC7882944 DOI: 10.1111/jcmm.16217] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 11/28/2020] [Accepted: 12/08/2020] [Indexed: 12/19/2022] Open
Abstract
The peritoneum, especially the omentum, is a common site for gastric cancer (GC) metastasis. Our aim was to expound the role and mechanisms of Piezo1 on GC omentum metastasis. A series of functional assays were performed to examine cell proliferation, clone formation, apoptosis, Ca2+ influx, mitochondrial membrane potential (MMP) and migration after overexpression or knockdown of Piezo1. A GC peritoneal implantation and metastasis model was conducted. After infection by si‐Piezo1, the number and growth of tumours were observed in abdominal cavity. Fibre and angiogenesis were tested in metastatic tumour tissues. Piezo1 had higher expression in GC tissues with omentum metastasis and metastatic lymph node tissues than in GC tissues among 110 patients. High Piezo1 expression was associated with lymph metastasis, TNM and distant metastasis. Overexpressed Piezo1 facilitated cell proliferation and suppressed cell apoptosis in GC cells. Moreover, Ca2+ influx was elevated after up‐regulation of Piezo1. Piezo1 promoted cell migration and Calpain1/2 expression via up‐regulation of HIF‐1α in GC cells. In vivo, Piezo1 knockdown significantly inhibited peritoneal metastasis of GC cells and blocked EMT process and angiogenesis. Our findings suggested that Piezo1 is a key component during GC omentum metastasis, which could be related to up‐regulation of HIF‐1α.
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Affiliation(s)
- Xiaofei Wang
- Department of Pathology, North China University of Science and Technology Affiliated Hospital, Tangshan, China
| | - Guang Cheng
- Central Laboratory of Clinical Medical College, North China University of Science and Technology Affiliated Hospital, Tangshan, China
| | - Yu Miao
- Department of GI Medicine, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Fangyuan Qiu
- Department of Medical, Jining Second People's Hospital, Jining, China
| | - Lugen Bai
- Department of laboratory, Jingbian County People's Hospital, Yulin, China
| | - Zhongfei Gao
- Department of Medical, Jining First People's Hospital, Jining, China
| | - Yunning Huang
- Department of Gastrointestinal Surgery, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China
| | - Liru Dong
- Department of Pathology, North China University of Science and Technology Affiliated Hospital, Tangshan, China
| | - Xing Niu
- Department of Second Clinical College, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning, China
| | - Xin Wang
- Department of Pathology, North China University of Science and Technology Affiliated Hospital, Tangshan, China
| | - Yuyang Li
- Department of Pathology, North China University of Science and Technology Affiliated Hospital, Tangshan, China
| | - Hui Tang
- Department of Pathology, North China University of Science and Technology Affiliated Hospital, Tangshan, China
| | - Yuanyi Xu
- Department of Pathology, Ningxia Medical University, Yinchuan, China
| | - Xudong Song
- Department of Pathology, North China University of Science and Technology Affiliated Hospital, Tangshan, China
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28
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Zheng T, Yang Y, Castañeda CA. Structure, dynamics and functions of UBQLNs: at the crossroads of protein quality control machinery. Biochem J 2020; 477:3471-3497. [PMID: 32965492 PMCID: PMC7737201 DOI: 10.1042/bcj20190497] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/23/2020] [Accepted: 08/26/2020] [Indexed: 12/12/2022]
Abstract
Cells rely on protein homeostasis to maintain proper biological functions. Dysregulation of protein homeostasis contributes to the pathogenesis of many neurodegenerative diseases and cancers. Ubiquilins (UBQLNs) are versatile proteins that engage with many components of protein quality control (PQC) machinery in cells. Disease-linked mutations of UBQLNs are most commonly associated with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative disorders. UBQLNs play well-established roles in PQC processes, including facilitating degradation of substrates through the ubiquitin-proteasome system (UPS), autophagy, and endoplasmic-reticulum-associated protein degradation (ERAD) pathways. In addition, UBQLNs engage with chaperones to sequester, degrade, or assist repair of misfolded client proteins. Furthermore, UBQLNs regulate DNA damage repair mechanisms, interact with RNA-binding proteins (RBPs), and engage with cytoskeletal elements to regulate cell differentiation and development. Important to the myriad functions of UBQLNs are its multidomain architecture and ability to self-associate. UBQLNs are linked to numerous types of cellular puncta, including stress-induced biomolecular condensates, autophagosomes, aggresomes, and aggregates. In this review, we focus on deciphering how UBQLNs function on a molecular level. We examine the properties of oligomerization-driven interactions among the structured and intrinsically disordered segments of UBQLNs. These interactions, together with the knowledge from studies of disease-linked mutations, provide significant insights to UBQLN structure, dynamics and function.
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Affiliation(s)
- Tongyin Zheng
- Department of Chemistry, Syracuse University, Syracuse, NY 13244, U.S.A
| | - Yiran Yang
- Department of Chemistry, Syracuse University, Syracuse, NY 13244, U.S.A
| | - Carlos A. Castañeda
- Department of Chemistry, Syracuse University, Syracuse, NY 13244, U.S.A
- Departments of Biology and Chemistry, Syracuse University, Syracuse, NY 13244, U.S.A
- Bioinspired Institute, and the Interdisciplinary Neuroscience Program, Syracuse University, Syracuse, NY 13244, U.S.A
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29
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Li K, Huang F, Li Y, Li D, Lin H, Ni R, Zhang Q, Zhao M, Huang S, Zou L, Huang C. Stabilization of oncogenic transcripts by the IGF2BP3/ELAVL1 complex promotes tumorigenicity in colorectal cancer. Am J Cancer Res 2020; 10:2480-2494. [PMID: 32905413 PMCID: PMC7471344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 06/27/2020] [Indexed: 06/11/2023] Open
Abstract
The expression of RNA-binding proteins (RBPs) is dysregulated in colorectal cancer (CRC) and in other types of cancer. Among the RBPs, the insulin-like growth factor-2 messenger RNA binding protein (IGF2BP1-3) family is involved in the development of the colon and the progression of CRC. However, the regulation of mRNA fate by IGF2BP3 in CRC remains less well understood. Here, we show that IGF2BP3 interacts with ELAVL1 to coregulate a cohort of genes involved in the cell cycle and cell proliferation. Mechanistically, recognition of these mRNAs by the IGF2BP3/ELAVL1 complex leads to prolonged half-lives of the mRNA molecules and increased expression of the target genes, thereby driving CRC cell proliferation. Interestingly, knockdown of either IGF2BP3 or ELAVL1 impairs the IGF2BP3/ELAVL1 complex-enhanced mRNA stability, suggesting a functional interdependency between IGF2BP3 and ELAVL1 in CRC. Our findings reveal the molecular mechanism by which IGF2BP3 regulates mRNA stability and identify the cooperativity of the IGF2BP3/ELAVL1 complex as a novel therapeutic target in CRC.
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Affiliation(s)
- Kexin Li
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
- Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
| | - Furong Huang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
| | - Yan Li
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
- Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
| | - Dongdong Li
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
- Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
| | - Hong Lin
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
- Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
| | - Ruoxuan Ni
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
- Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
| | - Qiao Zhang
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
- Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
| | - Mei Zhao
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
- Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
| | - Shengkai Huang
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
| | - Liang Zou
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
| | - Changzhi Huang
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
- Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
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30
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Wang J, Zhu P, Toan S, Li R, Ren J, Zhou H. Pum2-Mff axis fine-tunes mitochondrial quality control in acute ischemic kidney injury. Cell Biol Toxicol 2020; 36:365-378. [PMID: 31993882 DOI: 10.1007/s10565-020-09513-9] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 01/24/2020] [Indexed: 12/31/2022]
Abstract
Mitochondrial fission factor (Mff) has been demonstrated to play a role in the activation of mitochondrial cleavage and mitochondrial death, denoting its role in the regulation of mitochondrial quality control. Recent evidence suggested that the mRNA translation of Mff is under the negative regulation by the RNA-binding protein Pumilio2 (Pum2). This study was designed to examine the role of Pum2 and Mff in the governance of mitochondrial quality control in a murine model of acute ischemic kidney injury. Our results indicated that genetic deletion of Mff overtly attenuated ischemic acute kidney injury (AKI)-induced renal failure through inhibition of pro-inflammatory response, tubular oxidative stress, and ultimately cell death in the kidney. Furthermore, Mff inhibition effectively preserved mitochondrial homeostasis through amelioration of mitochondrial mitosis, restoration of Sirt1/3 expression, and boost of mitochondrial respiration. Western blot analysis revealed that levels of Pum2 were significantly downregulated by ischemic AKI, inversely coinciding with levels of Mff. Overexpression of Pum2 reduced ischemic AKI-mediated Mff upregulation and offered protection on renal tubules through modulation of mitochondrial quality control. Taken together, our data have unveiled the molecular mechanism of the Pum2-Mff axis in mitochondrial quality control in a mouse model of ischemic AKI. These data indicated the therapeutic potential of Pum2 activation and Mff inhibition in the management of ischemic AKI.
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Affiliation(s)
- Jin Wang
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Pingjun Zhu
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Sam Toan
- Department of Chemical Engineering, University of Minnesota-Duluth, Duluth, MN, 55812, USA
| | - Ruibing Li
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Jun Ren
- Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY, 82071, USA.
| | - Hao Zhou
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China.
- Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY, 82071, USA.
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31
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Kurlawala Z, Saurabh K, Dunaway R, Shah PP, Siskind LJ, Beverly LJ. Ubiquilin proteins regulate EGFR levels and activity in lung adenocarcinoma cells. J Cell Biochem 2020; 122:43-52. [PMID: 32720736 DOI: 10.1002/jcb.29830] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/07/2020] [Accepted: 07/13/2020] [Indexed: 12/12/2022]
Abstract
Ubiquilin (UBQLN) proteins are involved in diverse cellular processes like endoplasmic reticulum-associated degradation, autophagy, apoptosis, and epithelial-to-mesenchymal transition. UBQLNs interact with a variety of substrates, including cell surface receptors, transcription factor regulators, proteasomal machinery proteins, and transmembrane proteins. In addition, previous work from our lab shows that UBQLN1 interacts with insulin-like growth factor receptor family members (IGF1R, IGF2R, and INSR) and this interaction regulates the activity and proteostasis of IGFR family members. We wondered whether UBQLN proteins could also bind and regulate additional receptor tyrosine kinases. Thus, we investigated a link between UBQLN and the oncogene epidermal growth factor receptor (EGFR) in lung adenocarcinoma cells. Loss of UBQLN1 occurs at high frequency in human lung cancer patient samples and we have shown that the loss of UBQLN1 is capable of altering processes involved in cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition in lung adenocarcinoma cell lines. Here, we present data that loss of UBQLN1 resulted in increased turnover of total EGFR while increasing the relative amount of phosphorylated EGFR in lung adenocarcinoma cells, especially in the presence of its ligand EGF. Furthermore, the loss of UBQLN1 led to a more invasive cell phenotype as manifested by increased proliferation, migration, and speed of movement of these lung adenocarcinoma cells. Taken together, UBQLN1 regulates the expression and stability of EGFR in lung cancer cells.
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Affiliation(s)
- Zimple Kurlawala
- James Graham Brown Cancer Center, School of Medicine, University of Louisville, Louisville, Kentucky
| | - Kumar Saurabh
- James Graham Brown Cancer Center, School of Medicine, University of Louisville, Louisville, Kentucky
| | - Rain Dunaway
- School of Medicine, University of Louisville, Louisville, Kentucky
| | - Parag P Shah
- James Graham Brown Cancer Center, School of Medicine, University of Louisville, Louisville, Kentucky
| | - Leah J Siskind
- James Graham Brown Cancer Center, School of Medicine, University of Louisville, Louisville, Kentucky.,Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky
| | - Levi J Beverly
- James Graham Brown Cancer Center, School of Medicine, University of Louisville, Louisville, Kentucky.,Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky.,Division of Hematology and Oncology, School of Medicine, University of Louisville, Louisville, Kentucky
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32
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ROCK1 knockdown inhibits non-small-cell lung cancer progression by activating the LATS2-JNK signaling pathway. Aging (Albany NY) 2020; 12:12160-12174. [PMID: 32554853 PMCID: PMC7343464 DOI: 10.18632/aging.103386] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 05/01/2020] [Indexed: 12/12/2022]
Abstract
Rho-associated kinase 1 (ROCK1) regulates tumor metastasis by maintaining cellular cytoskeleton homeostasis. However, the precise role of ROCK1 in non-small-cell lung cancer (NSCLC) apoptosis remains largely unknown. In this study, we examined the function of ROCK1 in NSCLS survival using RNA interference-mediated knockdown. Our results showed that ROCK1 knockdown reduced A549 lung cancer cell viability in vitro. It also inhibited A549 cell migration and proliferation. Transfection of ROCK1 siRNA was associated with increased expression of large tumor suppressor kinase 2 (LATS2) and c-Jun N-terminal kinase (JNK). Moreover, ROCK1 knockdown-induced A549 cell apoptosis and inhibition of proliferation were suppressed by LATS2 knockdown or JNK inactivation, suggesting that ROCK1 deficiency triggers NSCLC apoptosis in a LATS2-JNK pathway-dependent manner. Functional analysis further demonstrated that ROCK1 knockdown dysregulated mitochondrial dynamics and inhibited mitochondrial biogenesis. This effect too was reversed by LATS2 knockdown or JNK inactivation. We have thus identified a potential pathway by which ROCK1 downregulation triggers apoptosis in NSCLC by inducing LATS2-JNK-dependent mitochondrial damage.
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33
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Jantrapirom S, Lo Piccolo L, Pruksakorn D, Potikanond S, Nimlamool W. Ubiquilin Networking in Cancers. Cancers (Basel) 2020; 12:E1586. [PMID: 32549375 PMCID: PMC7352256 DOI: 10.3390/cancers12061586] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 06/11/2020] [Accepted: 06/11/2020] [Indexed: 12/13/2022] Open
Abstract
Ubiquilins or UBQLNs, members of the ubiquitin-like and ubiquitin-associated domain (UBL-UBA) protein family, serve as adaptors to coordinate the degradation of specific substrates via both proteasome and autophagy pathways. The UBQLN substrates reveal great diversity and impact a wide range of cellular functions. For decades, researchers have been attempting to uncover a puzzle and understand the role of UBQLNs in human cancers, particularly in the modulation of oncogene's stability and nucleotide excision repair. In this review, we summarize the UBQLNs' genetic variants that are associated with the most common cancers and also discuss their reliability as a prognostic marker. Moreover, we provide an overview of the UBQLNs networks that are relevant to cancers in different ways, including cell cycle, apoptosis, epithelial-mesenchymal transition, DNA repairs and miRNAs. Finally, we include a future prospective on novel ubiquilin-based cancer therapies.
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Affiliation(s)
- Salinee Jantrapirom
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.J.); (S.P.)
| | - Luca Lo Piccolo
- Omics Center for Health Science, Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (L.L.P.); (D.P.)
| | - Dumnoensun Pruksakorn
- Omics Center for Health Science, Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (L.L.P.); (D.P.)
- Department of Orthopedics, Orthopedic Laboratory and Research Network Center (OLARN), Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
- Excellence Center in Osteology Research and Training Center (ORTC), Chiang Mai University, Chiang Mai 50200, Thailand
| | - Saranyapin Potikanond
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.J.); (S.P.)
- Research Center of Pharmaceutical Nanotechnology, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Wutigri Nimlamool
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Muang, Chiang Mai 50200, Thailand; (S.J.); (S.P.)
- Research Center of Pharmaceutical Nanotechnology, Chiang Mai University, Chiang Mai 50200, Thailand
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34
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Maghsoudloo M, Azimzadeh Jamalkandi S, Najafi A, Masoudi-Nejad A. An efficient hybrid feature selection method to identify potential biomarkers in common chronic lung inflammatory diseases. Genomics 2020; 112:3284-3293. [PMID: 32540493 DOI: 10.1016/j.ygeno.2020.06.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 05/21/2020] [Accepted: 06/04/2020] [Indexed: 12/13/2022]
Abstract
Asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF) are three serious lung inflammatory diseases. The understanding of the pathogenesis mechanism and the identification of potential prognostic biomarkers of these diseases can provide the patients with more efficient treatments. In this study, an efficient hybrid feature selection method was introduced in order to extract informative genes. We implemented an ontology-based ranking approach on differentially expressed genes following a wrapper method. The examination of the different gene ontologies and their combinations motivated us to propose a biological functional-based method to improve the performance of further wrapper methods. The results identified: TOM1L1, SRSF1, and GIT2 in asthma; CHCHD4, PAIP2, CRLF3, UBQLN4, TRAK1, PRELID1, VAMP4, CCM2, and APBB1IP in COPD; and TUFT1, GAB2, B4GALNT1, TNFRSF17, PRDM8, and SETDB2 in IPF as the potential biomarkers. The proposed method can be used to identify hub genes in other high-throughput datasets.
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Affiliation(s)
- Mazaher Maghsoudloo
- Laboratory of Systems Biology and Bioinformatics (LBB), Department of Bioinformatics, Kish International Campus, University of Tehran, Kish Island, Iran; Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | | | - Ali Najafi
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Tehran, Iran
| | - Ali Masoudi-Nejad
- Laboratory of Systems Biology and Bioinformatics (LBB), Department of Bioinformatics, Kish International Campus, University of Tehran, Kish Island, Iran; Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
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35
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Hu Z, Long T, Ma Y, Zhu J, Gao L, Zhong Y, Wang X, Wang X, Li Z. Downregulation of GLYR1 contributes to microsatellite instability colorectal cancer by targeting p21 via the p38MAPK and PI3K/AKT pathways. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:76. [PMID: 32370786 PMCID: PMC7201645 DOI: 10.1186/s13046-020-01578-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 04/22/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND GLYR1 has a high mutation frequency in microsatellite instability colorectal cancer (MSI CRC) and is presumed to be a novel tumor suppressor. However, the role of GLYR1 in tumors has never been studied. In particular, the downregulation of GLYR1 in MSI CRC is worthy of further investigation. METHODS Western blot and immunohistochemistry analyses were used to detect GLYR1 protein expression in CRC tissues and cell lines, and the clinical significance of GLYR1 was also analyzed. The relationship between GLYR1 and MLH1 was validated by immunofluorescence, immunoprecipitation and bioinformatics analyses. Western blotting, qRT-PCR, CCK-8 assays, colony formation assays, flow cytometry and Hoechst 33258 staining assays were used to assess the effect of GLYR1 on the cell cycle progression, proliferation, differentiation and apoptosis of CRC cells in vitro. The related mechanisms were initially investigated by Western blotting. RESULTS GLYR1 was significantly downregulated in MSI CRC and its expression was negatively correlated with tumor size and positively correlated with tumor differentiation in CRC patients. In addition, GLYR1 interacted with MLH1 to regulate its nuclear import and expression. Moreover, downregulation of GLYR1 accelerated G1/S phase transition, promoted proliferation and inhibited differentiation of SW480 and SW620 cells in vitro. Furthermore, downregulation of GLYR1 decreased the sensitivity to 5-fluorouracil (5-FU) by inhibiting the mitochondrial apoptosis pathway in CRC cells. Inhibition of the p38 mitogen-activated protein kinase (p38MAPK) and activation of the phosphatidyl 3-kinase/protein kinase B (PI3K/Akt) signaling pathways were involved in the mechanism by which GLYR1 downregulated p21. CONCLUSIONS Ours is the first study to elucidate the role of GLYR1 in tumors and provide evidence for GLYR1 as a biological marker that reflects the degree of malignancy and sensitivity to 5-FU in MSI CRC.
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Affiliation(s)
- Zhiyan Hu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China
| | - Ting Long
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China
| | - Yidan Ma
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China
| | - Jiaxian Zhu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China
| | - Lingfang Gao
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China
| | - Yan Zhong
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China
| | - Xia Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China
| | - Xiaoyan Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China
| | - Zuguo Li
- Department of Pathology, Shenzhen Hospital of Southern Medical University, Shenzhen, China. .,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China. .,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China.
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36
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Xin T, Lu C. Irisin activates Opa1-induced mitophagy to protect cardiomyocytes against apoptosis following myocardial infarction. Aging (Albany NY) 2020; 12:4474-4488. [PMID: 32155590 PMCID: PMC7093202 DOI: 10.18632/aging.102899] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 03/02/2020] [Indexed: 12/11/2022]
Abstract
Myocardial infarction is characterized by sudden ischemia and cardiomyocyte death. Mitochondria have critical roles in regulating cardiomyocyte viability and can sustain damage under ischemic conditions. Mitophagy is a mechanism by which damaged mitochondria are removed by autophagy to maintain mitochondrial structure and function. We investigated the role of the dynamin-like GTPase optic atrophy 1 (Opa1) in mitophagy following myocardial infarction. Opa1 expression was downregulated in infarcted hearts in vivo and in hypoxia-treated cardiomyocytes in vitro. We found that Opa1 overexpression protected cardiomyocytes against hypoxia-induced damage and enhanced cell viability by inducing mitophagy. Opa1-induced mitophagy was activated by treatment with irisin, which protected cardiomyocytes from further damage following myocardial infarction. Opa1 knockdown abolished the cardioprotective effects of irisin resulting in an enhanced inflammatory response, increased oxidative stress, and mitochondrial dysfunction in cardiomyocytes. Our data indicate that Opa1 plays an important role in maintaining cardiomyocyte viability and mitochondrial function following myocardial infarction by inducing mitophagy. Irisin can activate Opa1-induced mitophagy and protect against cardiomyocyte injury following myocardial infarction.
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Affiliation(s)
- Ting Xin
- The First Center Clinic College of Tianjin Medical University, Tianjin First Center Hospital, Tianjin, China.,Department of Cardiology, Tianjin First Center Hospital, Tianjin, China
| | - Chengzhi Lu
- Department of Cardiology, Tianjin First Center Hospital, Tianjin, China
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37
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Yu Y, Xu P, Cui G, Xu X, Li K, Chen X, Bao J. UBQLN4 promotes progression of HCC via activating wnt-β-catenin pathway and is regulated by miR-370. Cancer Cell Int 2020; 20:3. [PMID: 31911755 PMCID: PMC6942288 DOI: 10.1186/s12935-019-1078-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 12/17/2019] [Indexed: 12/21/2022] Open
Abstract
Background Ubiquilin-4 (UBQLN4) is a member of the ubiquitin–proteasome system that is usually upregulated in many tumor cells. Its overexpression has been associated with poor disease outcomes in various cancer diseases. However, the underlying mechanism of UBQLN4 in the development of hepatocellular carcinoma (HCC) has not been elucidated. Methods Immunochemistry, real-time PCR, and western blotting were used to evaluate the expression levels of UBQLN4 in cancer tissues. Univariate, Cox-regression, and Kaplan–Meier analyses were performed to determine the association between UBQLN4 expression and HCC prognosis. Cell Counting Kit-8 (CCK-8), transwell, EDU and colony formation assays were conducted to evaluate the role of UBQLN4 in HCC cell progression. The gene set enrichment analysis and luciferase reporter experiments were conducted to find the mechanism of UBQLN4 in HCC. Results Ubiquilin-4 (UBQLN4) was overexpressed in HCC tissues. Besides, overexpression of UBQLN4 was associated with poor overall survival and disease-free survival rate of HCC patients. The loss-of-function analysis revealed that suppression of UBQLN4 inhibited the proliferation and invasion of HCC cells in vivo and in vitro. The KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis showed that UBQLN4 could regulate activation of the wnt-β-catenin pathway in HCC cells. Furthermore, our results showed that UBQLN4 was downregulated by miR-370, which acted as a tumor suppressor gene in HCC progression. Conclusion The results of the present study suggest that the miR-370/UBQLN4 axis may play a critical role in the progression of HCC. These findings may inform future strategies for the development of therapeutic agents against HCC.
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Affiliation(s)
- Yan Yu
- 1Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China.,2Key Laboratory of Clinical Medicine, Department of Digestive Diseases, The First Affiliated Hospital of Zhengzhou University, 1# Jianshe East Road, Zhengzhou, 450052 China
| | - Penglin Xu
- 2Key Laboratory of Clinical Medicine, Department of Digestive Diseases, The First Affiliated Hospital of Zhengzhou University, 1# Jianshe East Road, Zhengzhou, 450052 China
| | - Guangying Cui
- 1Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China.,2Key Laboratory of Clinical Medicine, Department of Digestive Diseases, The First Affiliated Hospital of Zhengzhou University, 1# Jianshe East Road, Zhengzhou, 450052 China
| | - Xiaodong Xu
- 2Key Laboratory of Clinical Medicine, Department of Digestive Diseases, The First Affiliated Hospital of Zhengzhou University, 1# Jianshe East Road, Zhengzhou, 450052 China
| | - Kongfei Li
- 3Department of Hematology, Yinzhou People's Hospital Affiliated to Medical College of Ningbo University, Ningbo, China
| | - Xiaolong Chen
- 1Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China.,2Key Laboratory of Clinical Medicine, Department of Digestive Diseases, The First Affiliated Hospital of Zhengzhou University, 1# Jianshe East Road, Zhengzhou, 450052 China
| | - Jie Bao
- 2Key Laboratory of Clinical Medicine, Department of Digestive Diseases, The First Affiliated Hospital of Zhengzhou University, 1# Jianshe East Road, Zhengzhou, 450052 China
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38
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Fan J, Zhu Q, Wu Z, Ding J, Qin S, Liu H, Miao P. Protective effects of irisin on hypoxia-reoxygenation injury in hyperglycemia-treated cardiomyocytes: Role of AMPK pathway and mitochondrial protection. J Cell Physiol 2019; 235:1165-1174. [PMID: 31268170 DOI: 10.1002/jcp.29030] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 06/12/2019] [Indexed: 12/22/2022]
Abstract
Recent evidence has verified the cardioprotective actions of irisin in different diseases models. However, the beneficial action of irisin on hypoxia-reoxygenation (HR) injury under high glucose stress has not been described. Herein our research investigated the influence of irisin on HR-triggered cardiomyocyte death under high glucose stress. HR model was established in vitro under high glucose treatment. The results illuminated that HR injury augmented apoptotic ratio of cardiomyocyte under high glucose stress; this effect could be abolished by irisin via modulating mitochondrial function. Irisin treatment attenuated cellular redox stress, improved cellular ATP biogenetics, sustained mitochondria potential, and impaired mitochondrion-related cell death. At the molecular levels, irisin treatment activated the 5'-adenosine monophosphate-activated protein kinase (AMPK) pathway and the latter protected cardiomyocyte and mitochondria against HR injury under high glucose stress. Altogether, our results indicated a novel role of irisin in HR-treated cardiomyocyte under high glucose stress. Irisin-activated AMPK pathway and the latter sustained cardiomyocyte viability and mitochondrial function.
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Affiliation(s)
- Jiamao Fan
- Department of Cardiology, Linfen Central Hospital, Linfen, China
| | - Qing Zhu
- Department of Cardiology, Linfen Central Hospital, Linfen, China.,Institutes of Biomedical Sciences, Shanghai Medical School, Fudan University, Shanghai, China
| | - Zhenhua Wu
- Department of Cardiology, Linfen Central Hospital, Linfen, China
| | - Jiao Ding
- Department of Cardiology, Linfen Central Hospital, Linfen, China
| | - Shuai Qin
- Department of Cardiovascular Surgery, Linfen Central Hospital, Linfen, China
| | - Hui Liu
- Department of Cardiovascular Surgery, Linfen Central Hospital, Linfen, China
| | - Pengfei Miao
- Department of Cardiology, Linfen Central Hospital, Linfen, China
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39
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Spradlin JN, Hu X, Ward CC, Brittain SM, Jones MD, Ou L, To M, Proudfoot A, Ornelas E, Woldegiorgis M, Olzmann JA, Bussiere DE, Thomas JR, Tallarico JA, McKenna JM, Schirle M, Maimone TJ, Nomura DK. Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nat Chem Biol 2019; 15:747-755. [PMID: 31209351 PMCID: PMC6592714 DOI: 10.1038/s41589-019-0304-8] [Citation(s) in RCA: 282] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 05/08/2019] [Indexed: 12/22/2022]
Abstract
Nimbolide, a terpenoid natural product derived from the Neem tree, impairs cancer pathogenicity; however, the direct targets and mechanisms by which nimbolide exerts its effects are poorly understood. Here, we used activity-based protein profiling (ABPP) chemoproteomic platforms to discover that nimbolide reacts with a novel functional cysteine crucial for substrate recognition in the E3 ubiquitin ligase RNF114. Nimbolide impairs breast cancer cell proliferation in-part by disrupting RNF114 substrate recognition, leading to inhibition of ubiquitination and degradation of the tumor-suppressors such as p21, resulting in their rapid stabilization. We further demonstrate that nimbolide can be harnessed to recruit RNF114 as an E3 ligase in targeted protein degradation applications and show that synthetically simpler scaffolds are also capable of accessing this unique reactive site. Our study highlights the utility of ABPP platforms in uncovering unique druggable modalities accessed by natural products for cancer therapy and targeted protein degradation applications.
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Affiliation(s)
- Jessica N Spradlin
- Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.,Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA
| | - Xirui Hu
- Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.,Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA
| | - Carl C Ward
- Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.,Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
| | - Scott M Brittain
- Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.,Novartis Institutes for BioMedical Research, Cambridge, MA, USA
| | - Michael D Jones
- Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.,Novartis Institutes for BioMedical Research, Cambridge, MA, USA
| | - Lisha Ou
- Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.,Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA
| | - Milton To
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA
| | - Andrew Proudfoot
- Novartis Institutes for BioMedical Research, Emeryville, CA, USA
| | | | | | - James A Olzmann
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA.,Chan Zuckerberg Biohub, San Francisco, CA, USA
| | - Dirksen E Bussiere
- Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.,Novartis Institutes for BioMedical Research, Emeryville, CA, USA
| | - Jason R Thomas
- Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.,Novartis Institutes for BioMedical Research, Cambridge, MA, USA.,Vertex Pharmaceuticals, Boston, MA, USA
| | - John A Tallarico
- Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.,Novartis Institutes for BioMedical Research, Cambridge, MA, USA
| | - Jeffrey M McKenna
- Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.,Novartis Institutes for BioMedical Research, Cambridge, MA, USA
| | - Markus Schirle
- Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.,Novartis Institutes for BioMedical Research, Cambridge, MA, USA
| | - Thomas J Maimone
- Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA. .,Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.
| | - Daniel K Nomura
- Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA. .,Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA. .,Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. .,Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA.
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Non-Proteasomal UbL-UbA Family of Proteins in Neurodegeneration. Int J Mol Sci 2019; 20:ijms20081893. [PMID: 30999567 PMCID: PMC6514573 DOI: 10.3390/ijms20081893] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 04/09/2019] [Accepted: 04/15/2019] [Indexed: 12/11/2022] Open
Abstract
Ubiquitin-like/ubiquitin-associated proteins (UbL-UbA) are a well-studied family of non-proteasomal ubiquitin receptors that are evolutionarily conserved across species. Members of this non-homogenous family facilitate and support proteasomal activity by promoting different effects on proteostasis but exhibit diverse extra-proteasomal activities. Dysfunctional UbL-UbA proteins render cells, particularly neurons, more susceptible to stressors or aging and may cause earlier neurodegeneration. In this review, we summarized the properties and functions of UbL-UbA family members identified to date, with an emphasis on new findings obtained using Drosophila models showing a direct or indirect role in some neurodegenerative diseases.
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Zeng F, Huang L, Cheng X, Yang X, Li T, Feng G, Tang Y, Yang Y. Overexpression of LASS2 inhibits proliferation and causes G0/G1 cell cycle arrest in papillary thyroid cancer. Cancer Cell Int 2018; 18:151. [PMID: 30302058 PMCID: PMC6167791 DOI: 10.1186/s12935-018-0649-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 09/26/2018] [Indexed: 12/11/2022] Open
Abstract
Background The aim of this study was to investigate the role of LAG1 longevity-assurance homologue 2 (LASS2) in papillary thyroid cancer (PTC). Methods Immunohistochemistry staining was conducted to explore the expression levels of LASS2 in PTC tissues and adjacent normal thyroid tissues and nodular goiter tissues. Western blotting and RT-qPCR were performed to explore the expression levels of LASS2 in three PTC cell lines (TPC-1, K1, BCPAP). An Adv-LASS2-GFP recombinant adenovirus vector was constructed and transduced into BCPAP cells. Then CCK-8 assay, colony formation assay, cell cycle distribution, and apoptosis were performed. Western blotting was used to examine the expression of p21, cyclin D1, cyclin-dependent kinase 4, p53 and p-p53. Results LASS2 was downregulated in PTC tissues compared with adjacent thyroid tissues or nodular goiter tissues. In addition, the expression of LASS2 was found to be associated with TNM stage and lymph node metastasis. BCPAP cells expressed the lowest LASS2 compared to TPC-1 cells or K1 cells. Overexpression of LASS2 significantly inhibited proliferation, promoted apoptosis and caused G0/G1 cell cycle arrest in BCPAP cells. Furthermore, overexpression of LASS2 significantly increased the expression of p21, inhibited the expression of cyclin D1 and cyclin-dependent kinase 4, and increased the expression of p-p53, but did not effect the expression of p53 in BCPAP cells. Conclusion Our findings indicate that overexpression of LASS2 inhibits PTC cell proliferation, promotes apoptosis and causes G0/G1 cell cycle arrest via a p53-dependent pathway. Thus, LASS2 may serve as a novel biomarker in PTC.
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Affiliation(s)
- Feng Zeng
- 1Medical Center of Breast and Thyroid Disease, Affiliated Hospital of ZunYi Medical College, Zunyi, 563003 Guizhou People's Republic of China
| | - Liangliang Huang
- 1Medical Center of Breast and Thyroid Disease, Affiliated Hospital of ZunYi Medical College, Zunyi, 563003 Guizhou People's Republic of China
| | - Xiaoming Cheng
- 1Medical Center of Breast and Thyroid Disease, Affiliated Hospital of ZunYi Medical College, Zunyi, 563003 Guizhou People's Republic of China
| | - Xiaoli Yang
- 2College of Laboratory Medicine, Affiliated Hospital of ZunYi Medical College, Zunyi, 563003 Guizhou People's Republic of China.,3Department of Clinical Laboratory, Affiliated Hospital of ZunYi Medical College, 149 Dalian Road, Zunyi, 563003 Guizhou People's Republic of China
| | - Taolang Li
- 1Medical Center of Breast and Thyroid Disease, Affiliated Hospital of ZunYi Medical College, Zunyi, 563003 Guizhou People's Republic of China
| | - Guoli Feng
- 1Medical Center of Breast and Thyroid Disease, Affiliated Hospital of ZunYi Medical College, Zunyi, 563003 Guizhou People's Republic of China
| | - Yingqi Tang
- 1Medical Center of Breast and Thyroid Disease, Affiliated Hospital of ZunYi Medical College, Zunyi, 563003 Guizhou People's Republic of China
| | - Yan Yang
- 2College of Laboratory Medicine, Affiliated Hospital of ZunYi Medical College, Zunyi, 563003 Guizhou People's Republic of China.,3Department of Clinical Laboratory, Affiliated Hospital of ZunYi Medical College, 149 Dalian Road, Zunyi, 563003 Guizhou People's Republic of China
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