Supplementary Information
The online version contains supplementary material available at 10.1186/s12964-022-00952-x.
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Affiliation(s)
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Cited by Other Article(s) |
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1
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Wen P, Li J, Wen Z, Guo X, Ma G, Hu S, Xu J, Zhao H, Li R, Liu Y, Wang Y, Gao J. MICAL-L2, as an estrogen-responsive gene, is involved in ER-positive breast cancer cell progression and tamoxifen sensitivity via the AKT/mTOR pathway. Biochem Pharmacol 2024; 225:116256. [PMID: 38729448 DOI: 10.1016/j.bcp.2024.116256] [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: 11/15/2023] [Revised: 03/25/2024] [Accepted: 05/02/2024] [Indexed: 05/12/2024]
Abstract
Endocrine treatment, particularly tamoxifen, has shown significant improvement in the prognosis of patients with estrogen receptor-positive (ER-positive) breast cancer. However, the clinical utility of this treatment is often hindered by the development of endocrine resistance. Therefore, a comprehensive understanding of the underlying mechanisms driving ER-positive breast cancer carcinogenesis and endocrine resistance is crucial to overcome this clinical challenge. In this study, we investigated the expression of MICAL-L2 in ER-positive breast cancer and its impact on patient prognosis. We observed a significant upregulation of MICAL-L2 expression in ER-positive breast cancer, which correlated with a poorer prognosis in these patients. Furthermore, we found that estrogen-ERβ signaling promoted the expression of MICAL-L2. Functionally, our study demonstrated that MICAL-L2 not only played an oncogenic role in ER-positive breast cancer tumorigenesis but also influenced the sensitivity of ER-positive breast cancer cells to tamoxifen. Mechanistically, as an estrogen-responsive gene, MICAL-L2 facilitated the activation of the AKT/mTOR signaling pathway in ER-positive breast cancer cells. Collectively, our findings suggest that MICAL-L2 could serve as a potential prognostic marker for ER-positive breast cancer and represent a promising molecular target for improving endocrine treatment and developing therapeutic approaches for this subtype of breast cancer.
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Affiliation(s)
- Pushuai Wen
- Department of Pathophysiology, Jinzhou Medical University, Jinzhou 121001, China; Biological Anthropology Institute, Jinzhou Medical University, Jinzhou 121001, China.
| | - Jing Li
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou 121001, China
| | - Zihao Wen
- Department of Pathophysiology, Jinzhou Medical University, Jinzhou 121001, China
| | - Xiaoyan Guo
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou 121001, China
| | - Guoqun Ma
- Department of Pathophysiology, Jinzhou Medical University, Jinzhou 121001, China
| | - Shuzhen Hu
- Department of Pathophysiology, Jinzhou Medical University, Jinzhou 121001, China
| | - Jiamei Xu
- Department of Pathophysiology, Jinzhou Medical University, Jinzhou 121001, China
| | - Hongli Zhao
- Department of Pathophysiology, Jinzhou Medical University, Jinzhou 121001, China
| | - Ruixin Li
- Department of Pathophysiology, Jinzhou Medical University, Jinzhou 121001, China
| | - Ying Liu
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou 121001, China.
| | - Yu Wang
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou 121001, China.
| | - Jing Gao
- Department of Ultrasonography, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou 121001, China.
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2
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Wang J, Tan Y, Jia QY, Tang FQ. Transcriptional factor III A promotes colorectal cancer progression by upregulating cystatin A. World J Gastrointest Oncol 2022; 14:1918-1932. [PMID: 36310710 PMCID: PMC9611429 DOI: 10.4251/wjgo.v14.i10.1918] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 07/23/2022] [Accepted: 09/07/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Advanced colorectal cancer (CRC) generally has poor outcomes and high mortality rates. Clarifying the molecular mechanisms underlying CRC progression is necessary to develop new diagnostic and therapeutic strategies to improve CRC outcome and decrease mortality. Transcriptional factor III A (GTF3A), an RNA polymerase III transcriptional factor, is a critical driver of tumorgenesis and aggravates CRC cell growth.
AIM To confirm whether GTF3A promotes CRC progression by regulating the expression of cystatin A (Csta) gene and investigate whether GTF3A can serve as a prognostic biomarker and therapeutic target for patients with CRC.
METHODS Human tissue microarrays containing 90 pairs of CRC tissues and adjacent non-tumor tissues, and human tissue microarrays containing 20 pairs of CRC tissues, adjacent non-tumor tissues, and metastatic tissues were examined for GTF3A expression using immunohistochemistry. The survival rates of patients were analyzed. Short hairpin GTF3As and CSTAs were designed and packaged into the virus to block the expression of Gtf3a and Csta genes, respectively. In vivo tumor growth assays were performed to confirm whether GTF3A promotes CRC cell proliferation in vivo. Electrophoretic mobility shift assay and fluorescence in situ hybridization assay were used to detect the interaction of GTF3A with Csta, whereas luciferase activity assay was used to evaluate the expression of the Gtf3a and Csta genes. RNA-Sequencing (RNA-Seq) and data analyses were used to screen for target genes of GTF3A.
RESULTS The expression of GTF3A was higher in CRC tissues and lymph node metastatic tissues than in the adjacent normal tissues. GTF3A was associated with CRC prognosis, and knockdown of the Gtf3a gene impaired CRC cell proliferation, invasion, and motility in vitro and in vivo. Moreover, RNA-Seq analysis revealed that GTF3A might upregulate the expression of Csta, whereas the luciferase activity assay showed that GTF3A bound to the promoter of Csta gene and increased Csta transcription. Furthermore, CSTA regulated the expression of epithelial-mesenchymal transition (EMT) markers.
CONCLUSION GTF3A increases CSTA expression by binding to the Csta promoter, and increased CSTA level promotes CRC progression by regulating the EMT. Inhibition of GTF3A prevents CRC progression. Therefore, GTF3A is a potential novel therapeutic target and biomarker for CRC.
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Affiliation(s)
- Jing Wang
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Yuan Tan
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Qun-Ying Jia
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Fa-Qin Tang
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
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3
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Wang Q, Qi C, Min P, Wang Y, Ye F, Xia T, Zhang Y, Du J. MICAL2 contributes to gastric cancer cell migration via Cdc42-dependent activation of E-cadherin/β-catenin signaling pathway. Cell Commun Signal 2022; 20:136. [PMID: 36064550 PMCID: PMC9442994 DOI: 10.1186/s12964-022-00952-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 08/06/2022] [Indexed: 11/10/2022] Open
Abstract
Background Gastric cancer is a common and lethal human malignancy worldwide and cancer cell metastasis is the leading cause of cancer-related mortality. MICAL2, a flavoprotein monooxygenase, is an important regulator of epithelial-to-mesenchymal transition. The aim of this study was to explore the effects of MICAL2 on gastric cancer cell migration and determine the underlying molecular mechanisms. Methods Cell migration was examined by wound healing and transwell assays. Changes in E-cadherin/β-catenin signaling were determined by qPCR and analysis of cytoplasmic and nuclear protein fractions. E-cadherin/β-catenin binding was determined by co-immunoprecipitation assays. Cdc42 activity was examined by pulldown assay. Results MICAL2 was highly expressed in gastric cancer tissues. The knockdown of MICAL2 significantly attenuated migratory ability and β-catenin nuclear translocation in gastric cancer cells while LiCl treatment, an inhibitor of GSK3β, reversed these MICAL2 knockdown-induced effects. Meanwhile, E-cadherin expression was markedly enhanced in MICAL2-depleted cells. MICAL2 knockdown led to a significant attenuation of E-cadherin ubiquitination and degradation in a Cdc42-dependent manner, then enhanced E-cadherin/β-catenin binding, and reduced β-catenin nuclear translocation. Conclusions Together, our results indicated that MICAL2 promotes E-cadherin ubiquitination and degradation, leading to enhanced β-catenin signaling via the disruption of the E-cadherin/β-catenin complex and, consequently, the promotion of gastric cell migration.
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Video Abstract
- Qianwen Wang
- Department of Physiology, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, Jiangsu, China
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- Chenxiang Qi
- Department of Physiology, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, Jiangsu, China
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- Pengxiang Min
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
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- Yueyuan Wang
- Experimental Teaching Center of Basic Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
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- Fengwen Ye
- Department of Physiology, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, Jiangsu, China
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- Tianxiang Xia
- Department of Physiology, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, Jiangsu, China
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- Yujie Zhang
- Department of Physiology, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, Jiangsu, China
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- Jun Du
- Department of Physiology, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, Jiangsu, China.
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4
Huang W, Zou L, Hao Z, Wang B, Mao F, Duan Q, Guo D. S645C Point Mutation Suppresses Degradation of EGFR to Promote Progression of Glioblastoma.
Front Oncol 2022;
12:904383. [PMID:
35814475 PMCID:
PMC9259983 DOI:
10.3389/fonc.2022.904383]
[Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 05/18/2022] [Indexed: 11/24/2022] Open
Abstract
Background
The tightly controlled activity of EGFR is important for the homeostasis of self-renewal of human tissue. Mutations in the extracellular domain of EGFR are frequent and function as a novel mechanism for oncogenic EGFR activation in GBM, and impact the response of patients to small-molecule inhibitors.
Methods
We constructed glioblastoma cell lines stably expressing wild-type EGFR and the mutant of EGFR S645C. We detected cell growth in vitro and in vivo. We evaluated the anti-tumor activity and effectiveness of gefitinib and osimertinib in cells.
Results
In the present study, we identified an oncogenic substituted mutation of EGFR—S645C. The mutation can promote the proliferation and colony formation of glioblastoma in vitro and in vivo. Mechanistically, the EGFR S645C mutation potentially changes the formation of hydrogen bonds within dimerized EGFR and inhibits the degradation of EGFR to prolong downstream signaling. The mutation induces resistance to gefitinib but presents an opportunity for osimertinib treatment.
Conclusion
The study indicated a novel oncogenic mutation and advises on the precise treatment of individual patients with the EGFR S645C mutation.
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Affiliation(s)
- Wenda Huang
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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- Ling Zou
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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- Zhaonian Hao
- Department of Neurosurgery, Beijing TianTan Hospital, Capital Medical University, Beijing, China
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- Baofeng Wang
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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- Feng Mao
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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- Qiuhong Duan
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Dongsheng Guo, ; Qiuhong Duan,
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- Dongsheng Guo
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Dongsheng Guo, ; Qiuhong Duan,
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5
Zhu G, Jin L, Sun W, Wang S, Liu N. Proteomics of post-translational modifications in colorectal cancer: Discovery of new biomarkers.
Biochim Biophys Acta Rev Cancer 2022;
1877:188735. [PMID:
35577141 DOI:
10.1016/j.bbcan.2022.188735]
[Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 05/08/2022] [Accepted: 05/09/2022] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is one of the costliest health problems and ranks second in cancer-related mortality in developed countries. With the aid of proteomics, many protein biomarkers for the diagnosis, prognosis, and precise management of CRC have been identified. Furthermore, some protein biomarkers exhibit structural diversity after modifications. Post-translational modifications (PTMs), most of which are catalyzed by a variety of enzymes, extensively increase protein diversity and are involved in many complex and dynamic cellular processes through the regulation of protein function. Accumulating evidence suggests that abnormal PTM events are associated with a variety of human diseases, such as CRC, thus highlighting the need for studying PTMs to discover both the molecular mechanisms and therapeutic targets of CRC. In this review, we begin with a brief overview of the importance of protein PTMs, discuss the general strategies for proteomic profiling of several key PTMs (including phosphorylation, acetylation, glycosylation, ubiquitination, methylation, and citrullination), shift the emphasis to describing the specific methods used for delineating the global landscapes of each of these PTMs, and summarize the recent applications of these methods to explore the potential roles of the PTMs in CRC. Finally, we discuss the current status of PTM research on CRC and provide future perspectives on how PTM regulation can play an essential role in translational medicine for early diagnosis, prognosis stratification, and therapeutic intervention in CRC.
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Affiliation(s)
- Gengjun Zhu
- Department Oncology and Hematology, The Second Hospital of Jilin University, Changchun, China
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- Lifang Jin
- Department Oncology and Hematology, The Second Hospital of Jilin University, Changchun, China
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- Wanchun Sun
- Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, China
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- Shuang Wang
- Dermatological department, The Second Hospital of Jilin University, Changchun, China.
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- Ning Liu
- Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, China; Central Laboratory, The Second Hospital of Jilin University, Changchun, China.
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Gu H, Li Y, Cui X, Cao H, Hou Z, Ti Y, Liu D, Gao J, Wang Y, Wen P. MICAL1 inhibits colorectal cancer cell migration and proliferation by regulating the EGR1/β-catenin signaling pathway.
Biochem Pharmacol 2022;
195:114870. [PMID:
34902339 DOI:
10.1016/j.bcp.2021.114870]
[Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 11/18/2021] [Accepted: 12/03/2021] [Indexed: 12/26/2022]
Abstract
MICAL1 has been reported to be involved in the malignant processes of several types of cancer cells, however, the roles of MICAL1 in colorectal cancer (CRC) have not been well-characterized. This study aims to investigate the cellular functions and molecular mechanisms of MICAL1 in CRC cells. Here, we found that both mRNA and protein levels of MICAL1 were down-regulated in colorectal cancer tissues compared with matched adjacent non-tumor tissues, and the expression level of MICAL1 was correlated with the metastatic status of colorectal cancer. Importantly, overexpression of MICAL1 significantly inhibited colorectal cancer cell migration and growth, and increased the level of E-cadherin and Occludin, and suppressed the expression level of Vimentin and N-cadherin; while silencing of MICAL1 promoted CRC cell migration and enhanced EMT. In addition, MICAL1 overexpression significantly inhibited the proliferation and growth of CRC in vitro and in vivo. Moreover, RNA sequencing and bioinformatics analysis identified that MICAL1 was closely correlated with "cell migration", "cell cycle" and "β-catenin signaling" genesets. Mechanistically, overexpression of MICAL1 downregulated the mRNA level of EGR1 and β-catenin, decreased the protein level and nuclear translocation of β-catenin, and inhibited the transcriptions of β-catenin downstream targets, c-myc and cyclin D1. The ectopic expression of EGR1 or β-catenin can significantly block the MICAL1-mediated inhibitory effects. Collectively, MICAL1 is down-regulated in CRC, and plays an inhibitory role in the migration and growth of CRC cells by suppressing the ERG1/β-catenin signaling pathway.
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Affiliation(s)
- Huanyu Gu
- Department of Pathophysiology, Jinzhou Medical University, Jinzhou 121000, Liaoning, China
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- Yi Li
- Department of Pathophysiology, Jinzhou Medical University, Jinzhou 121000, Liaoning, China
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- Xiuping Cui
- Life Science Institute, Jinzhou Medical University, Jinzhou 121000, Liaoning, China
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- Huiru Cao
- Department of Pathophysiology, Jinzhou Medical University, Jinzhou 121000, Liaoning, China
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- Zhijuan Hou
- Department of Pathophysiology, Jinzhou Medical University, Jinzhou 121000, Liaoning, China
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- Yunhe Ti
- Department of Pathophysiology, Jinzhou Medical University, Jinzhou 121000, Liaoning, China
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- Dahua Liu
- Biological Anthropology Institute, Jinzhou Medical University, Jinzhou 121000, Liaoning, China
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- Jing Gao
- Department of Ultrasonography, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China
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- Yu Wang
- Life Science Institute, Jinzhou Medical University, Jinzhou 121000, Liaoning, China.
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- Pushuai Wen
- Department of Pathophysiology, Jinzhou Medical University, Jinzhou 121000, Liaoning, China; Biological Anthropology Institute, Jinzhou Medical University, Jinzhou 121000, Liaoning, China.
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Pu B, Zhang X, Yan T, Li Y, Liu B, Jian Z, Mahgoub OK, Gu L, Xiong X, Zou N. MICAL2 Promotes Proliferation and Migration of Glioblastoma Cells Through TGF-β/p-Smad2/EMT-Like Signaling Pathway.
Front Oncol 2021;
11:735180. [PMID:
34868922 PMCID:
PMC8632809 DOI:
10.3389/fonc.2021.735180]
[Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 10/08/2021] [Indexed: 01/01/2023] Open
Abstract
Recent studies showed that molecule interacting with CasL2 (MICAL2) could be a novel tumor growth factor, and it is closely associated with tumor growth and invasion. However, the role it plays in glioblastoma (GBM) and its potential mechanisms are currently unknown. Our study is designed to identify the effect of MICAL2 on GBM cells and the potential mechanisms behind it. Here, we found that MICAL2 interacts with TGF receptor-type I (TGFRI) and promotes the proliferation and migration of glioblastoma through the TGF-β/p-Smad2/EMT-like signaling pathway. MICAL2-knockdown inhibited the proliferation of glioblastoma cells, which was related to cell cycle arrest and downregulation of DNA replication. The invasion abilities of U87 and U251 cells were reduced after the knockdown of MICAL2. MICAL2 promoted the growth of GBM in nude mice. High MICAL2 predicts poor outcome of GBM patients. MICAL2 could be identified as a novel promising therapeutic target for human GBM.
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Affiliation(s)
- Bei Pu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
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- Xu Zhang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
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- Tengfeng Yan
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
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- Yuntao Li
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Department of Neurosurgery, The Affiliated Huzhou Hospital, Zhejiang University School of Medicine (Huzhou Central Hospital), Huzhou, China
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- Baohui Liu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
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- Zhihong Jian
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
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- Omer Kamal Mahgoub
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
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- Lijuan Gu
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
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- Xiaoxing Xiong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Department of Neurosurgery, The Affiliated Huzhou Hospital, Zhejiang University School of Medicine (Huzhou Central Hospital), Huzhou, China
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- Ning Zou
- Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Qi C, Min P, Wang Q, Wang Y, Song Y, Zhang Y, Bibi M, Du J. MICAL2 Contributes to Gastric Cancer Cell Proliferation by Promoting YAP Dephosphorylation and Nuclear Translocation.
OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021;
2021:9955717. [PMID:
34650666 PMCID:
PMC8510804 DOI:
10.1155/2021/9955717]
[Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 08/12/2021] [Accepted: 09/16/2021] [Indexed: 01/19/2023]
Abstract
Dynamic cytoskeletal rearrangements underlie the changes that occur during cell division in proliferating cells. MICAL2 has been reported to possess reactive oxygen species- (ROS-) generating properties and act as an important regulator of cytoskeletal dynamics. However, whether it plays a role in gastric cancer cell proliferation is not known. In the present study, we found that MICAL2 was highly expressed in gastric cancer tissues, and this high expression level was associated with carcinogenesis and poor overall survival in gastric cancer patients. The knockdown of MICAL2 led to cell cycle arrest in the S phase and attenuated cell proliferation. Concomitant with S-phase arrest, a decrease in CDK6 and cyclin D protein levels was observed. Furthermore, MICAL2 knockdown attenuated intracellular ROS generation, while MICAL2 overexpression led to a decrease in the p-YAP/YAP ratio and promoted YAP nuclear localization and cell proliferation, effects that were reversed by pretreatment with the ROS scavenger N-acetyl-L-cysteine (NAC) and SOD-mimetic drug tempol. We further found that MICAL2 induced Cdc42 activation, and activated Cdc42 mediated the effect of MICAL2 on YAP dephosphorylation and nuclear translocation. Collectively, our results showed that MICAL2 has a promotive effect on gastric cancer cell proliferation through ROS generation and Cdc42 activation, both of which independently contribute to YAP dephosphorylation and its nuclear translocation.
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Affiliation(s)
- Chenxiang Qi
- Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
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- Pengxiang Min
- Key Laboratory of Cardio Vascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 211166, China
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- Qianwen Wang
- Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
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- Yueyuan Wang
- The Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China
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- Yixuan Song
- Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
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- Yujie Zhang
- Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
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- Maria Bibi
- Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
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- Jun Du
- Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
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Bai Y, Qi W, Liu L, Zhang J, Pang L, Gan T, Wang P, Wang C, Chen H. Identification of Seven-Gene Hypoxia Signature for Predicting Overall Survival of Hepatocellular Carcinoma.
Front Genet 2021;
12:637418. [PMID:
33912215 PMCID:
PMC8075060 DOI:
10.3389/fgene.2021.637418]
[Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/15/2021] [Indexed: 01/01/2023] Open
Abstract
Background
Hepatocellular carcinoma (HCC) is ranked fifth among the most common cancer worldwide. Hypoxia can induce tumor growth, but the relationship with HCC prognosis remains unclear. Our study aims to construct a hypoxia-related multigene model to predict the prognosis of HCC.
Methods
RNA-seq expression data and related clinical information were download from TCGA database and ICGC database, respectively. Univariate/multivariate Cox regression analysis was used to construct prognostic models. KM curve analysis, and ROC curve were used to evaluate the prognostic models, which were further verified in the clinical traits and ICGC database. GSEA analyzed pathway enrichment in high-risk groups. Nomogram was constructed to predict the personalized treatment of patients. Finally, real-time fluorescence quantitative PCR (RT-qPCR) was used to detect the expressions of KDELR3 and SCARB1 in normal hepatocytes and 4 HCC cells. The expressions of SCARB1 in hepatocellular carcinoma tissue in 46 patients were detected by immunohistochemistry, and the correlation between its expressions and disease free survival of patient was calculated.
Results
Through a series of analyses, seven prognostic markers related to HCC survival were constructed. HCC patients were divided into the high and low risk group, and the results of KM curve showed that there was a significant difference between the two groups. Stratified analysis, found that there were significant differences in risk values of different ages, genders, stages and grades, which could be used as independent predictors. In addition, we assessed the risk value in the clinical traits analysis and found that it could accelerate the progression of cancer, while the results of GSEA enrichment analysis showed that the high-risk group patients were mainly distributed in the cell cycle and other pathways. Then, Nomogram was constructed to predict the overall survival of patients. Finally, RT-qPCR showed that KDELR3 and SCARB1 were highly expressed in HepG2 and L02, respectively. Results of IHC staining showed that SCARB1 was highly expressed in cancer tissues compared to adjacent normal liver tissues and its expression was related to hepatocellular carcinoma differentiation status. The Kaplan-Meier survival showed a poor percent survival in the SCARB1 high group compared to that in the SCARB1 low group.
Conclusion
This study provides a potential diagnostic indicator for HCC patients, and help clinicians to deepen the comprehension in HCC pathogenesis so as to make personalized medical decisions.
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Affiliation(s)
- Yuping Bai
- Department of MR, Lanzhou University Second Hospital, Lanzhou, China.,The Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
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- Wenbo Qi
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
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- Le Liu
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
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- Jing Zhang
- Department of MR, Lanzhou University Second Hospital, Lanzhou, China
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- Lan Pang
- Department of MR, Lanzhou University Second Hospital, Lanzhou, China
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- Tiejun Gan
- Department of MR, Lanzhou University Second Hospital, Lanzhou, China
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- Pengfei Wang
- Department of MR, Lanzhou University Second Hospital, Lanzhou, China
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- Chen Wang
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China
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- Hao Chen
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
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10
Signal-regulated oxidation of proteins via MICAL.
Biochem Soc Trans 2021;
48:613-620. [PMID:
32219383 DOI:
10.1042/bst20190866]
[Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/09/2020] [Accepted: 03/11/2020] [Indexed: 12/12/2022]
Abstract
Processing of and responding to various signals is an essential cellular function that influences survival, homeostasis, development, and cell death. Extra- or intracellular signals are perceived via specific receptors and transduced in a particular signalling pathway that results in a precise response. Reversible post-translational redox modifications of cysteinyl and methionyl residues have been characterised in countless signal transduction pathways. Due to the low reactivity of most sulfur-containing amino acid side chains with hydrogen peroxide, for instance, and also to ensure specificity, redox signalling requires catalysis, just like phosphorylation signalling requires kinases and phosphatases. While reducing enzymes of both cysteinyl- and methionyl-derivates have been characterised in great detail before, the discovery and characterisation of MICAL proteins evinced the first examples of specific oxidases in signal transduction. This article provides an overview of the functions of MICAL proteins in the redox regulation of cellular functions.
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11
Min P, Zhang L, Wang Y, Qi C, Song Y, Bibi M, Zhang Y, Ma Y, Zhao X, Yu M, Du J. MICAL-L2 Is Essential for c-Myc Deubiquitination and Stability in Non-small Cell Lung Cancer Cells.
Front Cell Dev Biol 2021;
8:575903. [PMID:
33520979 PMCID:
PMC7841116 DOI:
10.3389/fcell.2020.575903]
[Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 12/16/2020] [Indexed: 01/01/2023] Open
Abstract
Objectives: MICAL-L2, a member of the molecules interacting with the CasL (MICAL) family, was reported to be highly expressed in several types of cancers, however, the roles of MICAL-L2 in NSCLC pathogenesis remain to be explored. This study is designed to clarify the mechanisms by which MICAL-L2 participates in NSCLC cell proliferation.
Materials and Methods: The expression levels of MICAL-L2 in human lung cancer samples were assessed by immunohistochemical staining. Cells were transfected with siRNA or plasmids to regulate MICAL-L2 expression. Cell proliferation was measured by EdU staining and CCK-8 assays. MICAL-L2 and phosphorylated/total c-Myc expression were examined by Western blotting analysis. Interaction between MICAL-L2 and c-Myc was assessed by immunofluorescence staining, Western blotting and co-immunoprecipitation assays. Western blotting, polyubiquitylation detection and protein stability assays were used to assess whether MICAL-L2 exerts its oncogenic effect via c-Myc.
Results: We found that MICAL-L2 was highly expressed in human NSCLC. While overexpressing MICAL-L2 increased NSCLC cell proliferation, MICAL-L2 depletion decreased the proliferation of NSCLC cells, an effect that was linked to cell cycle arrest. MICAL-L2 physically interacted with the c-Myc protein and functioned to maintain nuclear c-Myc levels and prolonged its half-life. Knockdown of MICAL-L2 expression led to decreased c-Myc protein stability through accelerating polyubiquitylation of c-Myc and gave rise to c-Myc degradation. We further found that MICAL-L2 deubiquitinated c-Myc and blocked its degradation, presumably by inhibiting c-Myc phosphorylation at threonine residue 58.
Conclusions: These results indicate that MICAL-L2 is a key regulator of c-Myc deubiquitination and stability in the nucleus, and this activity may be involved in promoting NSCLC cell proliferation.
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Affiliation(s)
- Pengxiang Min
- Department of Physiology, Nanjing Medical University, Nanjing, China.,Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China
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- Lin Zhang
- Department of Pathology, Xuzhou Medical University, Xuzhou, China
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- Yueyuan Wang
- Department of Physiology, Nanjing Medical University, Nanjing, China
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- Chenxiang Qi
- Department of Physiology, Nanjing Medical University, Nanjing, China
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- Yixuan Song
- Department of Physiology, Nanjing Medical University, Nanjing, China
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- Maria Bibi
- Department of Physiology, Nanjing Medical University, Nanjing, China
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- Yujie Zhang
- Department of Physiology, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
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- Yadong Ma
- Department of Physiology, Nanjing Medical University, Nanjing, China
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- Xuyang Zhao
- Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
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- Minjie Yu
- The First Clinical Medical College, Nanjing Medical University, Nanjing, China
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- Jun Du
- Department of Physiology, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
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12
Jiang F, Cao J, Kong R, Fang L, Wang B, Zhang S, Yang L, Cao X. MICAL2 regulates myofibroblasts differentiation in epidural fibrosis via SRF/MRTF-A signaling pathway.
Life Sci 2021;
269:119045. [PMID:
33453238 DOI:
10.1016/j.lfs.2021.119045]
[Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 12/28/2020] [Accepted: 01/05/2021] [Indexed: 01/01/2023]
Abstract
AIM
To determine the role of MICAL2 in myofibroblasts differentiation and epidural fibrosis.
BACKGROUND
Epidural fibrosis (EF) may develop following laminectomy and aberrant myofibroblasts differentiation and excessive extracellular matrix (ECM) accumulation play key roles in the formation of EF. Dense epidural fibrosis results to the poor surgical outcomes and failed back surgery syndrome (FBSS), and there is no effective treatment available. Molecule interacting with Casl2 (MICAL2) has been demonstrated to participate in multiple cellular processes by regulating actin cytoskeleton dynamics. However, its role in epidural fibrosis remains totally unverified.
MATERIALS AND METHODS
The potential functions and mechanisms of MICAL2 were explored using western blotting, immunofluorescence and lentivirus infection.
KEY FINDINGS
In our study, we determined that the MICAL2 expression was elevated in epidural fibrotic tissues and TGF-β1-stimulated fibroblasts. Moreover, knockdown of MICAL2 using MICAL2-specific short hairpin RNA attenuated TGF-β1-induced myofibroblasts differentiation and epidural fibrosis both in vitro and vivo, as indicated by decreased scar formation, reduced collagen production and down-regulated expression of α-SMA, collagen-1 and fibronectin. We also demonstrated that MICAL2 knockdown affected the migratory capability of fibroblasts in vitro. By further mechanistic research, we revealed that the MRTF-A nuclear translocation was inhibited in response to the knockdown of MICAL2 in fibroblasts and MICAL2 served as a pro-fibrotic factor in an SRF/MRTF-A-dependent manner.
SIGNIFICANCE
In conclusion, our results indicated that MICAL2 mediated myofibroblasts differentiation and promoted epidural fibrogenesis via SRF/MRTF-A signaling pathway, suggesting manipulation of MICAL2 activity as a novel alternative strategy for the prevention of epidural fibrosis.
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Affiliation(s)
- Fan Jiang
- Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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- Jiang Cao
- Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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- Renyi Kong
- Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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- Le Fang
- Department of Critical Care Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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- Binyu Wang
- Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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- Sheng Zhang
- Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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- Lei Yang
- Department of Orthopedics, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
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- Xiaojian Cao
- Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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13
Lu J, Li Y, Wu Y, Zhou S, Duan C, Dong Z, Kang T, Tang F. Retraction of "MICAL2 Mediates p53 Ubiquitin Degradation through Oxidating p53 Methionine 40 and 160 and Promotes Colorectal Cancer Malignance".
Am J Cancer Res 2021;
11:1176. [PMID:
33391528 PMCID:
PMC7738885 DOI:
10.7150/thno.55371]
[Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
14
Zhou W, Liu Y, Gao Y, Cheng Y, Chang R, Li X, Zhou Y, Wang S, Liang L, Duan C, Zhang C. MICAL2 is a novel nucleocytoplasmic shuttling protein promoting cancer invasion and growth of lung adenocarcinoma.
Cancer Lett 2020;
483:75-86. [PMID:
32360180 DOI:
10.1016/j.canlet.2020.04.019]
[Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 04/02/2020] [Accepted: 04/22/2020] [Indexed: 12/16/2022]
Abstract
MICAL2 is a tumor-promoting factor involved in cell migration, invasion, deformation, and proliferation not yet fully explored in lung adenocarcinoma (LUAD). This study demonstrated that MICAL2 was overexpressed and cytoplasm-enriched in LUAD tissues. Moreover, high cytoplasmic MICAL2 and/or total MICAL2 expression levels were positively correlated with lymphatic metastasis and shorter overall survival in LUAD patients. MICAL2 promoted LUAD cell proliferation, migration, invasion, and epithelial to mesenchymal transition-all of which involved the AKT and myosin-9 pathways. Furthermore, MICAL2 was identified as a nucleoplasm shuttling protein dependent on myosin-9 and its C-terminal fragment. MICAL2-ΔC-enriched in the nucleus-had less impact on tumor malignancy in LUAD cells in vitro and in vivo. Tumor promotion by MICAL2 was reduced by nuclear-export inhibitor, myosin-9 inhibitor, or si-myosin-9-all of which effectively inhibited MICAL2's nuclear export. Finally, the expression and subcellular location as well as clinical significance of MICAL2 and myosin-9 were analyzed across TCGA data and LUAD tissue arrays. Our data revealed that MICAL2 overexpression and nuclear export were associated with cancer progression; inhibiting its expression and/or nuclear export may provide a new target for LUAD therapy.
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Affiliation(s)
- Wolong Zhou
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, PR China
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- Yuanqi Liu
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, PR China
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- Yang Gao
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, PR China
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- Yuanda Cheng
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, PR China
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- Ruimin Chang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, PR China
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- Xizhe Li
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, PR China
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- Yanwu Zhou
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, PR China
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- Shaoqiang Wang
- Department of Thoracic Surgery, Affiliated Hospital of Jining Medical College, Jining Medical College, Jining, 272000, PR China
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- Lubiao Liang
- Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi Medical University, Zunyi, 563000, PR China
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- Chaojun Duan
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, PR China.
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- Chunfang Zhang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, PR China; Hunan Engineering Research Center for Pulmonary Nodules Precise Diagnosis and Treatment, Xiangya Hospital, Central South University, Changsha, 410008, PR China.
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15
Xu C, Zhou X, Xie T, Zhou Y, Zhang Q, Jiang S, Zhang R, Liao L, Dong J. Renal tubular Bim mediates the tubule-podocyte crosstalk via NFAT2 to induce podocyte cytoskeletal dysfunction.
Theranostics 2020;
10:6806-6824. [PMID:
32550905 PMCID:
PMC7295056 DOI:
10.7150/thno.43145]
[Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 05/03/2020] [Indexed: 12/17/2022] Open
Abstract
Diabetic nephropathy (DN) is mainly regarded as diabetic glomerulopathy, and its progression is tightly correlated with tubular epithelial lesions. However, the underlying molecular mechanisms linking tubular damage and glomerulopathy are poorly understood.
Methods: We previously reported that the upregulation of Bim mediated proximal tubular epithelial cell (PTEC) apoptosis and was crucial in the early stages of DN. Herein we modulated Bim expression in PTECs and subsequently determined podocyte (PC) cytoskeletal arrangement by building a Transwell co-culture system in high glucose (HG).
Results: Compared to normal glucose, exposure to 40 mM of HG for 48 h induced significant expression of Bim in PTECs and disorganization in the PC cytoskeleton. When cocultured with PTECs in HG, exacerbated filamentous actin (F-actin) rearrangement and reduced synaptopodin levels were detected in PCs. In contrast, gene knockdown of Bim in PTECs was correlated with the absence of PC cytoskeletal disorganization. NFAT2 level and its nuclear translocation in PTECs were decreased by suppressing Bim expression. Upregulating NFAT2 disrupted the beneficial effects on F-actin organization in PCs obtained by inhibiting Bim. LncRNA microarray analysis identified NONHSAT179542.1, which was implicated in Bim-mediated PC cytoskeletal disorder.
Conclusion: Our study clarified the functional role of Bim, a pro-apoptotic factor, which is involved in the crosstalk between PTECs and PCs. Bim promotes NFAT2 activation in PTECs, inducing the downregulation of lncRNA NONHSAT179542.1 in PCs, contributing to the cytoskeletal damage. Identification of the role of the Bim/NFAT2 pathway may represent a promising research direction for a better understanding of DN development.
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16
Tang F, Yang Z, Tan Y, Li Y. Super-enhancer function and its application in cancer targeted therapy.
NPJ Precis Oncol 2020;
4:2. [PMID:
32128448 PMCID:
PMC7016125 DOI:
10.1038/s41698-020-0108-z]
[Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 12/31/2019] [Indexed: 12/12/2022] Open
Abstract
Recently, super-enhancers (SEs) have been identified as a unique type of transcriptional regulation involved in cancer development. SEs exhibit a size, high transcription factor density, and strong binding to the transcriptional machinery compared with typical enhancers. SEs play an essential role in cell growth, differentiation, and disease initiation and progression including tumorigenesis. In particular, cancer-specific SEs have been proven to be key oncogenic drivers types of tumor cells. Furthermore, it has been confirmed that cancer-specific SEs can mediate the dysregulation of signaling pathways and promote cancer cell growth. Additionally, therapeutic strategies directly targeting SE components, for example, by disrupting SE structure or inhibiting SE cofactors, have shown a good curative effect on various cancers.
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Affiliation(s)
- Faqing Tang
- 1Department of Clinical Laboratory, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410013 Changsha, China
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- Zongbei Yang
- 2Department of Clinical Laboratory, Zhuhai People's Hospital & Zhuhai Hospital of Jinan University, 519000 Zhuhai, China
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- Yuan Tan
- 1Department of Clinical Laboratory, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410013 Changsha, China
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- Yuejin Li
- 1Department of Clinical Laboratory, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410013 Changsha, China
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