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Kanameda K, Honda A, Hirao-Suzuki M, Sugihara N, Takiguchi M, Takeda S. Interactions between cadmium and 17β-estradiol at physiologically relevant levels evoke unsynchronized events in MCF-7 breast cancer cells: Impaired cell growth and activation of estrogen receptor α-related pathways. Toxicol Appl Pharmacol 2025; 500:117360. [PMID: 40320013 DOI: 10.1016/j.taap.2025.117360] [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: 02/04/2025] [Revised: 04/22/2025] [Accepted: 05/01/2025] [Indexed: 05/07/2025]
Abstract
Cadmium (Cd), a heavy metal, is implicated in the development of estrogen receptor α (ERα)-positive breast cancers (BCs). However, controversy surrounds whether Cd is estrogenic or anti-estrogenic for the malignancy of in vivo animal models and human observational/epidemiological studies, a debate also presents in in vitro experiments. The development of ERα-positive BCs is stimulated by circulating 17β-estradiol (E2). Thus, potential biological interactions between E2 and Cd in the progression of ERα-positive BCs exist. Although the interactions between Cd and E2 at physiologically relevant levels (1 nM each) may not have been confirmed in vitro, it is likely to occur. Therefore, this study aims to investigate the interactions of chemicals in human BC MCF-7 cells (ERα-positive) using a sequential exposure system in which chemicals are added to cells every 24-48 h. Pretreatment with Cd, but not secondary treatment, interfered with E2-mediated oncogenic actions by inducing cell cycle arrest at the S phase. This was accompanied by changes in the expression of genes regulating the cell cycle checkpoint and upregulation of the tumor suppressor metallothionein 1F gene, which E2 suppressed. Paradoxically, ERα-mediated estrogenic pathways were upregulated. In conclusion, this study is the first to show that physiologically relevant levels of Cd may dampen E2-induced oncogenic events independent of the E2/ERα-mediated pathway.
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Affiliation(s)
- Koki Kanameda
- Laboratory of Molecular Life Sciences, Graduate School of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Japan
| | - Azumi Honda
- Laboratory of Molecular Life Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Japan
| | - Masayo Hirao-Suzuki
- Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Japan
| | - Narumi Sugihara
- Laboratory of Molecular Life Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Japan
| | - Masufumi Takiguchi
- Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Japan
| | - Shuso Takeda
- Laboratory of Molecular Life Sciences, Graduate School of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Japan; Laboratory of Molecular Life Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Japan.
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Yuan S, Xu N, Yang J, Yuan B. Emerging role of PES1 in disease: A promising therapeutic target? Gene 2025; 932:148896. [PMID: 39209183 DOI: 10.1016/j.gene.2024.148896] [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] [Revised: 07/31/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
Pescadillo ribosomal biogenesis factor 1 (PES1), a nucleolar protein initially identified in zebrafish, plays an important role in embryonic development and ribosomal biogenesis. Notably, PES1 has been found to be overexpressed in a number of cancer types, where it contributes to tumorigenesis and cancer progression by promoting cell proliferation, suppressing cellular senescence, modulating the tumor microenvironment (TME) and promoting drug resistance in cancer cells. Moreover, recent emerging evidence suggests that PES1 expression is significantly elevated in the livers of Type 2 diabetes mellitus (T2DM) and obese patients, indicating its involvement in the pathogenesis of metabolic diseases through lipid metabolism regulation. In this review, we present the structural characteristics and biological functions of PES1, as well as complexes in which PES1 participates. Furthermore, we comprehensively summarize the multifaceted role of PES1 in various diseases and the latest insights into its underlying molecular mechanisms. Finally, we discuss the potential clinical translational perspectives of targeting PES1, highlighting its promising as a therapeutic intervention and treatment target.
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Affiliation(s)
- Siyu Yuan
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Nuo Xu
- First School of Clinical Medicine, Anhui Medical University, Hefei 230032, China
| | - Jing Yang
- Experimental Teaching Center for Preventive Medicine, School of Public Health, Anhui Medical University, Hefei 230032, China.
| | - Bin Yuan
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China.
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Kaur P, Sharma P, Bhatia P, Singh M. Current insights on m6A RNA modification in acute leukemia: therapeutic targets and future prospects. Front Oncol 2024; 14:1445794. [PMID: 39600630 PMCID: PMC11590065 DOI: 10.3389/fonc.2024.1445794] [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: 06/08/2024] [Accepted: 10/08/2024] [Indexed: 11/29/2024] Open
Abstract
RNA modification is the critical mechanism for regulating post-transcriptional processes. There are more than 150 RNA modifications reported so far, among which N6-Methyladenosine is the most prevalent one. M6A RNA modification complex consists of 'writers', 'readers' and 'erasers' which together in a group catalyze, recognize and regulate the methylation process of RNA and thereby regulate the stability and translation of mRNA. The discovery of erasers also known as demethylases, revolutionized the research on RNA modifications as it revealed that this modification is reversible. Since then, various studies have focused on discovering the role of m6A modification in various diseases especially cancers. Aberrant expression of these 'readers', 'writers', and 'erasers' is found to be altered in various cancers resulting in disturbance of cellular homeostasis. Acute leukemias are the most common cancer found in pediatric patients and account for 20% of adult cases. Dysregulation of the RNA modifying complex have been reported in development and progression of hematopoietic malignancies. Further, targeting m6A modification is the new approach for cancer immunotherapy and is being explored extensively. This review provides detailed information about current information on the role of m6A RNA modification in acute leukemia and their therapeutic potential.
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Affiliation(s)
| | | | | | - Minu Singh
- Haematology-Oncology Unit, Department of Paediatrics, Postgraduate Institute of Medical
Education and Research, Chandigarh, India
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Lin X, Sun D, Yang S, Cheng K, Wang X, Meng W, Wu H, Liu W, Wu X, Yang H, Wang X, Zhou L. UBE2M forms a positive feedback loop with estrogen receptor to drive breast cancer progression and drug resistance. Cell Death Dis 2024; 15:590. [PMID: 39138151 PMCID: PMC11322533 DOI: 10.1038/s41419-024-06979-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 08/04/2024] [Accepted: 08/06/2024] [Indexed: 08/15/2024]
Abstract
UBE2M, a NEDD8-conjugating enzyme, is dysregulated in various human cancers and promotes tumor cell proliferation. However, its role in estrogen receptor-positive (ER+) breast cancer remains unknown. We found that UBE2M expression was significantly higher in ER+ breast cancer tissues than in ER-negative (ER-) breast cancer tissues. Higher expression of UBE2M indicated a poorer prognosis in patients with ER+ breast cancer but not in those with ER- breast cancer. Of interest, a positive feedback loop was observed between UBE2M and ERα. Specifically, ERα enhanced the HIF-1α-mediated transcription of UBE2M. In turn, UBE2M maintained ERα expression by inhibiting its ubiquitination and degradation through UBE2M-CUL3/4A-E6AP-ERα axis. Functionally, silencing of UBE2M suppressed the growth of breast cancer cells by inducing cell cycle arrest and apoptosis and improved their sensitivity to fulvestrant both in vitro and in vivo. Altogether, our findings reveal that the UBE2M-ERα feedback loop drives breast cancer progression and fulvestrant resistance, suggesting UBE2M as a viable target for endocrine therapy of ER+ breast cancer.
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Affiliation(s)
- Xiongzhi Lin
- Taizhou Central Hospital (Taizhou University Hospital), School of Medicine, Taizhou University, Taizhou, Zhejiang, China
- Graduate School of Medicine, Hebei North University, Zhangjiakou, Hebei, China
| | - Dongsheng Sun
- Taizhou Central Hospital (Taizhou University Hospital), School of Medicine, Taizhou University, Taizhou, Zhejiang, China
| | - Shuhan Yang
- Taizhou Central Hospital (Taizhou University Hospital), School of Medicine, Taizhou University, Taizhou, Zhejiang, China
| | - Kai Cheng
- Taizhou Central Hospital (Taizhou University Hospital), School of Medicine, Taizhou University, Taizhou, Zhejiang, China
| | - XingYi Wang
- Taizhou Central Hospital (Taizhou University Hospital), School of Medicine, Taizhou University, Taizhou, Zhejiang, China
| | - Weijia Meng
- Taizhou Central Hospital (Taizhou University Hospital), School of Medicine, Taizhou University, Taizhou, Zhejiang, China
| | - Haowei Wu
- Taizhou Central Hospital (Taizhou University Hospital), School of Medicine, Taizhou University, Taizhou, Zhejiang, China
| | - Wenlin Liu
- Taizhou Central Hospital (Taizhou University Hospital), School of Medicine, Taizhou University, Taizhou, Zhejiang, China
| | - Xiaoyu Wu
- Taizhou Central Hospital (Taizhou University Hospital), School of Medicine, Taizhou University, Taizhou, Zhejiang, China
| | - Hui Yang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiaojun Wang
- Taizhou Central Hospital (Taizhou University Hospital), School of Medicine, Taizhou University, Taizhou, Zhejiang, China.
| | - Lisha Zhou
- Taizhou Central Hospital (Taizhou University Hospital), School of Medicine, Taizhou University, Taizhou, Zhejiang, China.
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Ren B, Yang Y, Lv Y, Liu K. Survival outcome and prognostic factors for early-onset and late-onset metastatic colorectal cancer: a population based study from SEER database. Sci Rep 2024; 14:4377. [PMID: 38388566 PMCID: PMC10883940 DOI: 10.1038/s41598-024-54972-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 02/19/2024] [Indexed: 02/24/2024] Open
Abstract
Colorectal cancer is the third most common cancer worldwide and there has been a concerning increase in the incidence rate of colorectal cancer among individuals under the age of 50. This study compared the survival outcome between early-onset and late-onset metastatic colorectal cancer to find the differences and identify their prognostic factors. We obtained patient data from SEER database. Survival outcome was estimated using Kaplan-Meier survival curves and compared using the log-rank test. Univariate and multivariate analyses were conducted utilizing COX models to identify their independent prognostic factors. A total of 10,036 early-onset metastatic colorectal (EOCRC) cancer patients and 56,225 late-onset metastatic colorectal cancer (LOCRC) patients between 2010 and 2019 were included in this study. EOCRC has more survival benefits than LOCRC. Tumor primary location (p < 0.001), the location of metastasis (p < 0.001) and treatment modalities (p < 0.001) affect the survival outcomes between these two groups of patients. Female patients had better survival outcomes in EOCRC group (p < 0.001), but no difference was found in LOCRC group (p = 0.57). In conclusion, our study demonstrated that EOCRC patients have longer survival time than LOCRC patients. The sex differences in survival of metastatic colorectal cancer patients are associated with patients' age. These findings contribute to a better understanding of the differences between metastatic EOCRC and LOCRC, and can help inform the development of more precise treatment guidelines to improve prognosis.
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Affiliation(s)
- Bingyi Ren
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Yichen Yang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Yi Lv
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Kang Liu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.
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Li K, Xia Y, He J, Wang J, Li J, Ye M, Jin X. The SUMOylation and ubiquitination crosstalk in cancer. J Cancer Res Clin Oncol 2023; 149:16123-16146. [PMID: 37640846 DOI: 10.1007/s00432-023-05310-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 08/16/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND The cancer occurrence and progression are largely affected by the post-translational modifications (PTMs) of proteins. Currently, it has been shown that the relationship between ubiquitination and SUMOylation is highly complex and interactive. SUMOylation affects the process of ubiquitination and degradation of substrates. Contrarily, SUMOylation-related proteins are also regulated by the ubiquitination process thus altering their protein levels or activity. Emerging evidence suggests that the abnormal regulation between this crosstalk may lead to tumorigenesis. PURPOSE In this review, we have discussed the study of the relationship between ubiquitination and SUMOylation, as well as the possibility of a corresponding application in tumor therapy. METHODS The relevant literatures from PubMed have been reviewed for this article. CONCLUSION The interaction between ubiquitination and SUMOylation is crucial for the occurrence and development of cancer. A greater understanding of the crosstalk of SUMOylation and ubiquitination may be more conducive to the development of more selective and effective SUMOylation inhibitors, as well as a promotion of synergy with other tumor treatment strategies.
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Affiliation(s)
- Kailang Li
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Yongming Xia
- Department of Oncology, Yuyao People's Hospital of Zhejiang, Yuyao, 315400, Zhejiang, China
| | - Jian He
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Jie Wang
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Jingyun Li
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Meng Ye
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China.
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China.
| | - Xiaofeng Jin
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China.
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China.
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Wang J, Novick S. DOSE-L1000: unveiling the intricate landscape of compound-induced transcriptional changes. Bioinformatics 2023; 39:btad683. [PMID: 37952162 PMCID: PMC10663987 DOI: 10.1093/bioinformatics/btad683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 10/31/2023] [Accepted: 11/10/2023] [Indexed: 11/14/2023] Open
Abstract
MOTIVATION The LINCS L1000 project has collected gene expression profiles for thousands of compounds across a wide array of concentrations, cell lines, and time points. However, conventional analysis methods often fall short in capturing the rich information encapsulated within the L1000 transcriptional dose-response data. RESULTS We present DOSE-L1000, a database that unravels the potency and efficacy of compound-gene pairs and the intricate landscape of compound-induced transcriptional changes. Our study uses the fitting of over 140 million generalized additive models and robust linear models, spanning the complete spectrum of compounds and landmark genes within the LINCS L1000 database. This systematic approach provides quantitative insights into differential gene expression and the potency and efficacy of compound-gene pairs across diverse cellular contexts. Through examples, we showcase the application of DOSE-L1000 in tasks such as cell line and compound comparisons, along with clustering analyses and predictions of drug-target interactions. DOSE-L1000 fosters applications in drug discovery, accelerating the transition to omics-driven drug development. AVAILABILITY AND IMPLEMENTATION DOSE-L1000 is publicly available at https://doi.org/10.5281/zenodo.8286375.
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Affiliation(s)
- Junmin Wang
- Data Sciences and Quantitative Biology, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, United States
| | - Steven Novick
- Global Statistical Sciences, Eli Lilly, Indianapolis, IN 46285, United States
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Lu TL, Li CL, Gong YQ, Hou FT, Chen CW. Identification of tumor antigens and immune subtypes of hepatocellular carcinoma for mRNA vaccine development. World J Gastrointest Oncol 2023; 15:1717-1738. [PMID: 37969406 PMCID: PMC10631436 DOI: 10.4251/wjgo.v15.i10.1717] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/10/2023] [Accepted: 09/18/2023] [Indexed: 10/10/2023] Open
Abstract
BACKGROUND mRNA vaccines have been investigated in multiple tumors, but limited studies have been conducted on their use for hepatocellular carcinoma (HCC). AIM To identify candidate mRNA vaccine antigens for HCC and suitable subpopulations for mRNA vaccination. METHODS Gene expression profiles and clinical information of HCC datasets were obtained from International Cancer Genome Consortium and The Cancer Genome Atlas. Genes with somatic mutations and copy number variations were identified by cBioPortal analysis. The differentially expressed genes with significant prognostic value were identified by Gene Expression Profiling Interactive Analysis 2 website analysis. The Tumor Immune Estimation Resource database was used to assess the correlation between candidate antigens and the abundance of antigen-presenting cells (APCs). Tumor-associated antigens were overexpressed in tumors and associated with prognosis, genomic alterations, and APC infiltration. A consensus cluster analysis was performed with the Consensus Cluster Plus package to identify the immune subtypes. The weighted gene coexpression network analysis (WGCNA) was used to determine the candidate biomarker molecules for appropriate populations for mRNA vaccines. RESULTS AURKA, CCNB1, CDC25C, CDK1, TRIP13, PES1, MCM3, PPM1G, NEK2, KIF2C, PTTG1, KPNA2, and PRC1 were identified as candidate HCC antigens for mRNA vaccine development. Four immune subtypes (IS1-IS4) and five immune gene modules of HCC were identified that were consistent in both patient cohorts. The immune subtypes showed distinct cellular and clinical characteristics. The IS1 and IS3 immune subtypes were immunologically "cold". The IS2 and IS4 immune subtypes were immunologically "hot", and the immune checkpoint genes and immunogenic cell death genes were upregulated in these subtypes. IS1-related modules were identified with the WGCNA algorithm. Ultimately, five hub genes (RBP4, KNG1, METTL7A, F12, and ABAT) were identified, and they might be potential biomarkers for mRNA vaccines. CONCLUSION AURKA, CCNB1, CDC25C, CDK1, TRIP13, PES1, MCM3, PPM1G, NEK2, KIF2C, PTTG1, KPNA2, and PRC1 have been identified as candidate HCC antigens for mRNA vaccine development. The IS1 and IS3 immune subtypes are suitable populations for mRNA vaccination. RBP4, KNG1, METTL7A, F12, and ABAT are potential biomarkers for mRNA vaccines.
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Affiliation(s)
- Tai-Liang Lu
- Department of General Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan Province, China
| | - Cheng-Long Li
- Department of General Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan Province, China
| | - Yong-Qiang Gong
- Department of General Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan Province, China
| | - Fu-Tao Hou
- Department of General Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan Province, China
| | - Chao-Wu Chen
- Department of General Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan Province, China
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Liu T, Zhao M, Peng L, Chen J, Xing P, Gao P, Chen L, Qiao X, Wang Z, Di J, Qu H, Jiang B, Su X. WFDC3 inhibits tumor metastasis by promoting the ERβ-mediated transcriptional repression of TGFBR1 in colorectal cancer. Cell Death Dis 2023; 14:425. [PMID: 37443102 PMCID: PMC10345115 DOI: 10.1038/s41419-023-05956-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 06/20/2023] [Accepted: 07/05/2023] [Indexed: 07/15/2023]
Abstract
Estrogen plays a protective role in colorectal cancer (CRC) and primarily functions through estrogen receptor β (ERβ). However, clinical strategies for CRC therapy associated with ERβ are still under investigation. Our discoveries identified WFDC3 as a tumor suppressor that facilitates estrogen-induced inhibition of metastasis through the ERβ/TGFBR1 signaling axis. WFDC3 interacts with ERβ and increases its protein stability by inhibiting its proteasome-dependent degradation. WFDC3 represses TGFBR1 expression through ERβ-mediated transcription. Blocking TGFβ signaling with galunisertib, a drug used in clinical trials that targets TGFBR1, impaired the migration of CRC cells induced by WFDC3 depletion. Moreover, there was clinical significance to WFDC3 in CRC, as CRC patients with high WFDC3 expression in tumor cells had favorable prognoses. Therefore, this work suggests that WFDC3 could be an indicator for therapies targeting the estrogen/ERβ pathway in CRC patients.
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Affiliation(s)
- Tianqi Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Min Zhao
- School of Science, Technology and Engineering, University of the Sunshine Coast, Maroochydore DC, Sunshine Coast, QLD, 4556, Australia
| | - Lin Peng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Jiangbo Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Pu Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Pin Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Lei Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Xiaowen Qiao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Zaozao Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Jiabo Di
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Hong Qu
- Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, 100871, Beijing, People's Republic of China.
| | - Beihai Jiang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 100142, Beijing, China.
| | - Xiangqian Su
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 100142, Beijing, China.
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Ma N, Hua R, Yang Y, Liu ZC, Pan J, Yu BY, Sun YF, Xie D, Wang Y, Li ZG. PES1 reduces CD8 + T cell infiltration and immunotherapy sensitivity via interrupting ILF3-IL15 complex in esophageal squamous cell carcinoma. J Biomed Sci 2023; 30:20. [PMID: 36959575 PMCID: PMC10037800 DOI: 10.1186/s12929-023-00912-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 03/11/2023] [Indexed: 03/25/2023] Open
Abstract
BACKGROUND Although immune checkpoint blockade (ICB) therapy has brought survival benefits to patients with specific cancer types, most of cancer patients remain refractory to the ICB therapy, which is largely attributed to the immunosuppressive tumor microenvironment. Thereby, it is urgent to profile key molecules and signal pathways responsible for modification of tumor microenvironment. METHODS Multiple databases of esophageal squamous cell carcinoma (ESCC) were integratively analyzed to screen candidate genes responsible for infiltration of CD8+ T cells. Expression of pescadillo ribosomal biogenesis factor 1 (PES1) in clinical ESCC samples was examined by qRT-PCR, western blotting, and immunohistochemistry. The mechanisms of PES1 were investigated via RNA sequencing and mass spectrometry followed by immunoprecipitation and proximity ligation assay. The clinical and therapeutic significance of PES1 in ESCC was comprehensively investigated using ESCC cells and mouse model. RESULTS PES1 was significantly upregulated and correlated with poor prognosis in ESCC patients. PES1 knockdown decreased ESCC cell growth in vitro and in vivo and enhanced the efficacy of ICB therapy in mouse model, which was established through subcutaneous inoculation with ESCC cells. Analyses on RNA sequencing and mass spectrometry suggested that PES1 expression was negatively correlated with IL15 and ILF3 was one of the PES1-associated proteins. It has been known that ILF3 interacts with and stabilizes IL15 mRNA to increase IL15 protein level. Our data further indicated that PES1 interfered with the interaction between ILF3 and IL15 mRNA and impaired ILF3-mediated stabilization of IL15 mRNA, which eventually reduced the protein level of IL15. Interestingly, the inhibitory effect of ICB therapy boosted by PES1 knockdown dramatically antagonized by knockdown of IL15, which suppressed the tumor-infiltrated CD8+ T cells in ESCC. Finally, we confirmed the relationships among PES1, IL15, and CD8+ T cell infiltration in 10 locally advanced ESCC patients receiving ICB neoadjuvant therapy and demonstrated that ICB therapy would be more effective in those with low expression of PES1. CONCLUSIONS Altogether, our findings herein provided novel insights on biological function and clinical significance of PES1 and suggested that high expression of PES1 could suppress ILF3-IL15 axis-mediated immunosurveillance and promote resistance to ICB through restraining tumor-infiltrated CD8+ T cells.
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Affiliation(s)
- Ning Ma
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rong Hua
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yang Yang
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhi-Chao Liu
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Pan
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bo-Yao Yu
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi-Feng Sun
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dong Xie
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Yan Wang
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
| | - Zhi-Gang Li
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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11
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Li D, Yao C, Ding Z, Liu P, Chen X, Liu W, Yi F, Jiang C, Li H, Liu Y, Wu J. Pescadillo ribosomal biogenesis factor 1 reduction suppresses tumour growth and renders chemosensitivity of head and neck squamous cell carcinoma. Cancer Med 2023; 12:5703-5717. [PMID: 36217758 PMCID: PMC10028059 DOI: 10.1002/cam4.5315] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/14/2022] [Accepted: 09/20/2022] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND As one of the most devastating cancers, head and neck squamous cell carcinoma (HNSCC) has a short survival time and poor prognosis. Pescadillo ribosomal biogenesis factor 1 (PES1) plays a critical role in the progression of numerous cancers. However, its role and underlying mechanisms in HNSCC remain unclear. METHODS A variety of bioinformatic approaches were used to identify the expressions, prognostic and diagnostic value of PES1 in HNSCC. qRT-PCR, immunofluorescence (IF) assay, western blotting and immunohistochemical (IHC) were used to evaluate the expression of PES1 in HNSCC cell lines and clinical tissues. PES1 was knocked down in TU177 and FaDu cells which have high PES1 expression. The effects of PES1 on cell proliferation and tumour growth in HNSCC were elevated by colony formation, CCK8 assays and tumorigenicity assay in nude mice. The effects on cisplatin (CDDP) sensitivity upon silencing of PES1 were assessed using a patient-derived xenograft (PDX) model. RESULTS PES1 expression was an independent prognostic factor for HNSCC and negatively associated with the overall survival rate. Silencing of PES1 reduces HNSCC cell proliferation and tumour growth. Moreover, PES1 inhibition significantly sensitises HNSCC cells to cisplatin. Furthermore, we found a PES1 has a high correlation with c-Myc and plays an essential role in the tumour immune microenvironment. CONCLUSION Our findings suggest that PES1 is associated with tumour growth and drug resistance and served as a potential cancer marker for diagnosis and a putative therapeutic target for HNSCC.
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Affiliation(s)
- Dapeng Li
- Department of Otolaryngology-Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China
- Anhui Medical University, Hefei, People's Republic of China
- Graduate School of Anhui Medical University, Hefei, People's Republic of China
| | - Changyu Yao
- Department of Otolaryngology-Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China
| | - Zhao Ding
- Department of Otolaryngology-Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China
- Anhui Medical University, Hefei, People's Republic of China
- Graduate School of Anhui Medical University, Hefei, People's Republic of China
| | - Ping Liu
- Department of Otolaryngology-Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China
- Anhui Medical University, Hefei, People's Republic of China
- Graduate School of Anhui Medical University, Hefei, People's Republic of China
- Anhui Public Health Clinical Center, Hefei, People's Republic of China
| | - Xue Chen
- Department of Otolaryngology-Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China
| | - Weiwei Liu
- Department of Otolaryngology-Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China
- Anhui Medical University, Hefei, People's Republic of China
- Graduate School of Anhui Medical University, Hefei, People's Republic of China
| | - Fangzheng Yi
- Department of Otolaryngology-Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China
- Anhui Medical University, Hefei, People's Republic of China
- Graduate School of Anhui Medical University, Hefei, People's Republic of China
| | - Chuanya Jiang
- Department of Otolaryngology-Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China
| | - Hongwu Li
- Department of Otolaryngology-Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China
- Anhui Public Health Clinical Center, Hefei, People's Republic of China
| | - Yehai Liu
- Department of Otolaryngology-Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China
| | - Jing Wu
- Department of Otolaryngology-Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China
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12
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Wang R, Li J, Zhang C, Guan X, Qin B, Jin R, Qin L, Xu S, Zhang X, Liu R, Ye Q, Cheng L. Lactate Dehydrogenase B Is Required for Pancreatic Cancer Cell Immortalization Through Activation of Telomerase Activity. Front Oncol 2022; 12:821620. [PMID: 35669414 PMCID: PMC9163669 DOI: 10.3389/fonc.2022.821620] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 04/22/2022] [Indexed: 11/13/2022] Open
Abstract
Telomerase activity is elevated in most cancer cells and is required for telomere length maintenance and immortalization of cancer cells. Glucose metabolic reprogramming is a hallmark of cancer and accompanied with increased expression of key metabolic enzymes. Whether these enzymes influence telomerase activity and cell immortalization remains unclear. In the current study, we screened metabolic enzymes using telomerase activity assay and identified lactate dehydrogenase B (LDHB) as a regulator of telomerase activity. Sodium lactate and sodium pyruvate did not influence telomerase activity, indicating LDHB regulates telomerase activity independent of its metabolism regulating function. Further studies revealed that LDHB directly interacted with TERT and regulated the interaction between TERT and TERC. Additionally, long-term knockdown of LDHB inhibited cancer cell growth and induced cell senescence in vitro and in vivo. Higher LDHB expression was detected in pancreatic cancer tissues compared with that in adjacent normal tissues and expression of LDHB correlated negatively with prognosis. Thus, we identified LDHB as the first glucose metabolic enzyme contributing to telomerase activity and pancreatic cancer cell immortalization.
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Affiliation(s)
- Ruiguan Wang
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Department of Hepatobiliary Surgery, the Eight Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Jiangbo Li
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Changjian Zhang
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
- Senior Department of Otolaryngology-Head & Neck Surgery, the Sixth Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Xin Guan
- Strategic Support Force Medical Center, Beijing, China
| | - Boyu Qin
- Department of Medical Oncology, the First Medical Centre, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Rui Jin
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Lingmei Qin
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Shanrong Xu
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
- School of Life Science, Anqing Normal University, Anqing, China
| | - Xiaona Zhang
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
- College of Life Sciences, Capital Normal University, Beijing, China
| | - Rong Liu
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Department of Hepatobiliary Surgery, the Eight Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- *Correspondence: Long Cheng, ; Qinong Ye, ; Rong Liu,
| | - Qinong Ye
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
- *Correspondence: Long Cheng, ; Qinong Ye, ; Rong Liu,
| | - Long Cheng
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
- *Correspondence: Long Cheng, ; Qinong Ye, ; Rong Liu,
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13
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Xu KD, Miao Y, Li P, Li PP, Liu J, Li J, Cao F. Licochalcone A inhibits cell growth through the downregulation of the Hippo pathway via PES1 in cholangiocarcinoma cells. ENVIRONMENTAL TOXICOLOGY 2022; 37:564-573. [PMID: 34845814 DOI: 10.1002/tox.23422] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 11/05/2021] [Accepted: 11/16/2021] [Indexed: 06/13/2023]
Abstract
Overexpression or activation of Yes-associated protein (YAP) is common in cancer cells. Thus, targeting YAP may be a strategy for cancer therapy. Licochalcone A (LicA) is a primary active compound of licorice root and is known to have medicinal effects, such as antioxidant, antibacterial, antiviral, and anticancer effects. However, the anticancer pharmacological mechanism of LicA has not been investigated in cholangiocarcinoma. In this study, we investigated the antiproliferative effect of LicA and the underlying molecular mechanism in HCCC-9810 and RBE human cholangiocarcinoma cells. Our experiments indicated that LicA suppressed the growth of cholangiocarcinoma cells through inactivation of the Hippo pathway. Pescadillo ribosomal biogenesis factor 1 (PES1) was notably upregulated and related to carcinogenesis. We also found that LicA suppressed the expression and nuclear localization of PES1, which was associated with the inhibition of YAP expression and transcriptional activity.
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Affiliation(s)
- Ke-Dong Xu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yi Miao
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Pan Li
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Ping-Ping Li
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jie Liu
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Juan Li
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Fang Cao
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
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14
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Xu S, Xie J, Zhou Y, Liu H, Wang Y, Li Z. Integrated Analysis of RNA Binding Protein-Related lncRNA Prognostic Signature for Breast Cancer Patients. Genes (Basel) 2022; 13:genes13020345. [PMID: 35205391 PMCID: PMC8872055 DOI: 10.3390/genes13020345] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/05/2022] [Accepted: 02/10/2022] [Indexed: 12/19/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) have been well known for their multiple functions in the tumorigenesis, development, and prognosis of breast cancer (BC). Mechanistically, their production, function, or stability can be regulated by RNA binding proteins (RBPs), which were also involved in the carcinogenesis and progression of BC. However, the roles and clinical implications of RBP-related lncRNAs in BC remain largely unknown. Therefore, we herein aim to construct a prognostic signature with RBP-relevant lncRNAs for the prognostic evaluation of BC patients. Firstly, based on the RNA sequencing data of female BC patients from The Cancer Genome Atlas (TCGA) database, we screened out 377 differentially expressed lncRNAs related to RBPs. The univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses were then performed to establish a prognostic signature composed of 12-RBP-related lncRNAs. Furthermore, we divided the BC patients into high- and low-risk groups by the prognostic signature and found the overall survival (OS) of patients in the high-risk group was significantly shorter than that of the low-risk group. Moreover, the 12-lncRNA signature exhibited independence in evaluating the prognosis of BC patients. Additionally, a functional enrichment analysis revealed that the prognostic signature was associated with some cancer-relevant pathways, including cell cycle and immunity. In summary, our 12-lncRNA signature may provide a theoretical reference for the prognostic evaluation or clinical treatment of BC patients.
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Affiliation(s)
- Shaohua Xu
- Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology, College of Biology, Hunan University, Changsha 410082, China; (S.X.); (J.X.); (Y.Z.); (H.L.)
| | - Jiahui Xie
- Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology, College of Biology, Hunan University, Changsha 410082, China; (S.X.); (J.X.); (Y.Z.); (H.L.)
| | - Yanjie Zhou
- Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology, College of Biology, Hunan University, Changsha 410082, China; (S.X.); (J.X.); (Y.Z.); (H.L.)
| | - Hui Liu
- Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology, College of Biology, Hunan University, Changsha 410082, China; (S.X.); (J.X.); (Y.Z.); (H.L.)
| | - Yirong Wang
- Bioinformatics Center, College of Biology, Hunan University, Changsha 410082, China
- Correspondence: (Y.W.); (Z.L.)
| | - Zhaoyong Li
- Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology, College of Biology, Hunan University, Changsha 410082, China; (S.X.); (J.X.); (Y.Z.); (H.L.)
- Research Institute of Hunan University in Chongqing, Chongqing 401120, China
- Correspondence: (Y.W.); (Z.L.)
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15
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Li YZ, Zhang C, Pei JP, Zhang WC, Zhang CD, Dai DQ. The functional role of Pescadillo ribosomal biogenesis factor 1 in cancer. J Cancer 2022; 13:268-277. [PMID: 34976188 PMCID: PMC8692700 DOI: 10.7150/jca.58982] [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: 02/03/2021] [Accepted: 07/20/2021] [Indexed: 12/13/2022] Open
Abstract
Tumors are neogrowths formed by the growth of normal cells or tissues through complex mechanisms under the influence of many factors. The occurrence and development of tumors are affected by many factors. Pescadillo ribosomal biogenesis factor 1 (PES1) has been identified as a cancer-related gene. The study of these genes may open up new avenues for early diagnosis, treatment and prognosis of tumors. As a nucleolar protein and part of the Pes1/Bop1/WDR12 (PeBoW) complex, PES1 is involved in ribosome biogenesis and DNA replication. Many studies have shown that high expression of PES1 is often closely related to the occurrence, proliferation, invasion, metastasis, prognosis and sensitivity to chemotherapeutics of various human malignant tumors through a series of molecular mechanisms and signaling pathways. The molecules that regulate the expression of PES1 include microRNA (miRNA), circular RNA (circRNA), c-Jun, bromodomain-containing protein 4 (BRD4) and nucleolar phosphoprotein B23. However, the detailed pathogenic mechanisms of PES1 overexpression in human malignancies remains unclear. This article summarizes the role of PES1 in the carcinogenesis, prognosis and treatment of multiple tumors, and introduces the molecular mechanisms and signal transduction pathways related to PES1.
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Affiliation(s)
- Yong-Zhi Li
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Cheng Zhang
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Jun-Peng Pei
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Wan-Chuan Zhang
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Chun-Dong Zhang
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.,Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Dong-Qiu Dai
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.,Cancer Center, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
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16
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Zhou J, Lu Y, Jia Y, Lu J, Jiang Z, Chen K. Ketogenic diet ameliorates lipid dysregulation in type 2 diabetic mice by downregulating hepatic pescadillo 1. Mol Med 2022; 28:1. [PMID: 34979900 PMCID: PMC8722053 DOI: 10.1186/s10020-021-00429-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/20/2021] [Indexed: 12/15/2022] Open
Abstract
Background Previous reports implied a possible link between PES1 and lipid metabolism. However, the role of PES1 in regulating T2DM related lipid metabolism and the effect of ketogenic diet (KD) on PES1 have not been reported. The aim of present study is to explore the role of PES1 in effects of KD on diabetic mice and its mediated mechanism. Methods Male C57BL/6J and KKAy mice were fed with standard diet (SD) and KD, respectively. Simultaneously, McArdle 7777 cells were treated by β-hydroxybutyric acid (β-HB), Pes1 siRNA or Pes1 overexpression plasmid, respectively. Additionally, liver-conditional knockout (CKO) of Pes1 in vivo was applied. Results Hepatic PES1 expression in diabetic mice was markedly increased, which was suppressed by KD feeding with an accompanying reduction of hepatic and plasma triglycerides (TG). In mice with CKO of Pes1, the protein levels of p300, SREBP1c, FASN, SCD1, Caspase1, NLRP3 and GSDMD were dramatically downregulated in livers, and the plasma and hepatic TG, IL-1β and IL-18 were decreased as well. The similar outcomes were also observed in β-HB and Pes1 knockdown treated hepatocytes. By contrast, Pes1 overexpression in cultured hepatocytes showed that these levels were significantly enhanced, which were, however reduced under β-HB treatment. Mechanistically, we discovered that β-HB decreased CHOP binding to the Pes1 promoters, resulting in the downregulation of PES1, thereby reducing PES1 binding to p300 and Caspase1 promoters. The inhibition of p300 and Caspase1 expression elicited the dramatic suppression of acetylation of SREBP1c via its interaction with p300, and the decreased GSDMD levels. Besides, knockdown of Caspase1 also alleviated the TG levels in cultured hepatocytes. Conclusion KD may improve lipid dysregulation in type 2 diabetic mice by downregulating hepatic PES1 expression. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-021-00429-6.
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Affiliation(s)
- Jielin Zhou
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Yao Lu
- Department of Anesthesiology, The First Affiliated Hospital, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Yajing Jia
- Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Jing Lu
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Zhengxuan Jiang
- Department of Ophthalmology, The Second Affiliated Hospital, Anhui Medical University, Hefei, 230021, Anhui, China.
| | - Keyang Chen
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, Anhui, China. .,Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, 230032, Anhui, China.
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17
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Mi L, Qi Q, Ran H, Chen L, Li D, Xiao D, Wu J, Cai Y, Zhang S, Li Y, Li B, Xie J, Huang H, Li T, Zhou T, Li A, Qi J, Li F, Man J. Suppression of Ribosome Biogenesis by Targeting WD Repeat Domain 12 (WDR12) Inhibits Glioma Stem-Like Cell Growth. Front Oncol 2021; 11:751792. [PMID: 34868955 PMCID: PMC8633585 DOI: 10.3389/fonc.2021.751792] [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: 08/02/2021] [Accepted: 10/26/2021] [Indexed: 01/05/2023] Open
Abstract
Glioma stem-like cells (GSCs) are a subset of tumor cells that initiate malignant growth and promote the therapeutic resistance of glioblastoma, the most lethal primary brain tumor. Ribosome biogenesis is an essential cellular process to maintain cell growth, but its regulatory mechanism in GSCs remains largely unknown. Here, we show that WD repeat domain 12 (WDR12), a component of the Pes1-Bop1 complex (PeBoW), is required for ribosome biogenesis in GSCs. WDR12 is preferentially expressed in GSCs compared to non-stem tumor cells and normal brain cells. High levels of WDR12 are associated with glioblastoma progression and poor prognosis. Silencing WDR12 results in the degradation of PeBoW complex components and prevents the maturation of 28S rRNA, thereby inhibiting ribosome biogenesis in GSCs. Subsequently, WDR12 depletion compromises GSC proliferation, inhibits GSC-derived orthotopic tumor growth, and extends animal survival. Together, our results suggest that WDR12 is crucial for ribosome biogenesis in GSCs, and is thus a potential target for GSC-directed therapy of glioblastoma.
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Affiliation(s)
- Lanjuan Mi
- State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
| | - Qinghui Qi
- State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
| | - Haowen Ran
- State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
| | - Lishu Chen
- State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
| | - Da Li
- State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
| | - Dake Xiao
- State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
| | - Jiaqi Wu
- State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
| | - Yan Cai
- State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
| | - Songyang Zhang
- State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
| | - Yuanyuan Li
- State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
| | - Bohan Li
- Department of Neurosurgery, Beijing Fengtai Hospital, Beijing, China
| | - Jiong Xie
- Department of Neurosurgery, Beijing Fengtai Hospital, Beijing, China
| | - Haohao Huang
- Department of Neurosurgery, General Hospital of Central Theater Command of Chinese People's Liberation Army, Wuhan, China
| | - Tao Li
- State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
| | - Tao Zhou
- State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
| | - Ailing Li
- State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
| | - Ji Qi
- Department of Neurosurgery, Beijing Fengtai Hospital, Beijing, China
| | - Fangye Li
- Department of Neurosurgery, First Medical Center of PLA General Hospital, Beijing, China
| | - Jianghong Man
- State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
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18
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In Leishmania major, the Homolog of the Oncogene PES1 May Play a Critical Role in Parasite Infectivity. Int J Mol Sci 2021; 22:ijms222212592. [PMID: 34830469 PMCID: PMC8618447 DOI: 10.3390/ijms222212592] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/14/2021] [Accepted: 11/15/2021] [Indexed: 01/09/2023] Open
Abstract
Leishmaniasis is a neglected tropical disease caused by Leishmania spp. The improvement of existing treatments and the discovery of new drugs remain ones of the major goals in control and eradication of this disease. From the parasite genome, we have identified the homologue of the human oncogene PES1 in Leishmania major (LmjPES). It has been demonstrated that PES1 is involved in several processes such as ribosome biogenesis, cell proliferation and genetic transcription. Our phylogenetic studies showed that LmjPES encodes a highly conserved protein containing three main domains: PES N-terminus (shared with proteins involved in ribosomal biogenesis), BRCT (found in proteins related to DNA repair processes) and MAEBL-type domain (C-terminus, related to erythrocyte invasion in apicomplexan). This gene showed its highest expression level in metacyclic promastigotes, the infective forms; by fluorescence microscopy assay, we demonstrated the nuclear localization of LmjPES protein. After generating mutant parasites overexpressing LmjPES, we observed that these clones displayed a dramatic increase in the ratio of cell infection within macrophages. Furthermore, BALB/c mice infected with these transgenic parasites exhibited higher footpad inflammation compared to those inoculated with non-overexpressing parasites.
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19
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Pereira Zambalde E, Bayraktar R, Schultz Jucoski T, Ivan C, Rodrigues AC, Mathias C, knutsen E, Silveira de Lima R, Fiori Gradia D, de Souza Fonseca Ribeiro EM, Hannash S, Adrian Calin G, Carvalhode Oliveira J. A novel lncRNA derived from an ultraconserved region: lnc- uc.147, a potential biomarker in luminal A breast cancer. RNA Biol 2021; 18:416-429. [PMID: 34387142 PMCID: PMC8677017 DOI: 10.1080/15476286.2021.1952757] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 06/02/2021] [Accepted: 07/04/2021] [Indexed: 02/06/2023] Open
Abstract
The human genome contains 481 ultraconserved regions (UCRs), which are genomic stretches of over 200 base pairs conserved among human, rat, and mouse. The majority of these regions are transcriptionally active (T-UCRs), and several have been found to be differentially expressed in tumours. Some T-UCRs have been functionally characterized, but of those few have been associated to breast cancer (BC). Using TCGA data, we found 302 T-UCRs related to clinical features in BC: 43% were associated with molecular subtypes, 36% with oestrogen-receptor positivity, 17% with HER2 expression, 12% with stage, and 10% with overall survival. The expression levels of 12 T-UCRs were further analysed in a cohort of 82 Brazilian BC patients using RT-qPCR. We found that uc.147 is high expressed in luminal A and B patients. For luminal A, a subtype usually associated with better prognosis, high uc.147 expression was associated with a poor prognosis and suggested as an independent prognostic factor. The lncRNA from uc.147 (lnc-uc.147) is located in the nucleus. Northern blotting results show that uc.147 is a 2,8 kb monoexonic trancript, and its sequence was confirmed by RACE. The silencing of uc.147 increases apoptosis, arrests cell cycle, and reduces cell viability and colony formation in BC cell lines. Additionally, we identifed 19 proteins that interact with lnc-uc.147 through mass spectrometry and demonstrated a high correlation of lnc-uc.147 with the neighbour gene expression and miR-18 and miR-190b. This is the first study to analyse the expression of all T-UCRs in BC and to functionally assess the lnc-uc.147.
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Affiliation(s)
- Erika Pereira Zambalde
- Laboratory of Human Cytogenetics and Oncogenetics, Department of Genetics, Universidade Federal Do Paraná, Curitiba, PR, Brazil
- Department of Experimental Therapeutics, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
| | - Recep Bayraktar
- Department of Experimental Therapeutics, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
| | - Tayana Schultz Jucoski
- Laboratory of Human Cytogenetics and Oncogenetics, Department of Genetics, Universidade Federal Do Paraná, Curitiba, PR, Brazil
| | - Cristina Ivan
- Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ana Carolina Rodrigues
- Laboratory of Human Cytogenetics and Oncogenetics, Department of Genetics, Universidade Federal Do Paraná, Curitiba, PR, Brazil
| | - Carolina Mathias
- Laboratory of Human Cytogenetics and Oncogenetics, Department of Genetics, Universidade Federal Do Paraná, Curitiba, PR, Brazil
| | - Erik knutsen
- Department of Experimental Therapeutics, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
- Department of Medical Biology, Faculty of Health Sciences, UiT - the Arctic University of Norway, Tromsø, Norway
| | | | - Daniela Fiori Gradia
- Laboratory of Human Cytogenetics and Oncogenetics, Department of Genetics, Universidade Federal Do Paraná, Curitiba, PR, Brazil
| | | | - Samir Hannash
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - George Adrian Calin
- Department of Experimental Therapeutics, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
- Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jaqueline Carvalhode Oliveira
- Laboratory of Human Cytogenetics and Oncogenetics, Department of Genetics, Universidade Federal Do Paraná, Curitiba, PR, Brazil
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20
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Ianniello Z, Sorci M, Ceci Ginistrelli L, Iaiza A, Marchioni M, Tito C, Capuano E, Masciarelli S, Ottone T, Attrotto C, Rizzo M, Franceschini L, de Pretis S, Voso MT, Pelizzola M, Fazi F, Fatica A. New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in chronic myeloid leukemia. Cell Death Dis 2021; 12:870. [PMID: 34561421 PMCID: PMC8463696 DOI: 10.1038/s41419-021-04169-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 09/03/2021] [Accepted: 09/16/2021] [Indexed: 12/13/2022]
Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the presence of tyrosine kinase BCR-ABL1 fusion protein, which deregulate transcription and mRNA translation. Tyrosine kinase inhibitors (TKIs) are the first-choice treatment. However, resistance to TKIs remains a challenge to cure CML patients. Here, we reveal that the m6A methyltransferase complex METTL3/METTL14 is upregulated in CML patients and that is required for proliferation of primary CML cells and CML cell lines sensitive and resistant to the TKI imatinib. We demonstrate that depletion of METTL3 strongly impairs global translation efficiency. In particular, our data show that METTL3 is crucial for the expression of genes involved in ribosome biogenesis and translation. Specifically, we found that METTL3 directly regulates the level of PES1 protein identified as an oncogene in several tumors. We propose a model in which nuclear METTL3/METTL14 methyltransferase complex modified nascent transcripts whose translation is enhanced by cytoplasmic localization of METTL3, independently from its catalytic activity. In conclusion, our results point to METTL3 as a novel relevant oncogene in CML and as a promising therapeutic target for TKI resistant CML.
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Affiliation(s)
- Zaira Ianniello
- Department of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, Rome, Italy
| | - Melissa Sorci
- Department of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, Rome, Italy
| | - Lavinia Ceci Ginistrelli
- Department of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, Rome, Italy
| | - Alessia Iaiza
- Department of Anatomical, Histological, Forensic & Orthopedic Sciences, Section of Histology & Medical Embryology, Sapienza University of Rome, Rome, Italy
| | - Marcella Marchioni
- Institute of Biology, Molecular Medicine and Nanobiotechnology, CNR, Sapienza University of Rome, Rome, Italy
| | - Claudia Tito
- Department of Anatomical, Histological, Forensic & Orthopedic Sciences, Section of Histology & Medical Embryology, Sapienza University of Rome, Rome, Italy
| | - Ernestina Capuano
- Department of Anatomical, Histological, Forensic & Orthopedic Sciences, Section of Histology & Medical Embryology, Sapienza University of Rome, Rome, Italy
| | - Silvia Masciarelli
- Department of Anatomical, Histological, Forensic & Orthopedic Sciences, Section of Histology & Medical Embryology, Sapienza University of Rome, Rome, Italy.,Histology and Embryology Section, Department of Life Science and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Tiziana Ottone
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.,Fondazione Santa Lucia, Laboratorio di Neuro-Oncoematologia, Rome, Italy
| | - Cristina Attrotto
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | | | | | - Stefano de Pretis
- Center for Genomic Science, Fondazione Istituto Italiano di Tecnologia, Milan, Italy
| | - Maria Teresa Voso
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.,Fondazione Santa Lucia, Laboratorio di Neuro-Oncoematologia, Rome, Italy
| | - Mattia Pelizzola
- Center for Genomic Science, Fondazione Istituto Italiano di Tecnologia, Milan, Italy
| | - Francesco Fazi
- Department of Anatomical, Histological, Forensic & Orthopedic Sciences, Section of Histology & Medical Embryology, Sapienza University of Rome, Rome, Italy. .,Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy.
| | - Alessandro Fatica
- Department of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, Rome, Italy.
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21
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Chen LJ, Hu B, Han ZQ, Zhu JH, Fan X, Chen XX, Li ZP, Zhou H. BAG2-Mediated Inhibition of CHIP Expression and Overexpression of MDM2 Contribute to the Initiation of Endometriosis by Modulating Estrogen Receptor Status. Front Cell Dev Biol 2021; 8:554190. [PMID: 33987175 PMCID: PMC8111302 DOI: 10.3389/fcell.2020.554190] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 11/17/2020] [Indexed: 12/16/2022] Open
Abstract
Endometriosis is an estrogen-dependent gynecological disease primarily affecting women of childbearing age, which gives rise to pelvic pain calling for multiple operations, and sometimes leading to infertility. However, the etiology of endometriosis remains poorly understood. In this study we investigated the roles of two Ubiquitin E3 Ligases, namely hsc70-interacting protein (CHIP) and mouse double minute 2 (MDM2), in the abnormal estrogenic activity in endometriosis. We first collected endometrial tissues from 91 cases of endometriosis and 78 cases of uterine myomas. Next, we established a murine endometriosis model by ectopic endometrial tissue implantation. In other studies, we isolated human endometrial stromal cells (HESCs) were isolated from the endometrial tissues, and performed HA- or FLAG-immunoprecipitation assays and immunoblotting with an anti-ubiquitin antibody to test the interactions among BAG2, CHIP, MDM2, estrogen receptor α (ERα), and ERβ. The expression of ERα was downregulated while that of ERβ, BAG2, and MDM2 was upregulated in human endometriosis and in the mouse model. CHIP degraded ERβ instead of ERα via the ubiquitin-proteasome pathway, while BAG2 impaired the CHIP-mediated degradation of ERβ in cultured HESCs derived from human endometriosis. The degradation of ERα by MDM2 in cultured endometriosis-HESCs also occurred through the ubiquitin-proteasome pathway. Knockdown of both BAG2 and MDM2 alleviated the development of endometriosis in mice. Our findings suggest that the interference of BAG2 and MDM2 may have therapeutic effects in endometriosis. Understanding better the molecular mechanisms underlying the regulation of the abnormal estrogenic activity in endometriosis is crucial for the advancement of targeted therapeutic strategies.
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Affiliation(s)
- Li-Juan Chen
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bin Hu
- Department of Obstetrics and Gynecology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhi-Qiang Han
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian-Hua Zhu
- Laboratory of Clinical Immunology, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xu Fan
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xue-Xing Chen
- Union Hospital, Tongji Medical College, Institute of Hematology, Huazhong University of Science and Technology, Wuhan, China
| | - Zi-Ping Li
- Union Hospital, Tongji Medical College, Institute of Hematology, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Zhou
- Union Hospital, Tongji Medical College, Institute of Hematology, Huazhong University of Science and Technology, Wuhan, China
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22
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Qin Y, Yuan H, Chen X, Yang X, Xing Z, Shen Y, Dong W, An S, Qi Y, Wu H. SUMOylation Wrestles With the Occurrence and Development of Breast Cancer. Front Oncol 2021; 11:659661. [PMID: 33968766 PMCID: PMC8097099 DOI: 10.3389/fonc.2021.659661] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 03/02/2021] [Indexed: 12/17/2022] Open
Abstract
Breast cancer has the highest incidence among cancers and is the most frequent cause of death in women worldwide. The detailed mechanism of the pathogenesis of breast cancer has not been fully elucidated, and there remains a lack of effective treatment methods for the disease. SUMOylation covalently conjugates a large amount of cellular proteins, and affects their cellular localization and biological activity to participate in numerous cellular processes. SUMOylation is an important process and imbalance of SUMOylation results in the progression of human diseases. Increasing evidence shows that numerous SUMOylated proteins are involved in the occurrence and development of breast cancer. This review summarizes a series of studies on protein SUMOylation in breast cancer in recent years. The study of SUMOylated proteins provides a comprehensive understanding of the pathophysiology of breast cancer and provides evolving therapeutic strategies for the treatment of breast cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Yitao Qi
- Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi’an, China
| | - Hongmei Wu
- Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi’an, China
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23
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Jiang Z, Zhang Y, Chen X, Wang Y, Wu P, Wu C, Chen D. microRNA-1271 impedes the development of prostate cancer by downregulating PES1 and upregulating ERβ. J Transl Med 2020; 18:209. [PMID: 32448371 PMCID: PMC7245853 DOI: 10.1186/s12967-020-02349-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 04/24/2020] [Indexed: 12/30/2022] Open
Abstract
Background As a nucleolar protein associated with ribosome biogenesis, pescadillo homolog 1 (PES1) has been reported to participate in the development of many cancers. However, its role in prostate cancer is not clearly defined. Therefore, the aim of this study is to explore the effects and the specific mechanism of PES1 in prostate cancer. Methods A microarray-based analysis was performed to analyze differentially expressed genes (DEGs) between prostate cancer and normal samples. Next, the interaction between PES1 and microRNA-1271 (miR-1271) was investigated using bioinformatics analysis in combination with dual-luciferase reporter gene assay. The expression of miR-1271 in prostate cancer cells and tissues was determined using RT-qPCR. Its effects on downstream estrogen receptor β (ERβ) signaling pathway were further examined. Moreover, we analyzed whether miR-1271 affects proliferation, apoptosis, migration and invasion of prostate cancer cells by EdU assay, flow cytometry, and Transwell assay. Lastly, a prostate cancer mouse model was conducted to measure their roles in the tumor growth. Results PES1 was identified as a prostate cancer-related DEG and found to be upregulated in prostate cancer. miR-1271, which was poorly expressed in both cells and tissues of prostate cancer, can specifically bind to PES1. Additionally, overexpression of miR-1271 activated the ERβ signaling pathway. Overexpression of miR-1271 or depletion of PES1 inhibited prostate cancer cell proliferation, migration and invasion, promoted apoptosis in vitro and suppressed tumor growth in vivo. Conclusions Taken together, overexpression of miR-1271 downregulates PES1 to activate the ERβ signaling pathway, leading to the delayed prostate cancer development. Our data highlights the potential of miR-1271 as a novel biomarker for the treatment of prostate cancer.
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Affiliation(s)
- Zhenming Jiang
- Department of Urology, The First Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Yuxi Zhang
- Department of Urology, The First Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China. .,Department of Urology, People's Hospital of Datong Hui and Tu Autonomous County, Xining, 810100, People's Republic of China.
| | - Xi Chen
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Yan Wang
- Department of Pathology, The First Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, 110001, People's Republic of China
| | - Pingeng Wu
- Department of Urology, The First Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Chengzhang Wu
- Department of Urology, People's Hospital of Datong Hui and Tu Autonomous County, Xining, 810100, People's Republic of China
| | - Dong Chen
- Central Lab, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China
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24
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Fu Z, Jiao Y, Li YQ, Ke JJ, Xu YH, Jia BX, Liu B. PES1 In Liver Cancer: A Prognostic Biomarker With Tumorigenic Roles. Cancer Manag Res 2019; 11:9641-9653. [PMID: 31814761 PMCID: PMC6861535 DOI: 10.2147/cmar.s226471] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 11/01/2019] [Indexed: 12/15/2022] Open
Abstract
PURPOSE Liver cancer has a high incidence of mortality. DNA replication and posttranscriptional modifications play important roles in the development of liver cancer. Pescadillo (PES1) is a nuclear protein that is involved in embryonic development, ribosome synthesis, DNA replication, and cell cycle progression. Recently, abnormal PES1 expression was reported in several tumors, including neuroblastoma, colon cancer, gastric cancer, and breast cancer. Based on bio-informatic analysis, cell experiments and animal models, the aim of this study is to investigate the expression patterns and specific roles of PES1 in liver cancer. PATIENTS AND METHODS PES1 expression was represented by boxplots. The correlation between PES1 expression and clinical features was assessed by the chi-squared test and Fisher's exact tests. Kaplan-Meier curves compared overall survival between different levels of PES1 expression, and Cox analysis selected potential variables associated with overall survival. The MTT assay investigated the proliferation rate, the scratch assay assessed the migratory ability, and the Transwell assay evaluated the invasion capacity of tumor cells in vitro. Animal models were used to confirm the tumorigenic roles of PES1 in vivo. GSEA illustrated the molecular mechanisms that PES1 participated in. RESULTS We found that PES1 was highly expressed in liver cancer tissues, served as a diagnostic marker, and correlated with poor overall survival (OS) and relapse-free survival (RFS) in patients. In vitro studies indicated that PES1 promoted tumor cell proliferation (P=0.0034), migration (P=0.0026), and invasion (P=0.0008), and this tumorigenic role was confirmed in animal models. GSEA further illuminated molecular mechanisms that PES1 participated in liver cancer occurrence and progression. CONCLUSION This study suggested that PES1 was upregulated in liver cancer and correlated with poor prognosis, by promoting tumor cell proliferation, migration, and invasion, and PES1 may be a novel diagnostic and prognostic bio-marker and a promising therapeutic target in liver cancer.
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Affiliation(s)
- Zhuo Fu
- Department of Hand and Foot Surgery, The First Hospital of Jilin University, Changchun, Jilin130021, People’s Republic of China
| | - Yan Jiao
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, Jilin130021, People’s Republic of China
| | - Yan-Qing Li
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin130021, People’s Republic of China
| | - Jian-Ji Ke
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, Jilin130021, People’s Republic of China
| | - Yan-Hui Xu
- Department of Digestive, China-Japan Union Hospital Affiliated to Jilin University, Changchun, Jilin130033, People’s Republic of China
| | - Bao-Xing Jia
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, Jilin130021, People’s Republic of China
| | - Bin Liu
- Department of Hand and Foot Surgery, The First Hospital of Jilin University, Changchun, Jilin130021, People’s Republic of China
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25
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PES1 promotes BET inhibitors resistance and cells proliferation through increasing c-Myc expression in pancreatic cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:463. [PMID: 31718704 PMCID: PMC6852745 DOI: 10.1186/s13046-019-1466-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 10/22/2019] [Indexed: 12/20/2022]
Abstract
Background Overexpressed PES1 promotes carcinogenesis in various types of malignant tumors. However, the biological role and clinical significance of PES1 in pancreatic cancer are still unexplored. Methods The expression level of PES1 in pancreatic cancer cell lines and pancreatic cancer patient samples was determined using Western Blotting analysis, RT-qPCR analysis, immunohistochemical (IHC) analysis of tissue microarray, and the GEPIA web tool. MTS assay, colony formation assay, and xenograft tumor assay were used to evaluate the tumor growth ability of pancreatic cancer cells. Results We established that the expression of PES1 was abnormally increased in pancreatic cancer tissues and led to poor prognosis of pancreatic cancer patients. We also found that PES1 was responsible for promoting cell growth and contributed to bromodomain and cancer cell resistance to extra-terminal (BET) inhibitors in pancreatic cancer. Furthermore, we showed that PES1 interacted with BRD4 to enhance c-Myc expression, which is the primary cause of cancer cell resistance to BET inhibitors in pancreatic cancer. Finally, CDK5 inhibitors were proven to destabilize PES1 and overcome cancer cell resistance to BET inhibitors in pancreatic cancer cells. Conclusions We have shown that PES1 could be one of the promoting factors of tumor growth and a prognosis-related protein of pancreatic cancer. Targeting PES1 with CDK5 inhibitors might help overcome cancer cell resistance to BET inhibitors in pancreatic cancer cells.
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26
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Bergqvist F, Ossipova E, Idborg H, Raouf J, Checa A, Englund K, Englund P, Khoonsari PE, Kultima K, Wheelock CE, Larsson K, Korotkova M, Jakobsson PJ. Inhibition of mPGES-1 or COX-2 Results in Different Proteomic and Lipidomic Profiles in A549 Lung Cancer Cells. Front Pharmacol 2019; 10:636. [PMID: 31231223 PMCID: PMC6567928 DOI: 10.3389/fphar.2019.00636] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 05/17/2019] [Indexed: 12/23/2022] Open
Abstract
Pharmacological inhibition of microsomal prostaglandin E synthase (mPGES)-1 for selective reduction in prostaglandin E2 (PGE2) biosynthesis is protective in experimental models of cancer and inflammation. Targeting mPGES-1 is envisioned as a safer alternative to traditional non-steroidal anti-inflammatory drugs (NSAIDs). Herein, we compared the effects of mPGES-1 inhibitor Compound III (CIII) with the cyclooxygenase (COX)-2 inhibitor NS-398 on protein and lipid profiles in interleukin (IL)-1β-induced A549 lung cancer cells using mass spectrometry. Inhibition of mPGES-1 decreased PGE2 production and increased PGF2α and thromboxane B2 (TXB2) formation, while inhibition of COX-2 decreased the production of all three prostanoids. Our proteomics results revealed that CIII downregulated multiple canonical pathways including eIF2, eIF4/P70S6K, and mTOR signaling, compared to NS-398 that activated these pathways. Moreover, pathway analysis predicted that CIII increased cell death of cancer cells (Z = 3.8, p = 5.1E-41) while NS-398 decreased the same function (Z = -5.0, p = 6.5E-35). In our lipidomics analyses, we found alterations in nine phospholipids between the two inhibitors, with a stronger alteration in the lysophospholipid (LPC) profile with NS-398 compared to CIII. Inhibition of mPGES-1 increased the concentration of sphinganine and dihydroceramide (C16:0DhCer), while inhibition of COX-2 caused a general decrease in most ceramides, again suggesting different effects on cell death between the two inhibitors. We showed that CIII decreased proliferation and potentiated the cytotoxic effect of the cytostatic drugs cisplatin, etoposide, and vincristine when investigated in a live cell imaging system. Our results demonstrate differences in protein and lipid profiles after inhibition of mPGES-1 or COX-2 with important implications on the therapeutic potential of mPGES-1 inhibitors as adjuvant treatment in cancer. We encourage further investigations to illuminate the clinical benefit of mPGES-1 inhibitors in cancer.
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Affiliation(s)
- Filip Bergqvist
- Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Elena Ossipova
- Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Helena Idborg
- Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Joan Raouf
- Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Antonio Checa
- Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Karin Englund
- Department of Analytical Chemistry, Stockholm University, Stockholm, Sweden
| | - Petter Englund
- Department of Analytical Chemistry, Stockholm University, Stockholm, Sweden
| | - Payam Emami Khoonsari
- Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
| | - Kim Kultima
- Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
| | - Craig E Wheelock
- Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Karin Larsson
- Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Marina Korotkova
- Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Per-Johan Jakobsson
- Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
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27
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Sahay D, Terry MB, Miller R. Is breast cancer a result of epigenetic responses to traffic-related air pollution? A review of the latest evidence. Epigenomics 2019; 11:701-714. [PMID: 31070457 DOI: 10.2217/epi-2018-0158] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Environmental toxicants can exert adverse health effects via epigenetic regulation. We conducted a review of studies assessing traffic-related air pollution (TRAP) exposure and breast cancer (BC) risk, and the evidence for epigenetic mediation. 14 epidemiological studies demonstrated associations between TRAP exposure and BC risk, in which a total of 26 comparisons were assessed. 11 of these comparisons reported a positive association; whereas 15 comparisons were negative. Five publications linked TRAP exposure to epigenetic alterations in genes that may be related to BC risk. One animal study provided evidence of TRAP-treatment inducing breast tumorigenesis. Associations between TRAP components polycyclic aromatic hydrocarbons (PAH) and nitrogen dioxide (NO2) and BC risk were more consistent. While evidence for epigenetic regulation remains limited, polycyclic aromatic hydrocarbons (PAH) and nitrogen dioxide (NO2) exposures may alter methylation of breast tumorigenic genes (e.g., EPHB2, LONP1). Future epigenomic studies with environmental measures are needed to interrogate the relationship between TRAP and BC risk.
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Affiliation(s)
- Debashish Sahay
- Division of Pulmonary, Allergy & Critical Care of Medicine, Department of Medicine, College of Physicians & Surgeons, Columbia University, New York City 10032, NY, USA
| | - Mary B Terry
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York City 10032, NY, USA.,Herbert Irving Comprehensive Cancer Center, Columbia University, New York City 10032, NY, USA
| | - Rachel Miller
- Division of Pulmonary, Allergy & Critical Care of Medicine, Department of Medicine, College of Physicians & Surgeons, Columbia University, New York City 10032, NY, USA.,Herbert Irving Comprehensive Cancer Center, Columbia University, New York City 10032, NY, USA.,Division of Pediatric Allergy, Immunology, & Rheumatology, Department of Pediatrics, College of Physicians & Surgeons, Columbia University, New York City 10032, NY, USA.,Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York City 10032, NY, USA
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28
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Cheng L, Yuan B, Ying S, Niu C, Mai H, Guan X, Yang X, Teng Y, Lin J, Huang J, Jin R, Wu J, Liu B, Chang S, Wang E, Zhang C, Hou N, Cheng X, Xu D, Yang X, Gao S, Ye Q. PES1 is a critical component of telomerase assembly and regulates cellular senescence. SCIENCE ADVANCES 2019; 5:eaav1090. [PMID: 31106266 PMCID: PMC6520020 DOI: 10.1126/sciadv.aav1090] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 04/09/2019] [Indexed: 05/04/2023]
Abstract
Telomerase defers the onset of telomere shortening and cellular senescence by adding telomeric repeat DNA to chromosome ends, and its activation contributes to carcinogenesis. Telomerase minimally consists of the telomerase reverse transcriptase (TERT) and the telomerase RNA (TR). However, how telomerase assembles is largely unknown. Here, we demonstrate that PES1 (Pescadillo), a protein overexpressed in many cancers, forms a complex with TERT and TR through direct interaction with TERT, regulating telomerase activity, telomere length maintenance, and senescence. PES1 does not interact with the previously reported telomerase components Reptin, Pontin, p23, and Hsp90. PES1 facilitates telomerase assembly by promoting direct interaction between TERT and TR without affecting TERT and TR levels. PES1 expression correlates positively with telomerase activity and negatively with senescence in patients with breast cancer. Thus, we identify a previously unknown telomerase complex, and targeting PES1 may open a new avenue for cancer therapy.
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Affiliation(s)
- Long Cheng
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China
| | - Bin Yuan
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, China
| | - Sunyang Ying
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China
| | - Chang Niu
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China
- Department of Biochemistry, College of Life Sciences, Capital Normal University, Beijing 100048, China
| | - Hongxu Mai
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China
| | - Xin Guan
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China
| | - Xiaohui Yang
- CAS Key Laboratory of Biomedical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China
| | - Yan Teng
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
| | - Jing Lin
- First Affiliated Hospital, Chinese PLA General Hospital, Beijing 100048, China
| | - Junjian Huang
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China
| | - Rui Jin
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China
| | - Jun Wu
- Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China
| | - Bo Liu
- Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China
| | - Shaohong Chang
- Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China
| | - Enqun Wang
- Department of Stomatology, Anqing Municipal Hospital of Anhui Medical University, Anqing, Anhui 246003, China
| | - Chunxia Zhang
- Department of Stomatology, Anqing Municipal Hospital of Anhui Medical University, Anqing, Anhui 246003, China
| | - Ning Hou
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
| | - Xuan Cheng
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
| | - Danyang Xu
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China
- Department of Biochemistry, College of Life Sciences, Capital Normal University, Beijing 100048, China
| | - Xiao Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
- Corresponding author. (Q.Y.); (S.G.); (X.Y.)
| | - Shan Gao
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China
- CAS Key Laboratory of Biomedical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China
- Corresponding author. (Q.Y.); (S.G.); (X.Y.)
| | - Qinong Ye
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China
- Corresponding author. (Q.Y.); (S.G.); (X.Y.)
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Qiu YB, Liao LY, Jiang R, Xu M, Xu LW, Chen GG, Liu ZM. PES1 promotes the occurrence and development of papillary thyroid cancer by upregulating the ERα/ERβ protein ratio. Sci Rep 2019; 9:1032. [PMID: 30705367 PMCID: PMC6355968 DOI: 10.1038/s41598-018-37648-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 12/07/2018] [Indexed: 02/07/2023] Open
Abstract
PES1, a BRCT domain-containing protein, has been shown to play a role in modulating the balance and ratio between ERα and ERβ protein, which is involved in the occurrence and development of breast and ovarian cancer. However, its role in connection with the balance and ratio between ERα and ERβ protein in papillary thyroid cancer (PTC) remains unclear. Here, we found that ERα and ERβ were co-expressed in human PTC tissues and cells. ERα promoted and ERβ inhibited the proliferation, invasion and migration of PTC cells. PES1 modulated the balance between ERα and ERβ by elevating the ERα protein level and simultaneously reducing the ERβ protein level, then upregulating the ERα/ERβ protein ratio and promoting the proliferation, invasion and migration of PTC cells. In PTC tissues, PES1 protein level was positively correlated with the ERα protein level and negatively correlated with the ERβ protein level. The PES1 and ERα protein levels were gradually increased and the ERβ protein level was decreased by degree in the occurrence and development of PTC. Increased PES1 and ERα protein levels and decreased ERβ protein level were correlated with the aggressive behaviors of PTC patients such as large tumor size, extrathyroidal extension (ETE), lymph node metastasis (LNM), high BRAFV600E expression and high TNM stage. It is suggested that PES1 promotes the occurrence and development of PTC by elevating the ERα protein level and reducing the ERβ protein level, and then upregulating the ERα/ERβ protein ratio.
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Affiliation(s)
- Yi-Bo Qiu
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Ling-Yao Liao
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Rong Jiang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Man Xu
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Lin-Wan Xu
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - George G Chen
- Department of Surgery, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong, China
| | - Zhi-Min Liu
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China.
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30
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PES1 enhances proliferation and tumorigenesis in hepatocellular carcinoma via the PI3K/AKT pathway. Life Sci 2019; 219:182-189. [PMID: 30630006 DOI: 10.1016/j.lfs.2018.12.054] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 12/27/2018] [Accepted: 12/29/2018] [Indexed: 12/29/2022]
Abstract
AIM We investigated the potential role of pescadillo ribosomal biogenesis factor 1 (PES1) in the development of hepatocellular carcinoma (HCC). MATERIAL AND METHODS One hundred and thirty-four patients with hepatocellular carcinoma were chosen to evaluate the association between the expression of PES1 and survival, clinical characteristics of these patients. Western blotting, real-time PCR, immunohistochemistry, CCK-8 assay, colony formation and subcutaneous tumors in nude mice were conducted. KEY FINDINGS We found that PES1 was commonly upregulated in HCC tissues and cells. Immunohistochemical analysis of 134 paraffin-embedded archived HCC tissues showed that the protein expression level of PES1 was positively correlated with clinical characteristics and reduced the survival time of HCC patients. Univariate and multivariate analysis revealed that PES1 expression may be an independent prognostic indicator of poorer overall survival in HCC patients. Furthermore, silencing of endogenous PES1 significantly inhibited the proliferation and tumorigenicity of SMMC 7721 and HepG2 cells in vitro as well as in vivo in nude mice. Finally, we found that PES1 affected cell proliferation by regulating the PI3K/AKT/GSK3β/cyclinD1 signaling pathway. SIGNIFICANCE Our data suggest that PES1 may promote proliferation and tumorigenicity, and potentially representing a novel prognostic marker for overall survival in HCC. CORE TIP We report that pescadillo ribosomal biogenesis factor 1 (PES1) plays an oncogenic role in hepatocellular carcinoma, which was commonly upregulated in hepatocellular carcinoma tissues and cells. Immunostaining analysis found that the protein expression level of PES1 was positively correlated with clinical characteristics and reduced survival time of hepatocellular carcinoma patients. Multivariate analysis revealed that PES1 expression might be an independent prognostic indicator of survival in hepatocellular carcinoma patients. Furthermore, PES1 knockdown inhibited the proliferation and tumorigenesis in hepatocellular carcinoma cell lines. Additionally, we found that PES1 is involved in the cell proliferation by regulating the AKT/GSK3β/cyclinD1 signaling pathway.
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31
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Wang L, Zhao L, Jia X, Jiang L, Song Y, Ye Q, Lyu Z. Aminophenols increase proliferation of thyroid tumor cells by inducing the transcription factor activity of estrogen receptor α. Biomed Pharmacother 2018; 109:621-628. [PMID: 30399599 DOI: 10.1016/j.biopha.2018.10.168] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 10/26/2018] [Accepted: 10/26/2018] [Indexed: 02/06/2023] Open
Abstract
Aminophenols, which are widely used as components of hair dye and medicine, may function as environmental endocrine disruptors by regulating the proliferation of endocrine-related cancers. Estrogen receptor α (ERα) is a key regulator of breast cancer. Recently, it was found that ERα may also participate in the transformation and progression of thyroid tumors, but its interaction with aminophenols and its function in thyroid tumors is not clear. In this study, the transcription factor activity of ERα in BHP10-3 cells (a thyroid tumor cell line) was examined using luciferase assays. The promoter recruitment of ERα was examined using chromatin co-precipitation (ChIP). Additionally, in an in vivo study, BHP10-3 cells were transplanted into nude mice. Upon administration of aminophenols, the transcription factor activity of ERα was significantly increased in BHP10-3 cells, and the recruitment of ERα to the promoter of its target gene was increased. Aminophenols enhanced the in vitro and in vivo proliferation of BHP10-3 cells. By discovering that aminophenols induce the onco-promoting activity of ERα, our study extends the understanding of the function of aminophenols and suggests that ERα is a potential therapeutic target for the treatment of thyroid tumors.
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Affiliation(s)
- Lin Wang
- Department of Endocrinology, Chinese PLA General Hospital, Medical College of Chinese PLA, Beijing, 100853, PR China; Department of Internal Medicine, No. 316 Hospital of PLA, Beijing, 100093, PR China.
| | - Ling Zhao
- Department of Endocrinology, Chinese PLA General Hospital, Medical College of Chinese PLA, Beijing, 100853, PR China.
| | - Xiaomeng Jia
- Department of Endocrinology, Chinese PLA General Hospital, Medical College of Chinese PLA, Beijing, 100853, PR China.
| | - Lina Jiang
- Department of Endocrinology, Chinese PLA General Hospital, Medical College of Chinese PLA, Beijing, 100853, PR China.
| | - Yeqiong Song
- Department of Endocrinology, The third people's hospital of Hangzhou, Hangzhou, 510150, PR China.
| | - Qinong Ye
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, 100850, PR China.
| | - Zhaohui Lyu
- Department of Endocrinology, Chinese PLA General Hospital, Medical College of Chinese PLA, Beijing, 100853, PR China.
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Shao Z, Li Y, Dai W, Jia H, Zhang Y, Jiang Q, Chai Y, Li X, Sun H, Yang R, Cao Y, Feng F, Guo Y. ETS-1 induces Sorafenib-resistance in hepatocellular carcinoma cells via regulating transcription factor activity of PXR. Pharmacol Res 2018; 135:188-200. [PMID: 30114438 DOI: 10.1016/j.phrs.2018.08.003] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 08/02/2018] [Accepted: 08/06/2018] [Indexed: 12/12/2022]
Abstract
Transcription factor E26 transformation specific sequence 1 (ETS-1) is a primary regulator in the metastasis of human cancer cells, especially hepatocellular carcinoma (HCC) cells; and it would affect the prognosis of HCC patients who received chemotherapies. However, the regulatory role of ETS-1 in the resistance of HCC cells to molecular-targeting agent remains poorly understood. In the present work, we demonstrate that high ETS-1 expression correlates with poor prognosis of advanced HCC patients received Sorafenib treatment. Mechanistically, ETS-1 binds to nuclear Pregnane X receptor (PXR) directly and enhances PXR's transcription factor activity, which further leads to the induction of the PXR's downstream multi-drug resistance related genes. Overexpression of ETS-1 accelerates the metabolic clearance of Sorafenib in HCC cells and leads to the better survival and faster migration of those cells. The therapeutic studies show that ETS-1 promotes the Sorafenib-resistance of HCC tumor models and ETS-1 blockade enhances the anti-tumor capacity of Sorafenib by decreasing PXR activation. Thus, our study suggests that ETS-1 could enhance the activation of PXR and be a potential therapeutic target for overcoming Sorafenib resistance in HCC treatment.
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Affiliation(s)
- Zhiyi Shao
- School of Mathematics and Information Science, Shaanxi Normal University, Xi'an, 710062, PR China; The Library, Shaanxi Normal University, Xi'an, 710062, PR China
| | - Yibo Li
- School of Psychology, Shaanxi Normal University, Xi'an, PR China
| | - Wenjie Dai
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA
| | - Hui Jia
- Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, 110016, PR China
| | - Yingshi Zhang
- Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, 110016, PR China
| | - Qiyu Jiang
- Research Center for Clinical and Translational Medicine, The 302nd Hospital of Chinese PLA, Beijing, 100039, PR China
| | - Yantao Chai
- Research Center for Clinical and Translational Medicine, The 302nd Hospital of Chinese PLA, Beijing, 100039, PR China
| | - Xiaojuan Li
- Research Center for Clinical and Translational Medicine, The 302nd Hospital of Chinese PLA, Beijing, 100039, PR China
| | - Huiwei Sun
- Research Center for Clinical and Translational Medicine, The 302nd Hospital of Chinese PLA, Beijing, 100039, PR China
| | - Ruichuang Yang
- Research Center for Clinical and Translational Medicine, The 302nd Hospital of Chinese PLA, Beijing, 100039, PR China
| | - Yu Cao
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
| | - Fan Feng
- The Library, Shaanxi Normal University, Xi'an, 710062, PR China; Research Center for Clinical and Translational Medicine, The 302nd Hospital of Chinese PLA, Beijing, 100039, PR China.
| | - Yingjie Guo
- School of Foreign Languages, Shaanxi Normal University, Xi'an, 710062, PR China.
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Li S, Wang M, Qu X, Xu Z, Yang Y, Su Q, Wu H. SUMOylation of PES1 upregulates its stability and function via inhibiting its ubiquitination. Oncotarget 2018; 7:50522-50534. [PMID: 27409667 PMCID: PMC5226600 DOI: 10.18632/oncotarget.10494] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 06/15/2016] [Indexed: 12/21/2022] Open
Abstract
PES1 is a component of the PeBoW complex, which is required for the maturation of 28S and 5.8S ribosomal RNAs, as well as for the formation of the 60S ribosome. Deregulation of ribosomal biogenesis can contribute to carcinogenesis. In this study, we showed that PES1 could be modified by the small ubiquitin-like modifier (SUMO) SUMO-1, SUMO-2 and SUMO-3, and SUMOylation of PES1 was stimulated by estrogen (E2). One major SUMOylation site (K517) was identified in the C-terminal Glu-rich domain of PES1. Substitution of K517 with arginine abolished the SUMOylation of PES1. SUMOylation also stabilized PES1 through inhibiting its ubiquitination. In addition, PES1 SUMOylation positively regulated the estrogen signaling pathway. SUMOylation enhanced the ability of PES1 to promote estrogen receptor α (ERα)-mediated transcription by increasing the stability of ERα, both in the presence and absence of E2. Moreover, SUMOylation of PES1 also increased the proportion of S-phase cells in the cell cycle and promoted the proliferation of breast cancer cells both in vitro and in vivo. These findings showed that posttranslational modification of PES1 by SUMOylation may serve as a key factor that regulates the function of PES1 in vivo.
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Affiliation(s)
- Shujing Li
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China
| | - Miao Wang
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China
| | - Xinjian Qu
- School of Life Science and Medicine, Dalian University of Technology, Panjin, China
| | - Zhaowei Xu
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China
| | - Yangyang Yang
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China
| | - Qiming Su
- School of Life Science and Medicine, Dalian University of Technology, Panjin, China
| | - Huijian Wu
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China.,School of Life Science and Medicine, Dalian University of Technology, Panjin, China
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Targeting CXCR7 improves the efficacy of breast cancer patients with tamoxifen therapy. Biochem Pharmacol 2017; 147:128-140. [PMID: 29175422 DOI: 10.1016/j.bcp.2017.11.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 11/21/2017] [Indexed: 01/09/2023]
Abstract
Chemokine (C-X-C motif) receptor 7 (CXCR7) has been established to be involved in breast cancer (BCa) progression. However, the role of CXCR7 in different subtype of BCa still remains unclear. Here we note that CXCR7 expression is significantly amplified in Luminal type BCa tissues as compared with Her2 and TNBC types through data-mining in TCGA datasets, and its protein level positively correlates with ERα expression by staining of human BCa tissue. Interestingly, alteration of CXCR7 expression in Luminal type BCa cells is able to modulate the expression of ERα through ubiquitination at post-translational level. Additionally, overexpression of CXCR7 in these cells greatly induces 4-OHT insensitivity in vitro and is associated with earlier recurrence in patients with tamoxifen therapy. Notably, silencing ERα expression potentially rescues the sensitivity of the above cells to 4-OHT, suggesting that elevated level of ERα is responsible for CXCR7-induced 4-OHT insensitivity in Luminal type BCa. Finally, mechanistic analyses show that the reduced BRCA1 (ubiquitin E3 ligase) and elevated OTUB1 (deubiquitinase) expression, which are regulated by CXCR7/ERK1/2 signaling pathway, are responsible for stabilizing ERα protein. In conclusion, our results suggest that targeting CXCR7 may serve as a potential therapeutic strategy for improving the efficacy of BCa patients with tamoxifen therapy.
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35
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Concomitant high expression of ERα36, EGFR and HER2 is associated with aggressive behaviors of papillary thyroid carcinomas. Sci Rep 2017; 7:12279. [PMID: 28947799 PMCID: PMC5612999 DOI: 10.1038/s41598-017-12478-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 09/08/2017] [Indexed: 12/20/2022] Open
Abstract
ERα, ERβ, PR, ERα36, EGFR and HER2 mRNA and protein expression in papillary thyroid carcinoma (PTC) were examined by real time RT-PCR and immunohistochemical staining. The mRNA and protein expression of ERα and PR were gradually increased and those of ERβ were gradually decreased from normal thyroid tissues to nodular hyperplasias (P < 0.05) and to PTCs (P < 0.05). However, the mRNA and protein expression of ERα36, EGFR and HER2 were only significantly increased in PTCs when compared with those in normal thyroid tissues (P < 0.001) and nodular hyperplasias (P < 0.001). There was some correlation between ERα, ERβ and PR, and between ERα36, EGFR and HER2 protein expression in PTCs. As for ERα, ERβ and PR, there was a significant positive correlation between ERα and PR, and a significant negative correlation between ERα and ERβ and between PR and ERβ protein expression. As for ERα36, EGFR and HER2, there was a significant positive correlation between ERα36, EGFR and HER2 protein expression in PTCs. Concomitant high expression of ERα36, EGFR and HER2 was strongly associated with aggressive behaviors including extrathyroidal extension (ETE), lymph node metastasis (LNM) and high TNM stage in PTCs (P < 0.001).
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36
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Rota SG, Roma A, Dude I, Ma C, Stevens R, MacEachern J, Graczyk J, Espiritu SMG, Rao PN, Minden MD, Kreinin E, Hess DA, Doxey AC, Spagnuolo PA. Estrogen Receptor β Is a Novel Target in Acute Myeloid Leukemia. Mol Cancer Ther 2017; 16:2618-2626. [DOI: 10.1158/1535-7163.mct-17-0292] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 07/11/2017] [Accepted: 08/16/2017] [Indexed: 11/16/2022]
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37
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Xu W, Jia G, Cai N, Huang S, Davie JR, Pitz M, Banerji S, Murphy L. A 16 Yin Yang gene expression ratio signature for ER+/node- breast cancer. Int J Cancer 2017; 140:1413-1424. [PMID: 27925180 DOI: 10.1002/ijc.30556] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 11/17/2016] [Indexed: 01/20/2023]
Abstract
Breast cancer is one of the leading causes of cancer death in women. It is a complex and heterogeneous disease with different clinical outcomes. Stratifying patients into subgroups with different outcomes could help guide clinical decision making. In this study, we used two opposing groups of genes, Yin and Yang, to develop a prognostic expression ratio signature. Using the METABRIC cohort we identified a16-gene signature capable of stratifying breast cancer patients into four risk levels with intention that low-risk patients would not undergo adjuvant systemic therapy, intermediate-low-risk patients will be treated with hormonal therapy only, and intermediate-high- and high-risk groups will be treated by chemotherapy in addition to the hormonal therapy. The 16-gene signature for four risk level stratifications of breast cancer patients has been validated using 14 independent datasets. Notably, the low-risk group (n = 51) of 205 estrogen receptor-positive and node negative (ER+/node-) patients from three different datasets who had not had any systemic adjuvant therapy had 100% 15-year disease-specific survival rate. The Concordance Index of YMR for ER+/node negative patients is close to the commercially available signatures. However, YMR showed more significance (HR = 3.7, p = 8.7e-12) in stratifying ER+/node- subgroup than OncotypeDx (HR = 2.7, p = 1.3e-7), MammaPrint (HR = 2.5, p = 5.8e-7), rorS (HR = 2.4, p = 1.4e-6), and NPI (HR = 2.6, p = 1.2e-6). YMR signature may be developed as a clinical tool to select a subgroup of low-risk ER+/node- patients who do not require any adjuvant hormonal therapy (AHT).
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Affiliation(s)
- Wayne Xu
- Research Institute of Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB.,Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB.,College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB
| | - Gaofeng Jia
- Research Institute of Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB
| | - Nianguang Cai
- Research Institute of Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB
| | - Shujun Huang
- Research Institute of Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB.,College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB
| | - James R Davie
- Research Institute of Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB.,Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB
| | - Marshall Pitz
- Research Institute of Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB.,Department of Medical Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB.,Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB
| | - Shantanu Banerji
- Research Institute of Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB.,Department of Medical Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB.,Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB
| | - Leigh Murphy
- Research Institute of Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB.,Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB
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38
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Gajulapalli VNR, Malisetty VL, Chitta SK, Manavathi B. Oestrogen receptor negativity in breast cancer: a cause or consequence? Biosci Rep 2016; 36:e00432. [PMID: 27884978 PMCID: PMC5180249 DOI: 10.1042/bsr20160228] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2016] [Revised: 11/23/2016] [Accepted: 11/24/2016] [Indexed: 02/07/2023] Open
Abstract
Endocrine resistance, which occurs either by de novo or acquired route, is posing a major challenge in treating hormone-dependent breast cancers by endocrine therapies. The loss of oestrogen receptor α (ERα) expression is the vital cause of establishing endocrine resistance in this subtype. Understanding the mechanisms that determine the causes of this phenomenon are therefore essential to reduce the disease efficacy. But how we negate oestrogen receptor (ER) negativity and endocrine resistance in breast cancer is questionable. To answer that, two important approaches are considered: (1) understanding the cellular origin of heterogeneity and ER negativity in breast cancers and (2) characterization of molecular regulators of endocrine resistance. Breast tumours are heterogeneous in nature, having distinct molecular, cellular, histological and clinical behaviour. Recent advancements in perception of the heterogeneity of breast cancer revealed that the origin of a particular mammary tumour phenotype depends on the interactions between the cell of origin and driver genetic hits. On the other hand, histone deacetylases (HDACs), DNA methyltransferases (DNMTs), miRNAs and ubiquitin ligases emerged as vital molecular regulators of ER negativity in breast cancers. Restoring response to endocrine therapy through re-expression of ERα by modulating the expression of these molecular regulators is therefore considered as a relevant concept that can be implemented in treating ER-negative breast cancers. In this review, we will thoroughly discuss the underlying mechanisms for the loss of ERα expression and provide the future prospects for implementing the strategies to negate ER negativity in breast cancers.
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Affiliation(s)
- Vijaya Narasihma Reddy Gajulapalli
- Department of Biochemistry, Molecular and Cellular Oncology Laboratory, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India
| | | | - Suresh Kumar Chitta
- Department of Biochemistry, Sri Krishnadevaraya University, Anantapur, Andhra Pradesh 515002, India
| | - Bramanandam Manavathi
- Department of Biochemistry, Molecular and Cellular Oncology Laboratory, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India
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39
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Notarnicola M, Barone M, Francavilla A, Tutino V, Bianco G, Tafaro A, Minoia M, Polimeno L, Napoli A, Scavo MP, Caruso MG. Lovastatin, but not orlistat, reduces intestinal polyp volume in an ApcMin/+ mouse model. Oncol Rep 2016; 36:893-899. [PMID: 27277576 DOI: 10.3892/or.2016.4856] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 01/21/2016] [Indexed: 02/07/2023] Open
Abstract
The statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) and orlistat, an inhibitor of fatty acid synthase (FAS), inhibit tumor cell growth by restricting cholesterol and fatty acid synthesis, respectively. We previously demonstrated that an omega (ω)-3 polyunsaturated fatty acid (PUFA)- or olive oil-enriched diet reduced the polyp number and volume in ApcMin/+ mice. This phenomenon was associated with a significant inhibition of FAS and HMGCoAR, as well as an increase in the estrogen receptor (ER)β/α ratio. Herein, we evaluated the effect of lovastatin and orlistat on polyp development and ER expression in ApcMin/+ mice, in order to confirm previous data obtained with ω‑3-PUFAs and olive oil. As expected, the use of lovastatin and orlistat significantly reduced HMGCoAR and FAS enzymatic activities and gene expression in colonic tissues, but did not affect the number of intestinal polyps, while there was a statistically significant reduction in polyp volume only in the mouse group treated with lovastatin. In the mice receiving orlistat, we observed a significant increase in cell proliferation in the polyp tissue, as well as enhanced expression of ERα. Moreover, the overexpression of ERα was associated with a statistically significant increase in PES1, Shh and Gli1 protein levels, considered ERα-related molecular targets.
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Affiliation(s)
- Maria Notarnicola
- Laboratory of Nutritional Biochemistry, National Institute for Digestive Diseases 'S. de Bellis', Castellana Grotte, Bari, Italy
| | - Michele Barone
- Gastroenterology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Antonio Francavilla
- Gastroenterology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Valeria Tutino
- Laboratory of Nutritional Biochemistry, National Institute for Digestive Diseases 'S. de Bellis', Castellana Grotte, Bari, Italy
| | - Giusy Bianco
- Animal Facility, National Institute for Digestive Diseases 'S. de Bellis', Castellana Grotte, Bari, Italy
| | - Angela Tafaro
- Animal Facility, National Institute for Digestive Diseases 'S. de Bellis', Castellana Grotte, Bari, Italy
| | - Mario Minoia
- Animal Facility, National Institute for Digestive Diseases 'S. de Bellis', Castellana Grotte, Bari, Italy
| | - Lorenzo Polimeno
- Gastroenterology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Anna Napoli
- Pathology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Maria Principia Scavo
- Gastroenterology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Maria Gabriella Caruso
- Laboratory of Nutritional Biochemistry, National Institute for Digestive Diseases 'S. de Bellis', Castellana Grotte, Bari, Italy
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Ma H, Yao Y, Wang C, Zhang L, Cheng L, Wang Y, Wang T, Liang E, Jia H, Ye Q, Hou M, Feng F. Transcription factor activity of estrogen receptor α activation upon nonylphenol or bisphenol A treatment enhances the in vitro proliferation, invasion, and migration of neuroblastoma cells. Onco Targets Ther 2016; 9:3451-63. [PMID: 27366082 PMCID: PMC4913548 DOI: 10.2147/ott.s105745] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Many kinds of endocrine-disrupting chemicals (EDCs), for example, the environmental estrogens bisphenol A and nonylphenol, may regulate the activity of estrogen receptor α (ERα) and therefore induce potential disruption of normal endocrine function. However, the involvement of EDCs in human cancers, especially in endocrine-related cancer neuroblastoma regulation, is not very clear. In this work, results showed that upon bisphenol A or nonylphenol treatment, the transcription factor activity of ERα was significantly increased in neuroblastoma cell line SH-SY5Y. Bisphenol A and nonylphenol could enhance ERα activity via recruiting it to the target gene promoter. Furthermore, treatment of bisphenol A and nonylphenol enhanced the in vitro proliferation, invasion, and migration ability of neuroblastoma cells. By investigating the role of EDC-induced ERα upregulation, our data extend the understanding of the function of EDCs and further suggest that ERα might be a potential therapeutic target in human neuroblastoma treatment.
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Affiliation(s)
- Hongda Ma
- Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, People's Republic of China
| | - Yao Yao
- Department of Pharmacy, Women & Infants Hospital of Zhengzhou, Zhengzhou, People's Republic of China
| | - Changli Wang
- Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, People's Republic of China
| | - Liyu Zhang
- Shaanxi Institute of Pediatric Disease, Xi'an Children's Hospital, Xi'an, People's Republic of China
| | - Long Cheng
- Institute of Biotechnology, Chinese Military Medical Science Academy, Beijing, People's Republic of China
| | - Yiren Wang
- School of Life Science, Shenyang Pharmaceutical University, Shenyang, People's Republic of China
| | - Tao Wang
- Institute of Toxicology and Pharmacology, Chinese Military Medical Science Academy, Beijing, People's Republic of China
| | - Erguang Liang
- Institute of Toxicology and Pharmacology, Chinese Military Medical Science Academy, Beijing, People's Republic of China
| | - Hui Jia
- Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, People's Republic of China
| | - Qinong Ye
- Institute of Biotechnology, Chinese Military Medical Science Academy, Beijing, People's Republic of China
| | - Mingxiao Hou
- Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, People's Republic of China
| | - Fan Feng
- Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, People's Republic of China
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41
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Zhao Z, Wang L, James T, Jung Y, Kim I, Tan R, Hoffmann FM, Xu W. Reciprocal Regulation of ERα and ERβ Stability and Activity by Diptoindonesin G. ACTA ACUST UNITED AC 2015; 22:1608-21. [PMID: 26670079 DOI: 10.1016/j.chembiol.2015.10.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Revised: 10/01/2015] [Accepted: 10/22/2015] [Indexed: 02/07/2023]
Abstract
ERβ is regarded as a "tumor suppressor" in breast cancer due to its anti-proliferative effects. However, unlike ERα, ERβ has not been developed as a therapeutic target in breast cancer due to loss of ERβ in aggressive cancers. In a small-molecule library screen for ERβ stabilizers, we identified Diptoindonesin G (Dip G), which significantly increases ERβ protein stability while decreasing ERα protein levels. Dip G enhances the transcription and anti-proliferative activities of ERβ, while attenuating the transcription and proliferative effects of ERα. Further investigation revealed that instead of targeting ER, Dip G targets the CHIP E3 ubiquitin ligase shared by ERα and ERβ. Thus, Dip G is a dual-functional moiety that reciprocally controls ERα and ERβ protein stability and activities via an indirect mechanism. The ERβ stabilization effects of Dip G may enable the development of ERβ-targeted therapies for human breast cancers.
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Affiliation(s)
- Zibo Zhao
- McArdle Laboratory for Cancer Research, Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA
| | - Lu Wang
- McArdle Laboratory for Cancer Research, Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA
| | - Taryn James
- McArdle Laboratory for Cancer Research, Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA
| | - Youngeun Jung
- College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 406-840, Republic of Korea
| | - Ikyon Kim
- College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 406-840, Republic of Korea
| | - Renxiang Tan
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, Nanjing University, Nanjing 210093, PR China
| | - F Michael Hoffmann
- McArdle Laboratory for Cancer Research, Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA
| | - Wei Xu
- McArdle Laboratory for Cancer Research, Wisconsin Institute for Medical Research, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA.
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Romes EM, Sobhany M, Stanley RE. The Crystal Structure of the Ubiquitin-like Domain of Ribosome Assembly Factor Ytm1 and Characterization of Its Interaction with the AAA-ATPase Midasin. J Biol Chem 2015; 291:882-93. [PMID: 26601951 DOI: 10.1074/jbc.m115.693259] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Indexed: 01/28/2023] Open
Abstract
The synthesis of eukaryotic ribosomes is a complex, energetically demanding process requiring the aid of numerous non-ribosomal factors, such as the PeBoW complex. The mammalian PeBoW complex, composed of Pes1, Bop1, and WDR12, is essential for the processing of the 32S preribosomal RNA. Previous work in Saccharomyces cerevisiae has shown that release of the homologous proteins in this complex (Nop7, Erb1, and Ytm1, respectively) from preribosomal particles requires Rea1 (midasin or MDN1 in humans), a large dynein-like protein. Midasin contains a C-terminal metal ion-dependent adhesion site (MIDAS) domain that interacts with the N-terminal ubiquitin-like (UBL) domain of Ytm1/WDR12 as well as the UBL domain of Rsa4/Nle1 in a later step in the ribosome maturation pathway. Here we present the crystal structure of the UBL domain of the WDR12 homologue from S. cerevisiae at 1.7 Å resolution and demonstrate that human midasin binds to WDR12 as well as Nle1 through their respective UBL domains. Midasin contains a well conserved extension region upstream of the MIDAS domain required for binding WDR12 and Nle1, and the interaction is dependent upon metal ion coordination because removal of the metal or mutation of residues that coordinate the metal ion diminishes the interaction. Mammalian WDR12 displays prominent nucleolar localization that is dependent upon active ribosomal RNA transcription. Based upon these results, we propose that release of the PeBoW complex and subsequent release of Nle1 by midasin is a well conserved step in the ribosome maturation pathway in both yeast and mammalian cells.
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Affiliation(s)
- Erin M Romes
- From the Signal Transduction Laboratory, NIEHS, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709
| | - Mack Sobhany
- From the Signal Transduction Laboratory, NIEHS, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709
| | - Robin E Stanley
- From the Signal Transduction Laboratory, NIEHS, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709
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Du P, Yuan B, Cao J, Zhao J, Ding L, Chen L, Ying S, Jiang L, Lin J, Xu X, Cheng L, Ye Q. Methyltransferase-like 17 physically and functionally interacts with estrogen receptors. IUBMB Life 2015; 67:861-8. [PMID: 26488768 DOI: 10.1002/iub.1444] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2015] [Accepted: 10/03/2015] [Indexed: 02/06/2023]
Abstract
Estrogen exerts its physiological and pathological functions through two estrogen receptors (ERs), ERα and ERβ, which act as transcription factors. Coregulators, including coactivators and corepressors, have been shown to be crucial for regulation of ER transcriptional activity. Although many coregulators have been identified to regulate activities of ERs, novel coregulators are still needed to be investigated. Here, we show that human methyltransferase-like 17 (METTL17), whose function is unknown, physically interacts with ERα and ERβ, and functionally acts as a coactivator for ERs. METTL17 interacts with ER in vitro and in yeast and mammalian cells. Activation function-1 (AF1) and AF2 domains of ERs are responsible for the interaction between METTL17 and ERs. Knockdown of METTL17 reduces transcriptional activities of ERα and ERβ in breast cancer cells, whereas METTL17 overexpression increases ERα and ERβ transcriptional activities. Inhibition of METTL17 expression decreases mRNA and protein levels of ER target genes, including PR, cathepsin D, and pS2. Moreover, METTL17 knockdown reduces breast cancer cell growth. These results indicate that METTL17 is a novel coactivator of ERs and may play a role in breast tumorigenesis.
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Affiliation(s)
- Peiyun Du
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, People's Republic of China
| | - Bin Yuan
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, People's Republic of China
| | - Jia Cao
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, People's Republic of China
| | - Jing Zhao
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, People's Republic of China
| | - Lihua Ding
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, People's Republic of China
| | - Lihan Chen
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, People's Republic of China
| | - Sunyang Ying
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, People's Republic of China
| | - Lina Jiang
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, People's Republic of China
| | - Jiajia Lin
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, People's Republic of China
| | - Xiaojie Xu
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, People's Republic of China
| | - Long Cheng
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, People's Republic of China
| | - Qinong Ye
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, People's Republic of China
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Li J, Zhou X, Lan X, Zeng G, Jiang X, Huang Z. Repression of PES1 expression inhibits growth of gastric cancer. Tumour Biol 2015; 37:3043-9. [DOI: 10.1007/s13277-015-4069-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 09/13/2015] [Indexed: 02/08/2023] Open
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Cao P, Feng F, Dong G, Yu C, Feng S, Song E, Shi G, Liang Y, Liang G. Estrogen receptor α enhances the transcriptional activity of ETS-1 and promotes the proliferation, migration and invasion of neuroblastoma cell in a ligand dependent manner. BMC Cancer 2015; 15:491. [PMID: 26122040 PMCID: PMC4486695 DOI: 10.1186/s12885-015-1495-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 06/17/2015] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND It is well known that estrogen receptor α (ERα) participates in the pathogenic progress of breast cancer, hepatocellular carcinoma and head and neck squamous cell carcinoma. In neuroblastoma cells and related cancer clinical specimens, moreover, the ectopic expression of ERα has been identified. However, the detailed function of ERα in the proliferation of neuroblastoma cell is yet unclear. METHODS The transcriptional activity of ETS-1 (E26 transformation specific sequence 1) was measured by luciferase analysis. Western blot assays and Real-time RT-PCR were used to examine the expression of ERα, ETS-1 and its targeted genes. The protein-protein interaction between ERα and ETS-1 was determined by co-IP and GST-Pull down assays. The accumulation of ETS-1 in nuclear was detected by western blot assays, and the recruitment of ETS-1 to its targeted gene's promoter was tested by ChIP assays. Moreover, SH-SY5Y cells' proliferation, anchor-independent growth, migration and invasion were quantified using the MTT, soft agar or Trans-well assay, respectively. RESULTS The transcriptional activity of ETS-1 was significantly increased following estrogen treatment, and this effect was related to ligand-mediated activation of ERα. The interaction between the ERα and ETS-1 was identified, and enhancement of ERα activation would up-regulate the ETS-1 transcription factor activity via modulating its cytoplasm/nucleus translocation and the recruitment of ETS-1 to its target gene's promoter. Furthermore, treatment of estrogen increased proliferation, migration and invasion of neuroblastoma cells, whereas the antagonist of ERα reduced those effects. CONCLUSIONS In this study, we provided evidences that activation of ERα promoted neuroblastoma cells proliferation and up-regulated the transcriptional activity of ETS-1. By investigating the role of ERα in the ETS-1 activity regulation, we demonstrated that ERα may be a novel ETS-1 co-activator and thus a potential therapeutic target in human neuroblastoma treatment.
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Affiliation(s)
- Peng Cao
- Department of Neurosurgery, Institute of Neurology, General Hospital of Shenyang Military Area Command, Shenyang Northern Hospital, 83 Wenhua Road, Shenhe District, Shenyang City, Liaoning Province, 110016, PR China.
| | - Fan Feng
- Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang Northern Hospital, 83 Wenhua Road, Shenhe District, Shenyang City, Liaoning Province, 110016, PR China.
| | - Guofu Dong
- Institute of Radiation Medicine, Military Medical Science Academy of the Chinese PLA, 27 Taiping Road, Beijing City, 100850, PR China.
| | - Chunyong Yu
- Department of Neurosurgery, Institute of Neurology, General Hospital of Shenyang Military Area Command, Shenyang Northern Hospital, 83 Wenhua Road, Shenhe District, Shenyang City, Liaoning Province, 110016, PR China.
| | - Sizhe Feng
- Department of Neurosurgery, Institute of Neurology, General Hospital of Shenyang Military Area Command, Shenyang Northern Hospital, 83 Wenhua Road, Shenhe District, Shenyang City, Liaoning Province, 110016, PR China.
| | - Erlin Song
- Department of Urology, General Hospital of the Chinese PLA, 28 Fuxing Road, Beijing City, 100853, PR China. .,Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, Harbin Medical University, Harbin, 150081, PR China.
| | - Guobing Shi
- Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang Northern Hospital, 83 Wenhua Road, Shenhe District, Shenyang City, Liaoning Province, 110016, PR China.
| | - Yong Liang
- Department of Neurosurgery, Institute of Neurology, General Hospital of Shenyang Military Area Command, Shenyang Northern Hospital, 83 Wenhua Road, Shenhe District, Shenyang City, Liaoning Province, 110016, PR China.
| | - Guobiao Liang
- Department of Neurosurgery, Institute of Neurology, General Hospital of Shenyang Military Area Command, Shenyang Northern Hospital, 83 Wenhua Road, Shenhe District, Shenyang City, Liaoning Province, 110016, PR China.
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Ren W, Lian P, Cheng L, Du P, Guan X, Wang H, Ding L, Gao Z, Huang X, Xiao F, Wang L, Bi X, Ye Q, Wang E. FHL1 inhibits the growth of tongue squamous cell carcinoma cells via G1/S cell cycle arrest. Mol Med Rep 2015; 12:3958-3964. [PMID: 26017856 DOI: 10.3892/mmr.2015.3844] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 04/30/2015] [Indexed: 11/05/2022] Open
Abstract
Four and a half LIM protein 1 (FHL1) has been characterized as a tumor suppressor in various types of tumor. However, the biological function and underlying mechanism of FHL1 in tongue squamous cell carcinoma (TSCC) remain to be elucidated. The present study demonstrated that FHL1 inhibits anchorage‑dependent and ‑independent growth of TSCC cells in vitro and tumor growth in nude mice, as determined by cell proliferation and soft agar assays. Knockdown of FHL1 with FHL1 small interfering RNA (siRNA) promoted tumor growth in nude mice. Mechanistically, flow cytometric analysis showed that knockdown of FHL1 promoted G1/S cell cycle progression. Furthermore, expression of cell cycle‑associated regulators, cyclin D and cyclin E, were detected by western blotting and reverse transcription‑quantitative polymerase chain reaction. Cyclin D and cyclin E were markedly elevated at both the protein and mRNA level in the FHL1 siRNA‑transfected cells. These results suggested that FHL1 has a tumor suppressive role in TSCC and that FHL1 may be a useful target for TSCC gene therapy.
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Affiliation(s)
- Wei Ren
- Department of Stomatology, Anqing Municipal Hospital of Anhui Medical University, Anqing, Anhui 246003, P.R. China
| | - Panfeng Lian
- Department of Stomatology, Anqing Municipal Hospital of Anhui Medical University, Anqing, Anhui 246003, P.R. China
| | - Long Cheng
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, P.R. China
| | - Peiyun Du
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, P.R. China
| | - Xin Guan
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, P.R. China
| | - Hongyuan Wang
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, P.R. China
| | - Lihua Ding
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, P.R. China
| | - Zhenyang Gao
- Department of Stomatology, Medical College of Chinese PLA, Beijing 100853, P.R. China
| | - Xin Huang
- Department of Oral and Maxillofacial Surgery, Beijing Stomatological Hospital, Beijing 100000, P.R. China
| | - Fengjun Xiao
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China
| | - Lisheng Wang
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China
| | - Xiaolin Bi
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, Liaoning 116000, P.R. China
| | - Qinong Ye
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, P.R. China
| | - Enqun Wang
- Department of Stomatology, Anqing Municipal Hospital of Anhui Medical University, Anqing, Anhui 246003, P.R. China
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Shi L, Xia TS, Wei XL, Zhou W, Xue J, Cheng L, Lou P, Li C, Wang Y, Wei JF, Ding Q. Estrogen receptor (ER) was regulated by RNPC1 stabilizing mRNA in ER positive breast cancer. Oncotarget 2015; 6:12264-78. [PMID: 25881544 PMCID: PMC4494937 DOI: 10.18632/oncotarget.3654] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 02/26/2015] [Indexed: 02/05/2023] Open
Abstract
Estrogen receptors (ERs), including ERα and ERβ, mainly mediate the genotype effect of estrogen. ERα is highly expressed in most breast cancers. Endocrine therapy is the most effective and safety adjunctive therapy for ER positive breast cancers. RNPC1, an RNA binding protein (RBP), post-transcriptionally regulating gene expression, is emerging as a critical mechanism for gene regulation in mammalian cells. In this study, we revealed RNPC1's capability of regulating ERα expression. There was a significant correlation between RNPC1 and ERα expression in breast cancer tissues. Ectopic expression of RNPC1 could increase ERα transcript and expression in breast cancer cells, and vice versa. Consistent with this, RNPC1 was able to bind to ERα transcript to increase its stability. Furthermore, overexpression of ERα could decrease the level of RNPC1 transcript and protein. It suggested a novel mechanism by which ERα expression was regulated via stabilizing mRNA. A regulatory feedback loop between RNPC1 and ERα was proved. It indicated that RNPC1 played a crucial role in ERα regulation in ER-positive breast cancers via binding to ERα mRNA. These findings might provide new insights into breast cancer endocrine therapy and ERα research.
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Affiliation(s)
- Liang Shi
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Tian-Song Xia
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Xiao-Long Wei
- Department of Pathology, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Wenbin Zhou
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Jinqiu Xue
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Lin Cheng
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Peipei Lou
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Chunlian Li
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Ying Wang
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Ji-Fu Wei
- Research Division of Clinical Pharmacology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Qiang Ding
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
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Chen L, Li W, Qiu W, Ren W, Li Q, Han B, Zhou L, Cheng L, Zhang H, Ye Q. RSRC1 SUMOylation enhances SUMOylation and inhibits transcriptional activity of estrogen receptor β. FEBS Lett 2015; 589:1476-84. [PMID: 25937118 DOI: 10.1016/j.febslet.2015.04.035] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 04/12/2015] [Accepted: 04/21/2015] [Indexed: 02/07/2023]
Abstract
The transcription factor estrogen receptor β (ERβ) plays roles in the central nervous, endocrine, cardiovascular, and immune systems. ERβ can be SUMOylated. However, the underlying mechanism remains unclear. Here, we show that RSRC1/SRrp53 interacts with ERβ and SUMOylation of RSRC1 is required for regulation of PIAS1-mediated ERβ SUMOylation. RSRC1 promotes ERβ SUMOylation through enhanced interaction between ERβ and PIAS1. RSRC1 represses ERβ transcriptional activity through regulation of ERβ SUMOylation. By establishing RSRC1 as a novel cofactor for SUMOylation, our data provide insight into regulation of ERβ SUMOylation and indicate that SUMOylation of one protein can regulate another protein SUMOylation.
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Affiliation(s)
- Lihan Chen
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China
| | - Weini Li
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China
| | - Weiyi Qiu
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China
| | - Wen Ren
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China
| | - Qincao Li
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China
| | - Baiyu Han
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China
| | - Lei Zhou
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China
| | - Long Cheng
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China.
| | - Hao Zhang
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China; Cardiovascular Drug Research Center, Tianjin Institute of Health and Environmental Medicine, Tianjin 300050, PR China.
| | - Qinong Ye
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China.
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Rajapaksa G, Nikolos F, Bado I, Clarke R, Gustafsson JÅ, Thomas C. ERβ decreases breast cancer cell survival by regulating the IRE1/XBP-1 pathway. Oncogene 2014; 34:4130-41. [PMID: 25347741 DOI: 10.1038/onc.2014.343] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 08/07/2014] [Accepted: 09/04/2014] [Indexed: 01/06/2023]
Abstract
Unfolded protein response (UPR) is an adaptive reaction that allows cancer cells to survive endoplasmic reticulum (EnR) stress that is often induced in the tumor microenvironment because of inadequate vascularization. Previous studies report an association between activation of the UPR and reduced sensitivity to antiestrogens and chemotherapeutics in estrogen receptor α (ERα)-positive and triple-negative breast cancers, respectively. ERα has been shown to regulate the expression of a key mediator of the EnR stress response, the X-box-binding protein-1 (XBP-1). Although network prediction models have associated ERβ with the EnR stress response, its role as regulator of the UPR has not been experimentally tested. Here, upregulation of wild-type ERβ (ERβ1) or treatment with ERβ agonists enhanced apoptosis in breast cancer cells in the presence of pharmacological inducers of EnR stress. Targeting the BCL-2 to the EnR of the ERβ1-expressing cells prevented the apoptosis induced by EnR stress but not by non-EnR stress apoptotic stimuli indicating that ERβ1 promotes EnR stress-regulated apoptosis. Downregulation of inositol-requiring kinase 1α (IRE1α) and decreased splicing of XBP-1 were associated with the decreased survival of the EnR-stressed ERβ1-expressing cells. ERβ1 was found to repress the IRE1 pathway of the UPR by inducing degradation of IRE1α. These results suggest that the ability of ERβ1 to target the UPR may offer alternative treatment strategies for breast cancer.
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Affiliation(s)
- G Rajapaksa
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
| | - F Nikolos
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
| | - I Bado
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
| | - R Clarke
- Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, DC, USA
| | - J-Å Gustafsson
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
| | - C Thomas
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
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Fu J, Cheng L, Wang Y, Yuan P, Xu X, Ding L, Zhang H, Jiang K, Song H, Chen Z, Ye Q. The RNA-binding protein RBPMS1 represses AP-1 signaling and regulates breast cancer cell proliferation and migration. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1853:1-13. [PMID: 25281386 DOI: 10.1016/j.bbamcr.2014.09.022] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 09/14/2014] [Accepted: 09/23/2014] [Indexed: 12/01/2022]
Abstract
The activator protein-1 (AP-1) transcription factor complex plays a crucial role in tumor growth and progression. However, how AP-1 transcriptional activity is repressed is not fully understood. Here, we show that RNA-binding protein with multiple splicing 1 (RBPMS1) physically and functionally interacts with AP-1 in vitro and in vivo. The RNA-recognition motif (RRM) and C-terminus of the RBPMS1 isoforms RBPMS1A and RBPMS1C, but not RBPMS1B, interacted with cFos, a member of the AP-1 family that dimerizes with cJun to stimulate AP-1 transcriptional activity. RBPMS1 did not associate with Jun proteins. RBPMS1A and RBPMS1C bound to the basic leucine zipper (bZIP) domain of cFos that mediates dimerization of AP-1 proteins. In addition, RBPMS1A-C interacted with the transcription factor Smad3, which was shown to interact with cJun and increase AP-1 transcriptional activity. RBPMS1 inhibited c-Fos or Smad3-mediated AP-1 transactivation and the expression of AP-1 target genes known to be the key regulators of cancer growth and progression, including vascular endothelial growth factor (VEGF) and cyclin D1. Mechanistically, RBPMS1 blocks the formation of the cFos/cJun or Smad3/cJun complex as well as the recruitment of cFos or Smad3 to the promoters of AP-1 target genes. In cultured cells and a mouse xenograft model, RBPMS1 inhibited the growth and migration of breast cancer cells through c-Fos or Smad3. These data suggest that RBPMS1 is a critical repressor of AP-1 signaling and RBPMS1 activation may be a useful strategy for cancer treatment.
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Affiliation(s)
- Jie Fu
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China; Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Long Cheng
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China
| | - Yu Wang
- School of Life Sciences, Shandong University, Shandong, China
| | - Ping Yuan
- Fujian Center for Disease Control and Prevention, Fujian, China
| | - Xiaojie Xu
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China
| | - Lihua Ding
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China
| | - Hao Zhang
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China
| | - Kai Jiang
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China
| | - Haifeng Song
- Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Zhongwu Chen
- Department of Interventional Radiology, The Affiliated First Hospital, Fujian Medical University, Fujian, China.
| | - Qinong Ye
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China.
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