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Chen X, Tu J, Yang M, Wang Y, Liu B, Qiu H, Yuan X. RUNX1-MUC13 Interaction Activates Wnt/β-Catenin Signaling Implications for Colorectal Cancer Metastasis. Int J Biol Sci 2024; 20:4999-5026. [PMID: 39309442 PMCID: PMC11414392 DOI: 10.7150/ijbs.98396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 09/07/2024] [Indexed: 09/25/2024] Open
Abstract
Background: Colorectal cancer (CRC) remains a significant global health challenge, often characterized by late-stage metastasis and poor prognosis. The Runt-related transcription factor 1 (RUNX1) plays a dual role as both an oncogene and a tumor suppressor in various cancers, including CRC. However, the specific regulatory mechanisms of RUNX1 in CRC, particularly its direct roles, are not fully understood. Objective: This study aimed to investigate the role of RUNX1 in CRC progression and its interaction with Mucin 13 (MUC13) as a potential regulatory target. Methods: RUNX1 expression was analyzed in CRC tissues and cell lines compared to controls. In vitro and in vivo assays were conducted to assess the effects of RUNX1 overexpression and knockdown on cell behavior. ChIP-seq and RNA-seq analyses were performed to identify RUNX1 targets, with a focus on MUC13. Results: RUNX1 expression was significantly upregulated in CRC tissues and cells, correlating with advanced pathological characteristics and poor patient outcomes. RUNX1 overexpression enhanced CRC cell proliferation, migration, invasion, and G2/M phase arrest, while its knockdown had the opposite effects. MUC13 was identified as a direct transcriptional target of RUNX1, with its expression contributing to the activation of the Wnt/β-catenin signaling pathway. Disruption of MUC13 partially reversed the malignant phenotypes induced by RUNX1. Conclusion: RUNX1 promotes CRC progression by upregulating MUC13 and activating the Wnt/β-catenin pathway. This RUNX1-MUC13 axis represents a potential therapeutic target for managing CRC.
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Affiliation(s)
| | | | | | | | - Bo Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hong Qiu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Shi Q, Song G, Song L, Wang Y, Ma J, Zhang L, Yuan E. Unravelling the function of prdm16 in human tumours: A comparative analysis of haematologic and solid tumours. Biomed Pharmacother 2024; 178:117281. [PMID: 39137651 DOI: 10.1016/j.biopha.2024.117281] [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: 04/26/2024] [Revised: 08/03/2024] [Accepted: 08/07/2024] [Indexed: 08/15/2024] Open
Abstract
Extensive research has shown that PR domain 16 (PRDM16) plays a critical role in adipose tissue metabolism, including processes such as browning and thermogenesis of adipocytes, beigeing of adipocytes, and adipogenic differentiation of myoblasts. These functions have been associated with diseases such as obesity and diabetes. Additionally, PRDM16 has been correlated with various other conditions, including migraines, heterochromatin abnormalities, metabolic syndrome, cardiomyopathy, sarcopenia, nonsyndromic cleft lip, and essential hypertension, among others. However, there is currently no systematic or comprehensive conclusion regarding the mechanism of PRDM16 in human tumours, including haematologic and solid tumours. The aim of this review is to provide an overview of the research progress on PRDM16 in haematologic and solid tumours by incorporating recent literature findings. Furthermore, we explore the prospects of PRDM16 in the precise diagnosis and treatment of human haematologic and solid tumours.
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Affiliation(s)
- Qianqian Shi
- Department of Laboratory Medicine, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Zhengzhou Key Laboratory for In Vitro Diagnosis of Hypertensive Disorders of Pregnancy, Zhengzhou, Henan 450052, China; Tianjian Laboratory of Advanced Biomedical Sciences, Institute of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan 450000, China.
| | - Guangyong Song
- Department of Laboratory Medicine, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Liying Song
- Department of Laboratory Medicine, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Zhengzhou Key Laboratory for In Vitro Diagnosis of Hypertensive Disorders of Pregnancy, Zhengzhou, Henan 450052, China
| | - Yu Wang
- Department of Laboratory Medicine, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Zhengzhou Key Laboratory for In Vitro Diagnosis of Hypertensive Disorders of Pregnancy, Zhengzhou, Henan 450052, China
| | - Jun Ma
- Department of Laboratory Medicine, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Zhengzhou Key Laboratory for In Vitro Diagnosis of Hypertensive Disorders of Pregnancy, Zhengzhou, Henan 450052, China
| | - Linlin Zhang
- Department of Laboratory Medicine, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Zhengzhou Key Laboratory for In Vitro Diagnosis of Hypertensive Disorders of Pregnancy, Zhengzhou, Henan 450052, China; Tianjian Laboratory of Advanced Biomedical Sciences, Institute of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan 450000, China.
| | - Enwu Yuan
- Department of Laboratory Medicine, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Zhengzhou Key Laboratory for In Vitro Diagnosis of Hypertensive Disorders of Pregnancy, Zhengzhou, Henan 450052, China; Tianjian Laboratory of Advanced Biomedical Sciences, Institute of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan 450000, China.
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3
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Wang L, Peng X, Ma C, Hu L, Li M, Wang Y. Research progress of epithelial-mesenchymal transformation-related transcription factors in peritoneal metastases. J Cancer 2024; 15:5367-5375. [PMID: 39247601 PMCID: PMC11375557 DOI: 10.7150/jca.98409] [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: 05/14/2024] [Accepted: 08/09/2024] [Indexed: 09/10/2024] Open
Abstract
Metastasis is the leading cause of mortality in patients with malignant tumors, particularly characterized by peritoneal metastases originating from gastric, ovarian, and colorectal cancers. Regarded as the terminal phase of tumor progression, peritoneal metastasis presents limited therapeutic avenues and is associated with a dismal prognosis for patients. The epithelial-mesenchymal transition (EMT) is a crucial phenomenon in which epithelial cells undergo significant changes in both morphology and functionality, transitioning to a mesenchymal-like phenotype. This transition plays a pivotal role in facilitating tumor metastasis, with transcription factors being key mediators of EMT's effects. Consequently, we provide a retrospective summary of the efforts to identify specific targets among EMT-related transcription factors, aimed at modulating the onset and progression of peritoneal metastatic cancer. This summary offers vital theoretical underpinnings for developing treatment strategies against peritoneal metastasis.
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Affiliation(s)
- Lei Wang
- Institute of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Xiaobei Peng
- Suzhou Medical College of Soochow University, Soochow University, Suzhou 215123, China
| | - Chang Ma
- Suzhou Medical College of Soochow University, Soochow University, Suzhou 215123, China
| | - Lin Hu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, Jiangsu, China
| | - Min Li
- Institute of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Yuhong Wang
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, China
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Hu JL, Guo ZJ, Wang C, Yan J, Yang H. Ovarian serous carcinoma with stomach metastasis: a rare case report and literature review. J Int Med Res 2024; 52:3000605241245000. [PMID: 38635893 PMCID: PMC11032054 DOI: 10.1177/03000605241245000] [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: 10/19/2023] [Accepted: 03/15/2024] [Indexed: 04/20/2024] Open
Abstract
Ovarian cancer is a common tumor among women. It is often asymptomatic in the early stages, with most cases already at stage III to IVE at the time of diagnosis. Direct spread and lymphatic metastasis are the primary modes of metastasis, whereas hematogenous spread is rare. An initial diagnosis of ovarian cancer that has metastasized to the stomach is also uncommon. Therefore, clear treatment methods and prognostic data for such metastasis are lacking. In our hospital, we encountered a patient with an initial imaging diagnosis of a gastric tumor and a history of an ovarian tumor with endoscopic abdominal metastasis. Based on the characteristics of the case, the two tumors were considered to be the same. After chemotherapy, a partial response was observed in the stomach and pelvic lesions, suggesting the effectiveness of the treatment. Through three treatments of recurrence, gastroscopy confirmed the stomach to be a metastatic site. Therefore, determining the primary source of advanced tumors is crucial in guiding treatment decisions. Clinicians must approach this comprehensively, relying on thorough evaluation and personal experience.
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Affiliation(s)
- Jia-Li Hu
- Department of Oncology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Zhao-Jiao Guo
- Department of Oncology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Chun Wang
- Department of Oncology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Jun Yan
- Department of Oncology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Hao Yang
- Department of Oncology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
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5
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Chen YY, Liu H, Li LY, Li LJ, Wang HQ, Song J, Wu YH, Guan J, Xing LM, Wang GJ, Qu W, Liu H, Wang XM, Shao ZH, Fu R. [Role and clinical significance of MUC4 gene mutations in thrombotic events in patients with classic paroxysmal nocturnal hemoglobinuria]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2023; 44:561-566. [PMID: 37749036 PMCID: PMC10509626 DOI: 10.3760/cma.j.issn.0253-2727.2023.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Indexed: 09/27/2023]
Abstract
Objective: This study aimed to investigate the role and clinical significance of MUC4 gene mutations in thrombotic events in patients with classic paroxysmal nocturnal hemoglobinuria (PNH) patients. Methods: A retrospective analysis was conducted on the clinical data and gene sequencing results of 45 patients with classic PNH admitted to the Department of Hematology, Tianjin Medical University General Hospital, from June 2018 to February 2022. MUC4 gene mutations in patients with classic PNH were summarized, and the risk factors for thrombotic events in these patients were analyzed. Additionally, the effects of MUC4 gene mutations on the cumulative incidence and survival of thrombotic events in patients with classic PNH were determined. Results: The detection rate of MUC4 gene mutations in patients with classic PNH who experienced thrombotic events (thrombotic group) was 68.8% (11/16), which was significantly higher than that in the non-thrombotic group [10.3% (3/29) ] (P<0.001). All mutations occurred in exon 2. MUC4 mutation (OR=20.815, P=0.010) was identified as an independent risk factor for thrombotic events in patients with classic PNH. The cumulative incidence of thrombotic events was 78.6% (11/14) in the MUC4 gene mutation group (mutation group) and 16.1% (5/31) in the non-mutation group, showing a statistically significant difference between the two groups (P<0.001). Survival analysis showed a lower overall survival (OS) rate in the thrombotic group compared with that in the non-thrombotic group [ (34.4±25.2) % vs. (62.7±19.3) % ] (P=0.045). The OS rate of patients was (41.7±29.9) % in the mutation group and (59.1±18.3) % in the non-mutation group (P=0.487) . Conclusion: MUC4 gene mutations are associated with an increased incidence of thrombotic events in classic PNH patients, highlighting their role as independent risk factors for thrombosis in this population. These mutations can be considered a novel predictive factor that aids in evaluating the risk of thrombosis in patients with classic PNH.
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Affiliation(s)
- Y Y Chen
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - H Liu
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - L Y Li
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - L J Li
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - H Q Wang
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - J Song
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Y H Wu
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - J Guan
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - L M Xing
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - G J Wang
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - W Qu
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - H Liu
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - X M Wang
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Z H Shao
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - R Fu
- Tianjin Medical University General Hospital, Tianjin 300052, China
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6
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Xiao X, Miao X, Duan S, Liu S, Cao Q, Wu R, Tao C, Zhao J, Qu Q, Markiewicz A, Peng R, Chen Y, Żaczek A, Liu J. Single-Cell Enzymatic Screening for Epithelial Mesenchymal Transition with an Ultrasensitive Superwetting Droplet-Array Microchip. SMALL METHODS 2023:e2300096. [PMID: 37086121 DOI: 10.1002/smtd.202300096] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 03/16/2023] [Indexed: 05/03/2023]
Abstract
The phenotypic changes of circulating tumor cells (CTCs) during the epithelial-mesenchymal transition (EMT) have been a hot topic in tumor biology and cancer therapeutic development. Here, an integrated platform of single-cell fluorescent enzymatic assays with superwetting droplet-array microchips (SDAM) for ultrasensitive functional screening of epithelial-mesenchymal sub-phenotypes of CTCs is reported. The SDAM can generate high-density, volume well-defined droplet (0.66 nL per droplet) arrays isolating single tumor cells via a discontinuous dewetting effect. It enables sensitive detection of MMP9 enzyme activities secreted by single tumor cells, correlating to their epithelial-mesenchymal sub-phenotypes. In the pilot clinical double-blind tests, the authors have demonstrated that SDAM assays allow for rapid identification and functional screening of CTCs with different epithelial-mesenchymal properties. The consistency with the clinical outcomes validates the usefulness of single-cell secreted MMP9 as a biomarker for selective CTC screening and tumor metastasis monitoring. Convenient addressing and recovery of individual CTCs from SDAM have been demonstrated for gene mutation sequencing, immunostaining, and transcriptome analysis, revealing new understandings of the signaling pathways between MMP9 secretion and the EMT regulation of CTCs. The SDAM approach combined with sequencing technologies promises to explore the dynamic EMT plasticity of tumors at the single-cell level.
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Affiliation(s)
- Xiang Xiao
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Joint International Research Laboratory of Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P. R. China
| | - Xinxing Miao
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Joint International Research Laboratory of Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P. R. China
| | - Shanzhou Duan
- Department of thoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215123, P. R. China
| | - Sidi Liu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Joint International Research Laboratory of Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P. R. China
| | - Qinghua Cao
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Joint International Research Laboratory of Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P. R. China
| | - Renfei Wu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Joint International Research Laboratory of Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P. R. China
| | - Chengcheng Tao
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Joint International Research Laboratory of Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P. R. China
| | - Jian Zhao
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Joint International Research Laboratory of Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P. R. China
| | - Qing Qu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Joint International Research Laboratory of Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P. R. China
| | - Aleksandra Markiewicz
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdansk, Gdańsk, 80-211, Poland
| | - Rui Peng
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Joint International Research Laboratory of Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P. R. China
| | - Yongbing Chen
- Department of thoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215123, P. R. China
| | - Anna Żaczek
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdansk, Gdańsk, 80-211, Poland
| | - Jian Liu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Joint International Research Laboratory of Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, P. R. China
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7
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Cutano V, Ferreira Mendes JM, Escudeiro-Lopes S, Machado S, Vinaixa Forner J, Gonzales-Morena JM, Prevorovsky M, Zemlianski V, Feng Y, Kralova Viziova P, Hartmanova A, Malcekova B, Jakoube P, Iyer S, Keckesova Z. LACTB exerts tumor suppressor properties in epithelial ovarian cancer through regulation of Slug. Life Sci Alliance 2023; 6:e202201510. [PMID: 36375842 PMCID: PMC9664245 DOI: 10.26508/lsa.202201510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 10/24/2022] [Accepted: 10/25/2022] [Indexed: 11/16/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a cellular mechanism used by cancer cells to acquire migratory and stemness properties. In this study, we show, through in vitro, in vivo, and 3D culture experiments, that the mitochondrial protein LACTB manifests tumor suppressor properties in ovarian cancer. We show that LACTB is significantly down-regulated in epithelial ovarian cancer cells and clinical tissues. Re-expression of LACTB negatively effects the growth of cancer cells but not of non-tumorigenic cells. Mechanistically, we show that LACTB leads to differentiation of ovarian cancer cells and loss of their stemness properties, which is achieved through the inhibition of the EMT program and the LACTB-dependent down-regulation of Snail2/Slug transcription factor. This study uncovers a novel role of LACTB in ovarian cancer and proposes new ways of counteracting the oncogenic EMT program in this model system.
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Affiliation(s)
- Valentina Cutano
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | | | - Sara Escudeiro-Lopes
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Susana Machado
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Judith Vinaixa Forner
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Juan M Gonzales-Morena
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Martin Prevorovsky
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Viacheslav Zemlianski
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Yuxiong Feng
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Petra Kralova Viziova
- The Czech Center for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czech Republic
| | - Andrea Hartmanova
- The Czech Center for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czech Republic
| | - Beata Malcekova
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Pavel Jakoube
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Sonia Iyer
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA
| | - Zuzana Keckesova
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
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Protein Glycosylation as Biomarkers in Gynecologic Cancers. Diagnostics (Basel) 2022; 12:diagnostics12123177. [PMID: 36553184 PMCID: PMC9777642 DOI: 10.3390/diagnostics12123177] [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: 09/25/2022] [Revised: 12/01/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
Gynecologic cancers are the leading cause of death in women. Endometrial, ovarian, and cervical cancer are the three main types of gynecologic cancers. Poor prognoses and high mortality rates of advanced-stage cancer are still challenges of all three types. Diagnostic tools for early cancer detection could be the cornerstone for further cancer treatment and prevention. Glycosylation plays a vital role in cell proliferation, adhesion, motility, and angiogenesis, and is aberrantly expressed in cancer cells. Alterations of glycosylation may represent promising biomarkers with potential diagnostic and monitoring applications, as well as disease prognosis. Many glycosylated biomarkers, including glycoprotein, glycan, and enzyme, were discovered and well-studied for application in gynecologic cancers. Some of them have been developed as targets for cancer treatment. The use of certain biomarkers for diagnostics and monitoring of gynecologic cancers has clinical advantages, as it is quantitative, comparable, convenient, and inexpensive. However, one of the single markers have sufficient sensitivity for the screening of gynecologic cancers. In this review, we introduced the details of glycosylation and the current application of glycosylated biomarkers in these three cancers. Moreover, we also reviewed the different roles of each biomarker in other cancers and aimed to understand these glycosylated biomarkers comprehensively.
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9
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The role of tumour microenvironment-driven miRNAs in the chemoresistance of muscle-invasive bladder cancer-a review. Urol Oncol 2022; 40:133-148. [PMID: 35246373 DOI: 10.1016/j.urolonc.2022.01.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 01/17/2022] [Accepted: 01/23/2022] [Indexed: 12/27/2022]
Abstract
Successful treatment for muscle-invasive bladder cancer is challenged by the ability of cancer cells to resist chemotherapy. While enormous progress has been made toward understanding the divergent molecular mechanisms underlying chemoresistance, the heterogenous interplay between the bladder tumour and its microenvironment presents significant challenges in comprehending the occurrence of chemoresistance. The last decade has seen exponential interest in the exploration of microRNA (miRNA) as a tool in the management of chemoresistance. In this review, we highlight the miRNAs involved in the tumour microenvironment crosstalk that contributes to the chemoresistance in bladder cancer. Decrypting the role of miRNAs in the interplay beholds scope for future clinical translational application in managing the long-standing concerns of chemoresistance in muscle-invasive bladder cancer.
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10
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Extracellular vesicles in ovarian cancer chemoresistance, metastasis, and immune evasion. Cell Death Dis 2022; 13:64. [PMID: 35042862 PMCID: PMC8766448 DOI: 10.1038/s41419-022-04510-8] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 12/09/2021] [Accepted: 12/30/2021] [Indexed: 12/13/2022]
Abstract
Chemoresistance and metastasis are the major challenges for the current ovarian cancer treatment. Understanding the mechanisms of ovarian cancer progression and metastasis is critically important for developing novel therapies. The advances in extracellular vesicles (EVs) research in recent years have attracted extensive attention. EVs contain a variety of proteins, RNAs, DNAs, and metabolites. Accumulating evidence indicates that ovarian cancer cells secrete a large amount of EVs, playing an important role in tumor progression and recurrence. In the microenvironment of ovarian tumor, EVs participate in the information transmission between stromal cells and immune cells, promoting the immune escape of ovarian cancer cells and facilitating cancer metastasis. Here, we review the recent advances of EVs in chemoresistance, mechanisms of metastasis, and immune evasion of ovarian cancer. Furthermore, we also discuss the challenges of EV research and future application of EVs as promising biomarker sources in response to therapy and in therapy-delivery approaches for ovarian cancer patients.
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11
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OUP accepted manuscript. Glycobiology 2022; 32:556-579. [DOI: 10.1093/glycob/cwac014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 02/22/2022] [Accepted: 03/09/2022] [Indexed: 11/12/2022] Open
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12
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Dreyer CA, VanderVorst K, Free S, Rowson-Hodel A, Carraway KL. The role of membrane mucin MUC4 in breast cancer metastasis. Endocr Relat Cancer 2021; 29:R17-R32. [PMID: 34726614 PMCID: PMC8697635 DOI: 10.1530/erc-21-0083] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 11/01/2021] [Indexed: 11/08/2022]
Abstract
A major barrier to the emergence of distant metastases is the survival of circulating tumor cells (CTCs) within the vasculature. Lethal stressors, including shear forces from blood flow, anoikis arising from cellular detachment, and exposure to natural killer cells, combine to subvert the ability of primary tumor cells to survive and ultimately seed distant lesions. Further attenuation of this rate-limiting process via therapeutic intervention offers a very attractive opportunity for improving cancer patient outcomes, in turn prompting the need for a deeper understanding of the molecular and cellular mechanisms underlying CTC viability. MUC4 is a very large and heavily glycosylated protein expressed at the apical surfaces of the epithelia of a variety of tissues, is involved in cellular growth signaling and adhesiveness, and contributes to the protection and lubrication of cellular linings. Analysis of patient-matched breast tumor specimens has demonstrated that MUC4 protein levels are upregulated in metastatic lesions relative to primary tumor among all breast tumor subtypes, pointing to a possible selective advantage for MUC4 overexpression in metastasis. Analysis of a genetically engineered mouse model of HER2-positive breast cancer has demonstrated that metastatic efficiency is markedly suppressed with Muc4 deletion and Muc4-knockout tumor cells are poorly associated with platelets and white blood cells known to support CTC viability. In this review, we discuss the diverse roles of MUC4 in tumor progression and metastasis and propose that intervening in MUC4 intercellular interactions with binding partners on blood-borne aggregating cells could potentially thwart breast cancer metastatic efficiency.
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Affiliation(s)
| | | | | | | | - Kermit L. Carraway
- To whom correspondence should be addressed: Kermit Carraway, Research Building III, Room 1100B, 4645 2nd Avenue, Sacramento, CA 95817, P: (916) 734-3114,
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13
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Kim YD, Choi YS, Na HG, Song SY, Bae CH. MUC4 Silencing Inhibits TGF-β1-Induced Epithelial-Mesenchymal Transition via the ERK1/2 Pathway in Human Airway Epithelial NCI-H292 Cells. Mol Biol 2021; 55:565-572. [DOI: 10.1134/s0026893321030079] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/17/2020] [Accepted: 08/19/2020] [Indexed: 07/25/2023]
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14
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Marimuthu S, Rauth S, Ganguly K, Zhang C, Lakshmanan I, Batra SK, Ponnusamy MP. Mucins reprogram stemness, metabolism and promote chemoresistance during cancer progression. Cancer Metastasis Rev 2021; 40:575-588. [PMID: 33813658 PMCID: PMC9635594 DOI: 10.1007/s10555-021-09959-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/15/2021] [Indexed: 02/06/2023]
Abstract
Mucins are high-molecular-weight glycoproteins dysregulated in aggressive cancers. The role of mucins in disease progression, tumor proliferation, and chemotherapy resistance has been studied extensively. This article provides a comprehensive review of mucin's function as a physical barrier and the implication of mucin overexpression in impeded drug delivery to solid tumors. Mucins regulate the epithelial to mesenchymal transition (EMT) of cancer cells via several canonical and non-canonical oncogenic signaling pathways. Furthermore, mucins play an extensive role in enriching and maintaining the cancer stem cell (CSC) population, thereby sustaining the self-renewing and chemoresistant cellular pool in the bulk tumor. It has recently been demonstrated that mucins regulate the metabolic reprogramming during oncogenesis and cancer progression, which account for tumor cell survival, proliferation, and drug-resistance. This review article focuses on delineating mucin's role in oncogenic signaling and aberrant regulation of gene expressions, culminating in CSC maintenance, metabolic rewiring, and development of chemoresistance, tumor progression, and metastasis.
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Affiliation(s)
- Saravanakumar Marimuthu
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Sanchita Rauth
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Koelina Ganguly
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Chunmeng Zhang
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Imayavaramban Lakshmanan
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
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15
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Olea-Flores M, Juárez-Cruz JC, Zuñiga-Eulogio MD, Acosta E, García-Rodríguez E, Zacapala-Gomez AE, Mendoza-Catalán MA, Ortiz-Ortiz J, Ortuño-Pineda C, Navarro-Tito N. New Actors Driving the Epithelial-Mesenchymal Transition in Cancer: The Role of Leptin. Biomolecules 2020; 10:E1676. [PMID: 33334030 PMCID: PMC7765557 DOI: 10.3390/biom10121676] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 12/12/2020] [Accepted: 12/13/2020] [Indexed: 12/24/2022] Open
Abstract
Leptin is a hormone secreted mainly by adipocytes; physiologically, it participates in the control of appetite and energy expenditure. However, it has also been linked to tumor progression in different epithelial cancers. In this review, we describe the effect of leptin on epithelial-mesenchymal transition (EMT) markers in different study models, including in vitro, in vivo, and patient studies and in various types of cancer, including breast, prostate, lung, and ovarian cancer. The different studies report that leptin promotes the expression of mesenchymal markers and a decrease in epithelial markers, in addition to promoting EMT-related processes such as cell migration and invasion and poor prognosis in patients with cancer. Finally, we report that leptin has the greatest biological relevance in EMT and tumor progression in breast, lung, prostate, esophageal, and ovarian cancer. This relationship could be due to the key role played by the enriched tumor microenvironment in adipose tissue. Together, these findings demonstrate that leptin is a key biomolecule that drives EMT and metastasis in cancer.
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Affiliation(s)
- Monserrat Olea-Flores
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (M.O.-F.); (J.C.J.-C.); (M.D.Z.-E.); (E.A.); (E.G.-R.)
| | - Juan C. Juárez-Cruz
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (M.O.-F.); (J.C.J.-C.); (M.D.Z.-E.); (E.A.); (E.G.-R.)
| | - Miriam D. Zuñiga-Eulogio
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (M.O.-F.); (J.C.J.-C.); (M.D.Z.-E.); (E.A.); (E.G.-R.)
| | - Erika Acosta
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (M.O.-F.); (J.C.J.-C.); (M.D.Z.-E.); (E.A.); (E.G.-R.)
| | - Eduardo García-Rodríguez
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (M.O.-F.); (J.C.J.-C.); (M.D.Z.-E.); (E.A.); (E.G.-R.)
| | - Ana E. Zacapala-Gomez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (A.E.Z.-G.); (M.A.M.-C.); (J.O.-O.)
| | - Miguel A. Mendoza-Catalán
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (A.E.Z.-G.); (M.A.M.-C.); (J.O.-O.)
| | - Julio Ortiz-Ortiz
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (A.E.Z.-G.); (M.A.M.-C.); (J.O.-O.)
| | - Carlos Ortuño-Pineda
- Laboratorio de Ácidos Nucleicos y Proteinas, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico;
| | - Napoleón Navarro-Tito
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (M.O.-F.); (J.C.J.-C.); (M.D.Z.-E.); (E.A.); (E.G.-R.)
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16
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Zhao H, Xu F, Li J, Ni M, Wu X. A Population-Based Study on Liver Metastases in Women With Newly Diagnosed Ovarian Cancer. Front Oncol 2020; 10:571671. [PMID: 33102229 PMCID: PMC7545579 DOI: 10.3389/fonc.2020.571671] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 08/28/2020] [Indexed: 11/17/2022] Open
Abstract
Aim: The purpose of this study was to analyze the incidence, clinical characteristics, prognostic factors and survival of ovarian cancer patients with liver metastases upon initial diagnosis. Methods: Patients with ovarian cancer liver metastases upon initial diagnosis between 2010 and 2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate logistic regression was performed to identify the predictors of the presence of liver metastases in newly diagnosed ovarian cancer patients. Overall survival (OS) was assessed using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression was conducted to determine the independent prognostic factors for OS. Results: A total of 1,744 ovarian cancer patients with liver metastases was identified from the SEER database, accounting for 6.7% of the entire ovarian cancer patients. As to the unique distant organ provided by SEER, liver was the most common metastatic site of ovarian cancer (4.65%). Age, race, laterality, histology, pathological grade, extrahepatic sites, stage of tumor were the predictors of the presence with liver metastases revealed by multivariable logistic regression model. Median OS for the patients with liver metastases at initial diagnosis of ovarian cancer was 16.0 months. Multivariate Cox regression model confirmed race, histology, extrahepatic metastatic sites, surgery and marital status were independent prognostic factors for OS. Conclusion: The study provided population-based estimates of the incidence and prognosis of newly diagnosed ovary cancer patients with liver metastases, which could be potentially used for the risk assessment and individualized treatment.
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Affiliation(s)
- Haiyun Zhao
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fei Xu
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jiajia Li
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Mengdong Ni
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xiaohua Wu
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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17
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Yao X, Ajani JA, Song S. Molecular biology and immunology of gastric cancer peritoneal metastasis. Transl Gastroenterol Hepatol 2020; 5:57. [PMID: 33073052 DOI: 10.21037/tgh.2020.02.08] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 02/03/2020] [Indexed: 12/24/2022] Open
Abstract
Peritoneal metastases occur in 55-60% of patients with gastric cancer (GC) and are associated with a 2% 5-year overall survival rate. There are limited treatment options for these patients, and no targeted therapy or immunotherapy is available. Rational therapeutic targets remain to be found. In this review, we present the published literature and our own recent experience in molecular biology to identify important molecules and signaling pathways as well as cellular immunity involved in the peritoneal metastasis of GC. We also suggest potential novel strategies for improving the outcomes of GC patients with peritoneal metastasis.
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Affiliation(s)
- Xiaodan Yao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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18
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Mallya K, Haridas D, Seshacharyulu P, Pothuraju R, Junker WM, Krishn SR, Muniyan S, Vengoji R, Batra SK, Rachagani S. Acinar transformed ductal cells exhibit differential mucin expression in a tamoxifen-induced pancreatic ductal adenocarcinoma mouse model. Biol Open 2020; 9:bio052878. [PMID: 32709695 PMCID: PMC7502593 DOI: 10.1242/bio.052878] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 07/16/2020] [Indexed: 11/24/2022] Open
Abstract
Pancreatic cancer (PC) is acquired postnatally; to mimic this scenario, we developed an inducible KrasG12D; Ptf1a-CreER™ (iKC) mouse model, in which Kras is activated postnatally at week 16 upon tamoxifen (TAM) administration. Upon TAM treatment, iKC mice develop pancreatic intraepithelial neoplasia (PanIN) lesions and PC with metastasis at the fourth and fortieth weeks, respectively, and exhibited acinar-to-ductal metaplasia (ADM) and transdifferentiation. Kras activation upregulated the transcription factors Ncoa3, p-cJun and FoxM1, which in turn upregulated expression of transmembrane mucins (Muc1, Muc4 and Muc16) and secretory mucin (Muc5Ac). Interestingly, knockdown of KrasG12D in multiple PC cell lines resulted in downregulation of MUC1, MUC4, MUC5AC and MUC16. In addition, iKC mice exhibited ADM and transdifferentiation. Our results show that the iKC mouse more closely mimics human PC development and can be used to investigate pancreatic ductal adenocarcinoma (PDAC) biomarkers, early onset of PDAC, and ADM. The iKC model can also be used for preclinical strategies such as targeting mucin axis alone or in combination with neo-adjuvant, immunotherapeutic approaches and to monitor chemotherapy response.
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Affiliation(s)
- Kavita Mallya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Dhanya Haridas
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Parthasarathy Seshacharyulu
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Ramesh Pothuraju
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Wade M Junker
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
- Sanguine Diagnostics and Therapeutics, Inc., Omaha, NE 68106-1423, USA
| | - Shiv Ram Krishn
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Sakthivel Muniyan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Raghupathy Vengoji
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68106, USA
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
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19
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Sohn SH, Sul HJ, Kim B, Kim BJ, Kim HS, Zang DY. Tepotinib Inhibits the Epithelial-Mesenchymal Transition and Tumor Growth of Gastric Cancers by Increasing GSK3β, E-Cadherin, and Mucin 5AC and 6 Levels. Int J Mol Sci 2020; 21:ijms21176027. [PMID: 32825724 PMCID: PMC7503648 DOI: 10.3390/ijms21176027] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 08/19/2020] [Accepted: 08/19/2020] [Indexed: 12/24/2022] Open
Abstract
Aberrant expression of mucins (MUCs) can promote the epithelial–mesenchymal transition (EMT), which leads to enhanced tumorigenesis. Carcinogenesis-related pathways involving c-MET and β-catenin are associated with MUCs. In this study, we characterized the expression of EMT-relevant proteins including MET, β-catenin, and E-cadherin in human gastric cancer (GC) cell lines, and further characterized the differential susceptibility of these cell lines compared with the c-MET inhibitor tepotinib. We assessed the antitumor activity of tepotinib in GC cell lines. The effects of tepotinib on cell viability, apoptotic cell death, EMT, and c-MET and β-catenin signaling were evaluated by 3-(4,5 dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl)-2H-tetrazolium (MTS), flow cytometry, Western blotting, and qRT-PCR. The antitumor efficacy was assessed in MKN45 xenograft mice. Tepotinib treatment induced apoptosis in c-MET-amplified SNU620, MKN45, and KATO III cells, but had no effect on c-MET-reduced MKN28 or AGS cells. Tepotinib treatment also significantly reduced the protein levels of phosphorylated and total c-MET, phosphorylated and total ERK, β-catenin, and c-MYC in SNU620 and MKN45 cells. In contrast, this drug was only slightly active against KATO III cells. Notably, tepotinib significantly reduced the expression of EMT-promoting genes such as MMP7, COX-2, WNT1, MUC5B, and c-MYC in c-MET-amplified GC cells and increased the expression of EMT-suppressing genes such as MUC5AC, MUC6, GSK3β, and E-cadherin. In a mouse model, tepotinib exhibited good antitumor growth activity along with increased E-cadherin and decreased phosphorylated c-MET (phospho-c-MET) protein levels. Collectively, these results suggest that tepotinib suppresses tumor growth and migration by negatively regulating c-MET-induced EMT. These findings provide new insights into the mechanism by which MUC5AC and MUC6 contribute to GC progression.
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Affiliation(s)
- Sung-Hwa Sohn
- Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang 14066, Korea; (S.-H.S.); (H.J.S.); (B.K.)
| | - Hee Jung Sul
- Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang 14066, Korea; (S.-H.S.); (H.J.S.); (B.K.)
| | - Bohyun Kim
- Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang 14066, Korea; (S.-H.S.); (H.J.S.); (B.K.)
| | - Bum Jun Kim
- Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Korea; (B.J.K.); (H.S.K.)
| | - Hyeong Su Kim
- Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Korea; (B.J.K.); (H.S.K.)
| | - Dae Young Zang
- Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang 14066, Korea; (S.-H.S.); (H.J.S.); (B.K.)
- Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Korea; (B.J.K.); (H.S.K.)
- Correspondence: ; Tel.: +82-31-380-4167
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20
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Yousefi M, Dehghani S, Nosrati R, Ghanei M, Salmaninejad A, Rajaie S, Hasanzadeh M, Pasdar A. Current insights into the metastasis of epithelial ovarian cancer - hopes and hurdles. Cell Oncol (Dordr) 2020; 43:515-538. [PMID: 32418122 DOI: 10.1007/s13402-020-00513-9] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/27/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Ovarian cancer is the most lethal gynecologic cancer and the fifth leading cause of cancer-related mortality in women worldwide. Despite various attempts to improve the diagnosis and therapy of ovarian cancer patients, the survival rate for these patients is still dismal, mainly because most of them are diagnosed at a late stage. Up to 90% of ovarian cancers arise from neoplastic transformation of ovarian surface epithelial cells, and are usually referred to as epithelial ovarian cancer (EOC). Unlike most human cancers, which are disseminated through blood-borne metastatic routes, EOC has traditionally been thought to be disseminated through direct migration of ovarian tumor cells to the peritoneal cavity and omentum via peritoneal fluid. It has recently been shown, however, that EOC can also be disseminated through blood-borne metastatic routes, challenging previous thoughts about ovarian cancer metastasis. CONCLUSIONS Here, we review our current understanding of the most updated cellular and molecular mechanisms underlying EOC metastasis and discuss in more detail two main metastatic routes of EOC, i.e., transcoelomic metastasis and hematogenous metastasis. The emerging concept of blood-borne EOC metastasis has led to exploration of the significance of circulating tumor cells (CTCs) as novel and non-invasive prognostic markers in this daunting cancer. We also evaluate the role of tumor stroma, including cancer associated fibroblasts (CAFs), tumor associated macrophages (TAMs), endothelial cells, adipocytes, dendritic cells and extracellular matrix (ECM) components in EOC growth and metastasis. Lastly, we discuss therapeutic approaches for targeting EOC. Unraveling the mechanisms underlying EOC metastasis will open up avenues to the design of new therapeutic options. For instance, understanding the molecular mechanisms involved in the hematogenous metastasis of EOC, the biology of CTCs, and the detailed mechanisms through which EOC cells take advantage of stromal cells may help to find new opportunities for targeting EOC metastasis.
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Affiliation(s)
- Meysam Yousefi
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Sadegh Dehghani
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Rahim Nosrati
- Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.,Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Ghanei
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arash Salmaninejad
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Halal Research Center of IRI, FDA, Tehran, Iran
| | - Sara Rajaie
- Department of Biology, Islamic Azad University, Arsanjan Branch, Arsanjan, Iran
| | - Malihe Hasanzadeh
- Department of Gynecologic Oncology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Pasdar
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. .,Bioinformatics Research Group, Mashhad University of Medical Sciences, Mashhad, Iran. .,Division of Applied Medicine, Faculty of Medicine, University of Aberdeen, Foresterhill, Aberdeen, UK.
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21
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Relationship between neuropilin-1 expression and prognosis, according to gastric cancer histology. J Mol Histol 2020; 51:199-208. [PMID: 32242307 DOI: 10.1007/s10735-020-09870-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 03/23/2020] [Indexed: 02/08/2023]
Abstract
Neuropilin-1 (NRP-1) is known to be related to various types of cancer and is considered a novel tumor marker or therapeutic target. The aim of this study was to identify the clinical implications of NRP-1 expression in terms of prognosis in patients with gastric cancer. A total of 265 patients who underwent radical gastrectomy for the treatment of gastric cancer from 2008 to 2011 were included in this retrospective study. NRP-1 expression of tumors was determined by immunohistochemistry. The patients' clinicopathological characteristics, operative details, and long-term outcomes were retrospectively analyzed. A total of 181 (68.3%) patients demonstrated expression of NRP-1. No survival difference was observed according to NRP-1 expression in any patient. The patients were divided into the gland formation (GF) and the no gland formation (nGF) types, according to histology. NRP-1 expression rates were 65.6% (84/128) and 70.8% (97/137), respectively. NRP-1 expression was not an independent prognostic factor in the GF group, although patients who expressed NRP-1 had better survival outcomes. In contrast, patients who expressed NRP-1 in the nGF group had worse 5-year survival rates (p = 0.027), and NRP-1 was an independent prognostic factor in a multivariate analysis (hazard ratio, 1.923; 95% confidence interval, 1.041-3.551). NRP-1 expression in patients with nGF type gastric cancer is predictive of a poor prognosis.
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22
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Reynolds IS, Fichtner M, McNamara DA, Kay EW, Prehn JHM, Burke JP. Mucin glycoproteins block apoptosis; promote invasion, proliferation, and migration; and cause chemoresistance through diverse pathways in epithelial cancers. Cancer Metastasis Rev 2020; 38:237-257. [PMID: 30680581 DOI: 10.1007/s10555-019-09781-w] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Overexpression of mucin glycoproteins has been demonstrated in many epithelial-derived cancers. The significance of this overexpression remains uncertain. The aim of this paper was to define the association of mucin glycoproteins with apoptosis, cell growth, invasion, migration, adhesion, and clonogenicity in vitro as well as tumor growth, tumorigenicity, and metastasis in vivo in epithelial-derived cancers by performing a systematic review of all published data. A systematic review of PubMed, Embase, and the Cochrane Central Register of Controlled Trials was performed to identify all papers that evaluated the association between mucin glycoproteins with apoptosis, cell growth, invasion, migration, adhesion, and clonogenicity in vitro as well as tumor growth, tumorigenicity, and metastasis in vivo in epithelial-derived cancers. PRISMA guidelines were adhered to. Results of individual studies were extracted and pooled together based on the organ in which the cancer was derived from. The initial search revealed 2031 papers, of which 90 were deemed eligible for inclusion in the study. The studies included details on MUC1, MUC2, MUC4, MUC5AC, MUC5B, MUC13, and MUC16. The majority of studies evaluated MUC1. MUC1 overexpression was consistently associated with resistance to apoptosis and resistance to chemotherapy. There was also evidence that overexpression of MUC2, MUC4, MUC5AC, MUC5B, MUC13, and MUC16 conferred resistance to apoptosis in epithelial-derived cancers. The overexpression of mucin glycoproteins is associated with resistance to apoptosis in numerous epithelial cancers. They cause resistance through diverse signaling pathways. Targeting the expression of mucin glycoproteins represents a potential therapeutic target in the treatment of epithelial-derived cancers.
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Affiliation(s)
- Ian S Reynolds
- Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland
- Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland
| | - Michael Fichtner
- Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland
| | - Deborah A McNamara
- Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland
- Department of Surgery, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland
| | - Elaine W Kay
- Department of Pathology, Beaumont Hospital, Dublin 9, Ireland
- Department of Pathology, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland
| | - Jochen H M Prehn
- Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland
| | - John P Burke
- Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland.
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Fei LR, Huang WJ, Wang Y, Lei L, Li ZH, Zheng YW, Wang Z, Yang MQ, Liu CC, Xu HT. PRDM16 functions as a suppressor of lung adenocarcinoma metastasis. J Exp Clin Cancer Res 2019; 38:35. [PMID: 30683132 PMCID: PMC6347838 DOI: 10.1186/s13046-019-1042-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 01/15/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The transcription factor PR domain containing 16 (PRDM16) is known to play a significant role in the determination and function of brown and beige fat. However, the role of PRDM16 in tumor biology has not been well addressed. Here we investigated the impact of PRDM16 on tumor growth and metastasis in lung cancer. METHODS UALCAN database, immunoblotting and immunohistochemistry analysis were used to assess PRDM16 expression in lung cancer patients. Kaplan-Meier plotter database was used to analyze the overall survival of patients with lung cancer stratified by PRDM16 expression. PRDM16 overexpression and knockdown experiments were conducted to assess the effects of PRDM16 on growth and metastasis in vitro and in vivo, and its molecular mechanism was investigated in lung adenocarcinoma cells by chromatin immunoprecipitation-sequencing (ChIP-Seq), real time-quantitative PCR (RT-qPCR), luciferase assay, xenograft models and rescue experiments. RESULTS PRDM16 was downregulated in lung adenocarcinomas, and its expression level correlated with key pathological characteristics and prognoses of lung adenocarcinoma patients. Overexpressing PRDM16 inhibited the epithelial-to-mesenchymal transition (EMT) of cancer cells both in vivo and in vitro by repressing the transcription of Mucin-4 (MUC4), one of the regulators of EMT in lung adenocarcinomas. Furthermore, deleting the PR domain from PRDM16 increased the transcriptional repression of MUC4 by exhibiting significant differences in histone modifications on its promoter. CONCLUSIONS Our findings demonstrate a critical interplay between transcriptional and epigenetic modifications during lung adenocarcinoma progression involving EMT of cancer cells and suggest that PRDM16 is a metastasis suppressor and potential therapeutic target for lung adenocarcinomas.
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Affiliation(s)
- Liang-Ru Fei
- Department of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122 People’s Republic of China
| | - Wen-Jing Huang
- Department of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122 People’s Republic of China
| | - Yuan Wang
- Department of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122 People’s Republic of China
| | - Lei Lei
- Department of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122 People’s Republic of China
| | - Zhi-Han Li
- Department of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122 People’s Republic of China
| | - Yi-Wen Zheng
- Department of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122 People’s Republic of China
| | - Zhao Wang
- Department of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122 People’s Republic of China
| | - Mai-Qing Yang
- Department of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122 People’s Republic of China
| | - Chen-Chen Liu
- Department of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122 People’s Republic of China
| | - Hong-Tao Xu
- Department of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122 People’s Republic of China
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Zeng W, Zhu JF, Liu JY, Li YL, Dong X, Huang H, Shan L. miR-133b inhibits cell proliferation, migration and invasion of esophageal squamous cell carcinoma by targeting EGFR. Biomed Pharmacother 2018; 111:476-484. [PMID: 30594787 DOI: 10.1016/j.biopha.2018.12.057] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 12/10/2018] [Accepted: 12/14/2018] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor entity characterized by early metastasis and late diagnosis. MicroRNA-133b (miR-133b) has been considered as a tumor suppressor in many human cancers by regulating epidermal growth factor receptor (EGFR). However, the specific effects of miR-133b and EGFR on ESCC remain unclear. METHODS qRT-PCR and western blotting were applied for measuring expression of mRNA and protein. Flow cytometry was used for detecting cell cycle and apoptosis. Cell proliferation, migration and invasion were detected by colony formation and transwell assays. Luciferase reporter assay was used to confirm the interaction between miR-133b and EGFR. RESULTS Low expression of miR-133b and high expression of EGFR were identified in ESCC cells and tissues. Overexpression of miR-133b or knockdown of EGFR suppressed the cell proliferation, migration, and invasion of ESCC cells, and raised the percentage of G1 phase cells. The apoptosis of ESCC cells were promoted by increasing miR-133b and decreasing EGFR expression. Luciferase reporter assay confirmed EGFR as the target of miR-133b in ESCC cells. Overexpression of miR-133b significantly decreased the phosphorylation of PI3K, ERK and AKT by directly down-regulating EGFR. Higher expression of E-cadherin and CK-18 and lower expression of Vimentin and N-cadherin were observed after the transfection of miR-133b mimics or shEGFR. CONCLUSION Overexpression of miR-133b could suppress proliferation, migration and invasion of ESCC cells by inhibiting MAPK/ERK and PI3K/AKT signaling pathways through targeting EGFR, indicating that miR-133b might be a potential therapeutic target for the treatment of ESCC.
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Affiliation(s)
- Wei Zeng
- First Department of Lung Cancer Chemotherapy, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi 830011, PR China; Department of Hematology and Oncology, Shenzhen University General Hospital, Shenzhen 518055, PR China
| | - Jin-Feng Zhu
- Department of Gastrointestinal Surgery, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi 830011, PR China
| | - Jun-Yuan Liu
- First Department of Lung Cancer Chemotherapy, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi 830011, PR China
| | - Ying-Long Li
- First Department of Lung Cancer Chemotherapy, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi 830011, PR China
| | - Xiang Dong
- Institute of Cancer Prevention and Treatment, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi 830011, PR China
| | - He Huang
- Department of Histology and Embryology, Xinjiang Medical University, Urumqi 830011, PR China; Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha 410013, PR China.
| | - Li Shan
- First Department of Lung Cancer Chemotherapy, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi 830011, PR China.
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Wu GJ. METCAM/MUC18 Decreases the Malignant Propensity of Human Ovarian Carcinoma Cells. Int J Mol Sci 2018; 19:E2976. [PMID: 30274262 PMCID: PMC6213002 DOI: 10.3390/ijms19102976] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 09/24/2018] [Accepted: 09/26/2018] [Indexed: 11/24/2022] Open
Abstract
METCAM/MUC18 is an integral membrane cell adhesion molecule (CAM) in the Ig-like gene super-family. It can carry out common functions of CAMs which is to perform intercellular interactions and interaction of cell with extracellular matrix in tumor microenvironment, to interact with various signaling pathways and to regulate general behaviors of cells. We and other two groups previously suggested that METCAM/MUC18 probably be utilized as a biomarker for predicting the malignant tendency of clinical ovarian carcinomas, since METAM/MUC18 expression appears to associate with the carcinoma at advanced stages. It has been further postulated to promote the malignant tendency of the carcinoma. However, our recent research results appear to support the conclusion that the above positive correlation is fortuitous; actually METCAM/MUC18 acts as a tumor and metastasis suppressor for the ovarian carcinoma cells. We also suggest possible mechanisms in the METCAM/MUC18-mediated early tumor development and metastasis of ovarian carcinoma. Moreover, we propose to employ recombinant METCAM/MUC18 proteins and other derived products as therapeutic agents to treat the ovarian cancer patients by decreasing the malignant potential of ovarian carcinoma.
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Affiliation(s)
- Guang-Jer Wu
- Department of Bioscience Technology and Center for Biomedical Technology, Chung Yuan Christian University, Chung Li 32023, Taiwan.
- Department of Microbiology & Immunology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
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Rowson-Hodel A, Wald J, Hatakeyama J, O’Neal W, Stonebraker J, VanderVorst K, Saldana M, Borowsky A, Sweeney C, Carraway K. Membrane Mucin Muc4 promotes blood cell association with tumor cells and mediates efficient metastasis in a mouse model of breast cancer. Oncogene 2018; 37:197-207. [PMID: 28892049 PMCID: PMC5930013 DOI: 10.1038/onc.2017.327] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 06/21/2017] [Accepted: 08/04/2017] [Indexed: 12/11/2022]
Abstract
Mucin-4 (Muc4) is a large cell surface glycoprotein implicated in the protection and lubrication of epithelial structures. Previous studies suggest that aberrantly expressed Muc4 can influence the adhesiveness, proliferation, viability and invasiveness of cultured tumor cells, as well as the growth rate and metastatic efficiency of xenografted tumors. Although it has been suggested that one of the major mechanisms by which Muc4 potentiates tumor progression is via its engagement of the ErbB2/HER2 receptor tyrosine kinase, other mechanisms exist and remain to be delineated. Moreover, the requirement for endogenous Muc4 for tumor growth progression has not been previously explored in the context of gene ablation. To assess the contribution of endogenous Muc4 to mammary tumor growth properties, we first created a genetically engineered mouse line lacking functional Muc4 (Muc4ko), and then crossed these animals with the NDL (Neu DeLetion mutant) model of ErbB2-induced mammary tumorigenesis. We observed that Muc4ko animals are fertile and develop normally, and adult mice exhibit no overt tissue abnormalities. In tumor studies, we observed that although some markers of tumor growth such as vascularity and cyclin D1 expression are suppressed, primary mammary tumors from Muc4ko/NDL female mice exhibit similar latencies and growth rates as Muc4wt/NDL animals. However, the presence of lung metastases is markedly suppressed in Muc4ko/NDL mice. Interestingly, histological analysis of lung lesions from Muc4ko/NDL mice revealed a reduced association of disseminated cells with platelets and white blood cells. Moreover, isolated cells derived from Muc4ko/NDL tumors interact with fewer blood cells when injected directly into the vasculature or diluted into blood from wild type mice. We further observed that blood cells more efficiently promote the viability of non-adherent Muc4wt/NDL cells than Muc4ko/NDL cells. Together, our observations suggest that Muc4 may facilitate metastasis by promoting the association of circulating tumor cells with blood cells to augment tumor cell survival in circulation.
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Affiliation(s)
- A.R. Rowson-Hodel
- Department of Biochemistry and Molecular Medicine, and UC Davis Comprehensive Cancer Center, University of California, Davis, School of Medicine, Sacramento, California, USA
| | - J.H. Wald
- Department of Biochemistry and Molecular Medicine, and UC Davis Comprehensive Cancer Center, University of California, Davis, School of Medicine, Sacramento, California, USA
| | - J. Hatakeyama
- Department of Biochemistry and Molecular Medicine, and UC Davis Comprehensive Cancer Center, University of California, Davis, School of Medicine, Sacramento, California, USA
| | - W.K. O’Neal
- Marsico Lung Institute/UNC Cystic Fibrosis Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - J.R. Stonebraker
- Marsico Lung Institute/UNC Cystic Fibrosis Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - K. VanderVorst
- Department of Biochemistry and Molecular Medicine, and UC Davis Comprehensive Cancer Center, University of California, Davis, School of Medicine, Sacramento, California, USA
| | - M.J. Saldana
- Department of Biochemistry and Molecular Medicine, and UC Davis Comprehensive Cancer Center, University of California, Davis, School of Medicine, Sacramento, California, USA
| | - A.D. Borowsky
- Department of Pathology and Laboratory Medicine, University of California, Davis, School of Medicine, Sacramento, California, USA
| | - C. Sweeney
- Department of Biochemistry and Molecular Medicine, and UC Davis Comprehensive Cancer Center, University of California, Davis, School of Medicine, Sacramento, California, USA
| | - K.L. Carraway
- Department of Biochemistry and Molecular Medicine, and UC Davis Comprehensive Cancer Center, University of California, Davis, School of Medicine, Sacramento, California, USA
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Chen K, Liu MX, Mak CSL, Yung MMH, Leung THY, Xu D, Ngu SF, Chan KKL, Yang H, Ngan HYS, Chan DW. Methylation-associated silencing of miR-193a-3p promotes ovarian cancer aggressiveness by targeting GRB7 and MAPK/ERK pathways. Am J Cancer Res 2018; 8:423-436. [PMID: 29290818 PMCID: PMC5743558 DOI: 10.7150/thno.22377] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 09/26/2017] [Indexed: 12/20/2022] Open
Abstract
Human growth factor receptor-bound protein-7 (GRB7) is a pivotal mediator involved in receptor tyrosine kinase signaling and governing diverse cellular processes. Aberrant upregulation of GRB7 is frequently associated with the progression of human cancers. However, the molecular mechanisms leading to the upregulation of GRB7 remain largely unknown. Here, we propose that the epigenetic modification of GRB7 at the post-transcriptional level may be a crucial factor leading to GRB7 upregulation in ovarian cancers. Methods: The upstream miRNA regulators were predicted by in silico analysis. Expression of GRB7 was examined by qPCR, immunoblotting and immunohistochemical analyses, while miR-193a-3p levels were evaluated by qPCR and in situ hybridization in ovarian cancer cell lines and clinical tissue arrays. MS-PCR and pyrosequencing analyses were used to assess the methylation status of miR-193a-3p. Stable overexpression or gene knockdown and Tet-on inducible approaches, in combination with in vitro and in vivo tumorigenic assays, were employed to investigate the functions of GRB7 and miR-193a-3p in ovarian cancer cells. Results: Both miR-193a-3p and its isoform, miR-193b-3p, directly targeted the 3' UTR of GRB7. However, only miR-193a-3p showed a significantly inverse correlation with GRB7-upregulated ovarian cancers. Epigenetic studies revealed that methylation-mediated silencing of miR-193a-3p led to a stepwise decrease in miR-193a-3p expression from low to high-grade ovarian cancers. Intriguingly, miR-193a-3p not only modulated GRB7 but also ERBB4, SOS2 and KRAS in the MAPK/ERK signaling pathway to enhance the oncogenic properties of ovarian cancer cells in vitro and in vivo. Conclusion: These findings suggest that epigenetic silencing of miR-193a-3p by DNA hypermethylation is a dynamic process in ovarian cancer progression, and miR-193a-3p may be explored as a promising miRNA replacement therapy in this disease.
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Antonini F, Laterza L, Fuccio L, Marcellini M, Angelelli L, Calcina S, Rubini C, Macarri G. Gastric metastasis from ovarian adenocarcinoma presenting as a subepithelial tumor and diagnosed by endoscopic ultrasound-guided tissue acquisition. World J Gastrointest Oncol 2017; 9:452-456. [PMID: 29204254 PMCID: PMC5700387 DOI: 10.4251/wjgo.v9.i11.452] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Revised: 07/19/2017] [Accepted: 08/17/2017] [Indexed: 02/05/2023] Open
Abstract
We describe an uncommon case of a patient with a metastatic adenocarcinoma of ovarian origin presented as a gastric subepithelial tumor (SET) and that was diagnosed by endoscopic ultrasound fine-needle biopsy (EUS-FNB). Malignant gastric lesions are rarely metastatic and the primary tumor is mainly breast, lung, esophageal cancer or cutaneous melanoma. Gastric metastasis from ovarian cancer is unusual, presenting synchronously with the primary tumor but also several years later than the initial diagnosis. From an endoscopic point of view, gastric metastasis does not present specific features. They may mimic both a primary gastric tumor or, less frequently, an SET. This case demonstrates the importance of EUS-FNB in distinguishing SETs and how this may alter treatment and prognosis.
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Affiliation(s)
- Filippo Antonini
- Department of Gastroenterology, A. Murri Hospital, Polytechnic University of Marche, Fermo 63900, Italy
| | | | - Lorenzo Fuccio
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy
| | - Massimo Marcellini
- Medical Oncology, Principe di Piemonte Hospital, Senigallia 60019, Italy
| | - Lucia Angelelli
- Medical Oncology, Mazzoni Hospital, Ascoli Piceno 63100, Italy
| | - Sonia Calcina
- Department of Gastroenterology, San Salvatore Hospital, University of L’Aquila, L’Aquila 67100, Italy
| | - Corrado Rubini
- Department of Biomedical Sciences and Public Health, Pathological Anatomy and Histopathology, Polytechnic University of Marche, Ancona 60126, Italy
| | - Giampiero Macarri
- Department of Gastroenterology, A. Murri Hospital, Polytechnic University of Marche, Fermo 63900, Italy
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29
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Cell membrane-anchored MUC4 promotes tumorigenicity in epithelial carcinomas. Oncotarget 2017; 8:14147-14157. [PMID: 27829225 PMCID: PMC5355169 DOI: 10.18632/oncotarget.13122] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Accepted: 10/26/2016] [Indexed: 12/17/2022] Open
Abstract
The cell surface membrane-bound mucin protein MUC4 promotes tumorigenicity, aggressive behavior, and poor outcomes in various types of epithelial carcinomas, including pancreatic, breast, colon, ovarian, and prostate cancer. This review summarizes the theories and findings regarding MUC4 function, and its role in epithelial carcinogenesis. Based on these insights, we developed an outline of the processes and mechanisms by which MUC4 critically supports the propagation and survival of cancer cells in various epithelial organs. MUC4 may therefore be a useful prognostic and diagnostic tool that improves our ability to eradicate various forms of cancer.
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Duan H, Yan Z, Chen W, Wu Y, Han J, Guo H, Qiao J. TET1 inhibits EMT of ovarian cancer cells through activating Wnt/β-catenin signaling inhibitors DKK1 and SFRP2. Gynecol Oncol 2017; 147:408-417. [PMID: 28851501 DOI: 10.1016/j.ygyno.2017.08.010] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 08/05/2017] [Accepted: 08/08/2017] [Indexed: 01/09/2023]
Abstract
OBJECTIVE Epithelial ovarian cancer (EOC) is the deadliest type of ovarian cancer, but the mechanisms contributing to its tumorigenesis are not well understood. Herein, we will elucidate the role of Ten-eleven translocation 1 (TET1) in EOC development. METHODS The expression of TET1 in EOC cell lines and primary samples was examined by western blot and immunohistochemistry. The biological role of ectopic TET1 overexpression was revealed by a series of in vitro functional studies. Its downstream signaling pathway was predicted by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of microarray data. The methylation level and expression of Wnt/β-catenin signaling inhibitors Dikkopf 1 (DKK1) and secreted Fzd receptor protein 2 (SFRP2) were examined by Chromatin immunoprecipitation (ChIP) assay, Epimark™ 5hmC and 5mC level analysis and quantitative RT-PCR. Small interference RNA (siRNA) technology was used to investigate the biological roles of DKK1 and SFRP2. RESULTS TET1 expression was inversely correlated with clinical stage in patients with EOC by tissue microarray (TMA). TET1 expression was undetected in 6 types of EOC cell lines. Ectopic expression of TET1 inhibited colony formation, cell migration and invasion in SKOV3 and OVCAR3 cells. Furthermore, TET1 overexpression reversed the epithelial-mesenchymal transition (EMT) process of SKOV3 cells. Mechanistically, TET1 potently inhibited canonical Wnt/β-catenin signaling by demethylating and upregulating two upstream antagonists of this pathway, SFRP2 and DKK1, which was associated with inhibition of EMT and cancer cell metastasis. CONCLUSION This study uncovers that TET1 has potent tumor-suppressive effects in EOC by activating Wnt/β-catenin signaling inhibitors DKK1 and SFRP2.
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Affiliation(s)
- Hongying Duan
- Key Laboratory of Assisted Reproduction, Ministry of Education, Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, PR China
| | - Zhiqiang Yan
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, PR China
| | - Wei Chen
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, PR China
| | - Yu Wu
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, PR China
| | - Jinsong Han
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, PR China
| | - Hongyan Guo
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, PR China
| | - Jie Qiao
- Key Laboratory of Assisted Reproduction, Ministry of Education, Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, PR China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, PR China; Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, PR China.
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31
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Ye J, Wei X, Shang Y, Pan Q, Yang M, Tian Y, He Y, Peng Z, Chen L, Chen W, Wang R. Core 3 mucin-type O-glycan restoration in colorectal cancer cells promotes MUC1/p53/miR-200c-dependent epithelial identity. Oncogene 2017; 36:6391-6407. [PMID: 28745318 DOI: 10.1038/onc.2017.241] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Revised: 05/25/2017] [Accepted: 06/14/2017] [Indexed: 12/31/2022]
Abstract
The attachment of cell-surface carbohydrates to proteins mediated by the amino acids serine or threonine (O-glycan) is involved in tumor metastasis; the roles of O-glycans vary depending on their structure, but the detailed mechanisms by which O-glycans trigger signaling to control tumor metastasis are largely unknown. In this study, we found that the reduced expression of core 3 synthase correlated with metastasis to lymph nodes and distant organs, resulting in poor prognosis for colorectal cancer (CRC) patients. Mechanically, we revealed that mucin-type core 3 O-glycan was synthesized at the membrane-tethered MUC1 N terminus because of core 3 synthase expression in colon cancer cells. This further inhibited the translocation of MUC1-C to the nucleus, initiated p53 gene transcription that was dependent on the inhibition of MUC1-C nucleus translocation, activated p53-mediated miR-200c expression and resulted in mesenchymal-epithelial transition (MET). Inhibition of MUC1 via small interfering RNA (siRNA) in re-expressed core 3 synthase colon cancer cells further inhibited MUC1-C nucleus translocation, increased p53 and miR-200c expression, and enhanced MET. However, inhibition of p53 via siRNA or miR-200c via miR-200c inhibitor in re-expressed core 3 synthase colon cancer cells promoted the epithelial-mesenchymal transition (EMT) in a reversible manner. Core 3 synthase mRNA levels and the p53 mRNA levels or miR-200c levels in the colon cancerous samples were positively correlated. Our findings suggest a novel mechanism linking mucin-type core 3 O-glycan to the EMT-MET plasticity of CRC cells via MUC1/p53/miR-200c-dependent signaling cascade and shed light on therapeutic strategies to treat this malignancy.
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Affiliation(s)
- J Ye
- Department of Gastroenterology, Institute of Gastroenterology of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - X Wei
- Department of Gastroenterology, Institute of Gastroenterology of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Y Shang
- Department of Gastroenterology, Institute of Gastroenterology of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Q Pan
- Department of Gastroenterology, Institute of Gastroenterology of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - M Yang
- Department of Gastroenterology, Institute of Gastroenterology of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Y Tian
- Department of Gastroenterology, Institute of Gastroenterology of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Y He
- Department of Gastroenterology, Institute of Gastroenterology of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Z Peng
- Department of Gastroenterology, Institute of Gastroenterology of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - L Chen
- Department of Gastroenterology, Institute of Gastroenterology of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - W Chen
- Department of Gastroenterology, Institute of Gastroenterology of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - R Wang
- Department of Gastroenterology, Institute of Gastroenterology of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China
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Fang D, Chen H, Zhu JY, Wang W, Teng Y, Ding HF, Jing Q, Su SB, Huang S. Epithelial-mesenchymal transition of ovarian cancer cells is sustained by Rac1 through simultaneous activation of MEK1/2 and Src signaling pathways. Oncogene 2017; 36:1546-1558. [PMID: 27617576 PMCID: PMC5346482 DOI: 10.1038/onc.2016.323] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 06/07/2016] [Accepted: 07/28/2016] [Indexed: 12/14/2022]
Abstract
Epithelial-mesenchymal transition (EMT) is regarded as a crucial contributing factor to cancer progression. Diverse factors have been identified as potent EMT inducers in ovarian cancer. However, molecular mechanism sustaining EMT of ovarian cancer cells remains elusive. Here we show that the presence of SOS1/EPS8/ABI1 complex is critical for sustained EMT traits of ovarian cancer cells. Consistent with the role of SOS1/EPS8/ABI1 complex as a Rac1-specific guanine nucleotide exchange factor, depleting Rac1 results in the loss of most of mesenchymal traits in mesenchymal-like ovarian cancer cells, whereas expressing constitutively active Rac1 leads to EMT in epithelial-like ovarian cancer cells. With the aid of clinically tested inhibitors targeting various EMT-associated signaling pathways, we show that only combined treatment of mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) and Src inhibitors can abolish constitutively active Rac1-led EMT and mesenchymal traits displayed by mesenchymal-like ovarian cancer cells. Further experiments also reveal that EMT can be induced in epithelial-like ovarian cancer cells by co-expressing constitutively active MEK1 and Src rather than either alone. As the activities of Erk and Src are higher in ovarian cancer cells with constitutively active Rac1, we conclude that Rac1 sustains ovarian cancer cell EMT through simultaneous activation of MEK1/2 and Src signaling pathways. Importantly, we demonstrate that combined use of MEK1/2 and Src inhibitors effectively suppresses development of intraperitoneal xenografts and prolongs the survival of ovarian cancer-bearing mice. This study suggests that cocktail of MEK1/2 and Src inhibitors represents an effective therapeutic strategy against ovarian cancer progression.
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Affiliation(s)
- Dongdong Fang
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- E-institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huijun Chen
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Jessica Y Zhu
- Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, USA
| | - Wei Wang
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yong Teng
- Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA
- Georgia Cancer Center, Augusta University, Augusta, GA, USA
| | - Han-Fei Ding
- Georgia Cancer Center, Augusta University, Augusta, GA, USA
| | - Qing Jing
- Department of Cardiology, Changhai Hospital, Shanghai, China
| | - Shi-Bing Su
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- E-institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shuang Huang
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- E-institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, USA
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33
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Pazos MC, Abramovich D, Bechis A, Accialini P, Parborell F, Tesone M, Irusta G. Gamma secretase inhibitor impairs epithelial-to-mesenchymal transition induced by TGF-β in ovarian tumor cell lines. Mol Cell Endocrinol 2017; 440:125-137. [PMID: 27908834 DOI: 10.1016/j.mce.2016.11.025] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 11/25/2016] [Accepted: 11/26/2016] [Indexed: 10/20/2022]
Abstract
Ovarian cancer is characterized by being highly metastatic, a feature that represents the main cause of failure of the treatment. This study investigated the effects of γ-secretase inhibition on the TGF-β-induced epithelial-mesenchymal transition (EMT) process in ovarian cancer cell lines. SKOV3 cells incubated in the presence of TGF-β showed morphological and biochemical changes related to EMT, which were blocked by co-stimulation with TGF-β and the γ-secretase inhibitor DAPT. In SKOV3 and IGROV1 cells, the co-stimulation blocked the cadherin switch and the increase in the transcription factors Snail, Slug, Twist and Zeb1 induced by TGF-β. DAPT impaired the translocation of phospho-β-catenin to the inner cell compartment observed in TGF-β-treated cells, but was not able to block the induction at protein level induced by TGF-β. Moreover, the inhibitor blocked the increased cell migration and invasiveness ability of both cell lines induced by TGF-β. Notch target genes (Hes1 and Hey1) were induced by TGF-β, decreased by DAPT treatment and remained low in the presence of both stimuli. However, DAPT alone caused no effects on most of the parameters analyzed. These results demonstrate that the γ-secretase inhibitor used in this study exerted a blockade on TGF-β-induced EMT in ovarian cancer cells.
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Affiliation(s)
- M C Pazos
- Instituto de Biología y Medicina Experimental (IByME-CONICET), Buenos Aires, Argentina.
| | - D Abramovich
- Instituto de Biología y Medicina Experimental (IByME-CONICET), Buenos Aires, Argentina.
| | - A Bechis
- Instituto de Biología y Medicina Experimental (IByME-CONICET), Buenos Aires, Argentina.
| | - P Accialini
- Instituto de Biología y Medicina Experimental (IByME-CONICET), Buenos Aires, Argentina.
| | - F Parborell
- Instituto de Biología y Medicina Experimental (IByME-CONICET), Buenos Aires, Argentina.
| | - M Tesone
- Instituto de Biología y Medicina Experimental (IByME-CONICET), Buenos Aires, Argentina.
| | - G Irusta
- Instituto de Biología y Medicina Experimental (IByME-CONICET), Buenos Aires, Argentina.
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34
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Xu D, Liu S, Zhang L, Song L. MiR-211 inhibits invasion and epithelial-to-mesenchymal transition (EMT) of cervical cancer cells via targeting MUC4. Biochem Biophys Res Commun 2016; 485:556-562. [PMID: 27923652 DOI: 10.1016/j.bbrc.2016.12.020] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 12/03/2016] [Indexed: 12/27/2022]
Abstract
The dysregulated molecules and their involvement in lymph node metastases of cervical cancer are far from been fully revealed. In this study, by reviewing MUC4 expression in The Human Protein Atlas and retrieving gene microarray data in GEO dataset (No. GDS4664), we found that MUC4 upregulation is associated with lymph node metastasis in cervical cancer. Knockdown of MUC4 in Hela and SiHa cells significantly reduced their invasion and also reduced the mesenchymal properties. By performing bioinformatics analysis, we observed that miR-211 is a potential suppressor of MUC4, which has a predicted highly conserved binding site in the 3'UTR of MUC among mammals. The following assays confirmed that miR-211 can directly target the 3'UTR of MUC4 and inhibit its expression at both mRNA and protein levels. In addition, enforced miR-211 expression phenocopies the effects of MUC4 siRNA in inhibiting cervical cancer cell invasion and reversing EMT properties. Therefore, we infer that miR-211 is a novel miRNA with suppressive effect on MUC4 expression and can inhibit cervical cancer cell invasion and EMT.
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Affiliation(s)
- Dongkui Xu
- Department of Obstetrics & Gynaecology, Cangzhou Central Hospital, Hebei, 061001, China
| | - Shikai Liu
- Department of Obstetrics & Gynaecology, Cangzhou Central Hospital, Hebei, 061001, China
| | - Liang Zhang
- Department of Obstetrics & Gynaecology, Cangzhou Central Hospital, Hebei, 061001, China
| | - Lili Song
- Department of Obstetrics & Gynaecology, Cangzhou Central Hospital, Hebei, 061001, China.
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35
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Lu L, Wang J, Wu Y, Wan P, Yang G. Rap1A promotes ovarian cancer metastasis via activation of ERK/p38 and notch signaling. Cancer Med 2016; 5:3544-3554. [PMID: 27925454 PMCID: PMC5224839 DOI: 10.1002/cam4.946] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 09/15/2016] [Accepted: 09/28/2016] [Indexed: 01/04/2023] Open
Abstract
As one of the Ras-associated proteins, Rap1A has been linked to cancer initiation and development. However, the precise function of Rap1A in ovarian cancer is still not understood. Here, we show that Rap1A promotes ovarian cancer tumorigenesis and metastasis via stimulating cell proliferation, migration and invasion both in vivo and in vitro. Mechanistic study showed that Rap1A activates extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and Notch pathways, leading to the enhanced expression of several epithelial-mesenchymal transition (EMT) markers such as slug, zeb1, vimentin, fibronectin, and MMP9. However, the pretreatment of Rap1A-overexpressing cells with the Notch inhibitor DAPT or ERK inhibitor (U0126) inhibited the up-regulated expression of those molecules. These findings provide the first evidence linking Rap1A with ovarian cancer development through the ERK/p38 and Notch signaling pathways, indicating that Rap1A may be used as a novel diagnostic marker or a therapeutic target for ovarian cancer.
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Affiliation(s)
- Lili Lu
- Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China.,Department of Biology, College of Life and Environmental Sciences, Shanghai Normal University, 100 Guilin Road, Shanghai, 200234, China
| | - Jingshu Wang
- Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China
| | - Yougen Wu
- Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China
| | - Ping Wan
- Department of Biology, College of Life and Environmental Sciences, Shanghai Normal University, 100 Guilin Road, Shanghai, 200234, China
| | - Gong Yang
- Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China.,Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China.,Department of Gynecological Oncology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China
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36
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Bernaudo S, Salem M, Qi X, Zhou W, Zhang C, Yang W, Rosman D, Deng Z, Ye G, Yang B, Vanderhyden B, Wu Z, Peng C. Cyclin G2 inhibits epithelial-to-mesenchymal transition by disrupting Wnt/β-catenin signaling. Oncogene 2016; 35:4816-27. [PMID: 26876206 PMCID: PMC5024152 DOI: 10.1038/onc.2016.15] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2015] [Revised: 12/14/2015] [Accepted: 01/05/2016] [Indexed: 12/13/2022]
Abstract
Epithelial ovarian cancer (EOC) has the highest mortality rate among gynecological malignancies owing to poor screening methods, non-specific symptoms and limited knowledge of the cellular targets that contribute to the disease. Cyclin G2 is an unconventional cyclin that acts to oppose cell cycle progression. Dysregulation of the cyclin G2 gene (CCNG2) in a variety of human cancers has been reported; however, the role of cyclin G2 in tumorigenesis remains unclear. In this study, we investigated the function of cyclin G2 in EOC. In vitro and in vivo studies using several EOC-derived tumor cell lines revealed that cyclin G2 inhibited cell proliferation, migration, invasion and spheroid formation, as well as tumor formation and invasion. By interrogating cDNA microarray data sets, we found that CCGN2 mRNA is reduced in several large cohorts of human ovarian carcinoma when compared with normal ovarian surface epithelium or borderline tumors of the ovary. Mechanistically, cyclin G2 was found to suppress epithelial-to-mesenchymal transition (EMT), as demonstrated by the differential regulation of various EMT genes, such as Snail, Slug, vimentin and E-cadherin. Moreover, cyclin G2 potently suppressed the Wnt/β-catenin signaling pathway by downregulating key Wnt components, namely LRP6, DVL2 and β-catenin, which could be linked to inhibition of EMT. Taken together, our novel findings demonstrate that cyclin G2 has potent tumor-suppressive effects in EOCs by inhibiting EMT through attenuating Wnt/β-catenin signaling.
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Affiliation(s)
- S Bernaudo
- Department of Biology, York University, Toronto, Ontario, Canada
| | - M Salem
- Department of Biology, York University, Toronto, Ontario, Canada
| | - X Qi
- Department of Biology, York University, Toronto, Ontario, Canada
| | - W Zhou
- Department of Biology, York University, Toronto, Ontario, Canada
| | - C Zhang
- Department of Biology, York University, Toronto, Ontario, Canada
| | - W Yang
- Department of Biology, York University, Toronto, Ontario, Canada
| | - D Rosman
- Department of Biology, York University, Toronto, Ontario, Canada
| | - Z Deng
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - G Ye
- Department of Biology, York University, Toronto, Ontario, Canada
| | - B Yang
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - B Vanderhyden
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Z Wu
- Department of Biology, York University, Toronto, Ontario, Canada
- Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, China
| | - C Peng
- Department of Biology, York University, Toronto, Ontario, Canada
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37
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Wang L, Zhi X, Zhu Y, Zhang Q, Wang W, Li Z, Tang J, Wang J, Wei S, Li B, Zhou J, Jiang J, Yang L, Xu H, Xu Z. MUC4-promoted neural invasion is mediated by the axon guidance factor Netrin-1 in PDAC. Oncotarget 2016; 6:33805-22. [PMID: 26393880 PMCID: PMC4741804 DOI: 10.18632/oncotarget.5668] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 08/26/2015] [Indexed: 12/19/2022] Open
Abstract
Neuralinvasion (NI) is an important oncological feature of pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanism of NI in PDAC remains unclear. In this study, we found that MUC4 was overexpressed in PDAC tissues and high expression of MUC4 indicated a higher NI incidencethan low expression. In vitro, MUC4 knockdown inhibited the migration and invasion of PDAC cells and impaired the migration of PDAC cells along nerve in dorsal root ganglia (DRG)-PDAC cell co-culture assay. In vivo, MUC4 knockdown suppressed the NI of PDAC cells in a murine NI model. Mechanistically, our data revealed that MUC4 silencing resulted in decreased netrin-1 expression and re-expression of netrin-1 in MUC4-silenced cells rescued the capability of NI. Furthermore, we identified that decreased netrin-1 expression was owed to the downregulation of HER2/AKT/NF-κB pathway in MUC4-silenced cells. Additionally, MUC4 knockdown also resulted in the downregulation of pFAK, pSrc, pJNK and MMP9. Taken together, our findings revealed a novelrole of MUC4 in potentiating NI via netrin-1 through the HER2/AKT/NF-κBpathway in PDAC.
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Affiliation(s)
- Linjun Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Xiaofei Zhi
- Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
| | - Yi Zhu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Qun Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Weizhi Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Zheng Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Jie Tang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Jiwei Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Song Wei
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Bowen Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Jianping Zhou
- Department of Gastrointestinal Surgery, The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, P.R. China
| | - Jianguo Jiang
- Department of Gastrointestinal Surgery, Taizhou People's Hospital, Taizhou, Jiangsu, P.R. China
| | - Li Yang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Hao Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.,Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
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38
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Tang J, Zhu Y, Xie K, Zhang X, Zhi X, Wang W, Li Z, Zhang Q, Wang L, Wang J, Xu Z. The role of the AMOP domain in MUC4/Y-promoted tumour angiogenesis and metastasis in pancreatic cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2016; 35:91. [PMID: 27287498 PMCID: PMC4902942 DOI: 10.1186/s13046-016-0369-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Accepted: 06/01/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND MUC4 is a high molecular weight membrane protein that is overexpressed in pancreatic cancer (PC) and is associated with the development and progression of this disease. However, the exact mechanisms through which MUC4 domains promote these biological processes have rarely been studied, partly because of its high molecular weight, difficulty to overexpress it. Here, we use MUC4/Y, one of the MUC4 transcript variants, as a model molecule to investigate the AMOP-domain of MUC4(MUC/Y). METHODS We used cell proliferation, migration, invasion and tube formation assays in vitro to explore the abilities of AMOP domain in PC. In vivo, the matrigel plug assay, orthotopic implantation and Kaplan-Meier survival curves were used to check the results we observed in vitro. Finally, we discovered the underlying mechanism through western blot and immunofluorescence. RESULTS We found that MUC4/Y overexpression could enhance the angiogenic and metastatic properties of PC cells, both in vitro and in vivo. However, the deletion of AMOP domain could cutback these phenomena. Additionally, Kaplan-Meier survival curves showed that mice injected with MUC4/Y overexpressed cells had shorter survival time, compared with empty-vector-transfected cells (MUC4/Y-EV), or cells expressing MUC4/Y without the AMOP domain (MUC4/Y-AMOP(△)). Our data also showed that overexpression of MUC4/Y could activate NOTCH3 signaling, increasing the expression of downstream genes: VEGF-A, MMP-9 and ANG-2. CONCLUSIONS The AMOP domain had an important role in MUC4/Y (MUC4)-mediated tumour angiogenesis and metastasis of PC cells; and the NOTCH3 signaling was involved. These findings provided new insights into PC therapies. Our study also supplies a new method to study other high molecular membrane proteins.
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Affiliation(s)
- Jie Tang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.,Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yi Zhu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Kunling Xie
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.,Department of General Surgery, the People's Hospital of Bozhou, Bozhou, Anhui, China
| | - Xiaoyu Zhang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.,Department of General Surgery, Huai'an People's Hospital, Xuzhou Medical College, Huai'an, Jiangsu, China
| | - Xiaofei Zhi
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.,Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Weizhi Wang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zheng Li
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qun Zhang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Linjun Wang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jiwei Wang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zekuan Xu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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39
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Alaee M, Danesh G, Pasdar M. Plakoglobin Reduces the in vitro Growth, Migration and Invasion of Ovarian Cancer Cells Expressing N-Cadherin and Mutant p53. PLoS One 2016; 11:e0154323. [PMID: 27144941 PMCID: PMC4856367 DOI: 10.1371/journal.pone.0154323] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 04/12/2016] [Indexed: 12/20/2022] Open
Abstract
Aberrant expression of cadherins and catenins plays pivotal roles in ovarian cancer development and progression. Plakoglobin (PG, γ-catenin) is a paralog of β-catenin with dual adhesive and signaling functions. While β-catenin has known oncogenic function, PG generally acts as a tumor/metastasis suppressor. We recently showed that PG interacted with p53 and that its growth/metastasis inhibitory function may be mediated by this interaction. Very little is known about the role of PG in ovarian cancer. Here, we investigated the in vitro tumor/metastasis suppressor effects of PG in ovarian cancer cell lines with mutant p53 expression and different cadherin profiles. We showed that the N-cadherin expressing and E-cadherin and PG deficient ES-2 cells were highly migratory and invasive, whereas OV-90 cells that express E-cadherin, PG and very little/no N-cadherin were not. Exogenous expression of PG or E-cadherin or N-cadherin knockdown in ES-2 cells (ES-2-E-cad, ES-2-PG and ES-2-shN-cad) significantly reduced their migration and invasion. Also, PG expression or N-cadherin knockdown significantly decreased ES-2 cells growth. Furthermore, PG interacted with both cadherins and with wild type and mutant p53 in normal ovarian and ES-2-PG cell lines, respectively.
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Affiliation(s)
- Mahsa Alaee
- Department of Oncology, University of Alberta, Edmonton, AB, T6G1Z2, Canada
| | - Ghazal Danesh
- Department of Oncology, University of Alberta, Edmonton, AB, T6G1Z2, Canada
| | - Manijeh Pasdar
- Department of Oncology, University of Alberta, Edmonton, AB, T6G1Z2, Canada
- * E-mail:
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40
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Qiu F, Yang L, Lu X, Chen J, Wu D, Wei Y, Nong Q, Zhang L, Fang W, Chen X, Ling X, Yang B, Zhang X, Zhou Y, Lu J. The MKK7 p.Glu116Lys Rare Variant Serves as a Predictor for Lung Cancer Risk and Prognosis in Chinese. PLoS Genet 2016; 12:e1005955. [PMID: 27028764 PMCID: PMC4814107 DOI: 10.1371/journal.pgen.1005955] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Accepted: 03/03/2016] [Indexed: 11/19/2022] Open
Abstract
Accumulated evidence indicates that rare variants exert a vital role on predisposition and progression of human diseases, which provides neoteric insights into disease etiology. In the current study, based on three independently retrospective studies of 5,016 lung cancer patients and 5,181 controls, we analyzed the associations between five rare polymorphisms (i.e., p.Glu116Lys, p.Asn118Ser, p.Arg138Cys, p.Ala195Thr and p.Leu259Phe) in MKK7 and lung cancer risk and prognosis. To decipher the precise mechanisms of MKK7 rare variants on lung cancer, a series of biological experiments was further performed. We found that the MKK7 p.Glu116Lys rare polymorphism was significantly associated with lung cancer risk, progression and prognosis. Compared with Glu/Glu common genotype, the 116Lys rare variants (Lys/Glu/+ Lys/Lys) presented an adverse effect on lung cancer susceptibility (odds ratio [OR] = 3.29, 95% confidence interval [CI] = 2.70-4.01). These rare variants strengthened patients' clinical progression that patients with 116Lys variants had a significantly higher metastasis rate and advanced N, M stages at diagnosis. In addition, the patients with 116Lys variants also contributed to worse cancer prognosis than those carriers with Glu/Glu genotype (hazard ratio [HR] = 1.53, 95% CI = 1.32-1.78). Functional experiments further verified that the MKK7 p.116Lys variants altered the expression of several cancer-related genes and thus affected lung cancer cells proliferation, tumor growth and metastasis in vivo and in vitro. Taken together, our findings proposed that the MKK7 p.Glu116Lys rare polymorphism incurred a pernicious impact on lung cancer risk and prognosis through modulating expressions of a serial of cancer-related genes.
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Affiliation(s)
- Fuman Qiu
- The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, School of Public Health, Guangzhou Medical University, Guangzhou, People's Republic of China
- Biomedicine Research Center and Department of Surgery, The Third Affiliated Hospital of Guangzhou Medicine University, Guangzhou, People's Republic of China
| | - Lei Yang
- The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, School of Public Health, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Xiaoxiao Lu
- School of Arts and Sciences, Colby-Sawyer College, New London, New Hampshire, United States of America
| | - Jiansong Chen
- The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, School of Public Health, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Di Wu
- The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, School of Public Health, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Yongfang Wei
- Center of Laboratory Animal, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Qingqing Nong
- Department of Environmental Health, Guangxi Medical University, Nanning, People's Republic of China
| | - Lisha Zhang
- The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, School of Public Health, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Wenxiang Fang
- The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, School of Public Health, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Xiaoliang Chen
- The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, School of Public Health, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Xiaoxuan Ling
- The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, School of Public Health, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Binyao Yang
- The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, School of Public Health, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Xin Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Yifeng Zhou
- Department of Genetics, Medical College of Soochow University, Suzhou, People's Republic of China
| | - Jiachun Lu
- The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, School of Public Health, Guangzhou Medical University, Guangzhou, People's Republic of China
- * E-mail:
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41
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GRHL2-miR-200-ZEB1 maintains the epithelial status of ovarian cancer through transcriptional regulation and histone modification. Sci Rep 2016; 6:19943. [PMID: 26887977 PMCID: PMC4757891 DOI: 10.1038/srep19943] [Citation(s) in RCA: 113] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 12/18/2015] [Indexed: 01/08/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT), a biological process by which polarized epithelial cells convert into a mesenchymal phenotype, has been implicated to contribute to the molecular heterogeneity of epithelial ovarian cancer (EOC). Here we report that a transcription factor—Grainyhead-like 2 (GRHL2) maintains the epithelial phenotype. EOC tumours with lower GRHL2 levels are associated with the Mes/Mesenchymal molecular subtype and a poorer overall survival. shRNA-mediated knockdown of GRHL2 in EOC cells with an epithelial phenotype results in EMT changes, with increased cell migration, invasion and motility. By ChIP-sequencing and gene expression microarray, microRNA-200b/a is identified as the direct transcriptional target of GRHL2 and regulates the epithelial status of EOC through ZEB1 and E-cadherin. Our study demonstrates that loss of GRHL2 increases the levels of histone mark H3K27me3 on promoters and GRHL2-binding sites at miR-200b/a and E-cadherin genes. These findings support GRHL2 as a pivotal gatekeeper of EMT in EOC via miR-200-ZEB1.
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Seshacharyulu P, Ponnusamy MP, Rachagani S, Lakshmanan I, Haridas D, Yan Y, Ganti AK, Batra SK. Targeting EGF-receptor(s) - STAT1 axis attenuates tumor growth and metastasis through downregulation of MUC4 mucin in human pancreatic cancer. Oncotarget 2016; 6:5164-81. [PMID: 25686822 PMCID: PMC4467140 DOI: 10.18632/oncotarget.3286] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Accepted: 12/30/2014] [Indexed: 12/18/2022] Open
Abstract
Transmembrane proteins MUC4, EGFR and HER2 are shown to be critical in invasion and metastasis of pancreatic cancer. Besides, we and others have demonstrated de novo expression of MUC4 in ~70-90% of pancreatic cancer patients and its stabilizing effects on HER2 downstream signaling in pancreatic cancer. Here, we found that use of canertinib or afatinib resulted in reduction of MUC4 and abrogation of in vitro and in vivo oncogenic functions of MUC4 in pancreatic cancer cells. Notably, silencing of EGFR family member in pancreatic cancer cells decreased MUC4 expression through reduced phospho-STAT1. Furthermore, canertinib and afatinib treatment also inhibited proliferation, migration and survival of pancreatic cancer cells by attenuation of signaling events including pERK1/2 (T202/Y204), cyclin D1, cyclin A, pFAK (Y925) and pAKT (Ser473). Using in vivo bioluminescent imaging, we demonstrated that canertinib treatment significantly reduced tumor burden (P=0.0164) and metastasis to various organs. Further, reduced expression of MUC4 and EGFR family members were confirmed in xenografts. Our results for the first time demonstrated the targeting of EGFR family members along with MUC4 by using pan-EGFR inhibitors. In conclusion, our studies will enhance the translational acquaintance of pan-EGFR inhibitors for combinational therapies to combat against lethal pancreatic cancer.
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Affiliation(s)
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Imayavaramban Lakshmanan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Dhanya Haridas
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ying Yan
- Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.,Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Apar K Ganti
- Department of Internal Medicine, VA Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
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Wu DI, Liu L, Ren C, Kong D, Zhang P, Jin X, Wang T, Zhang G. Epithelial-mesenchymal interconversions and the regulatory function of the ZEB family during the development and progression of ovarian cancer. Oncol Lett 2016; 11:1463-1468. [PMID: 26893761 DOI: 10.3892/ol.2016.4092] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 12/16/2015] [Indexed: 01/06/2023] Open
Abstract
This study assessed the role of epithelial-mesenchymal interconversions and the regulatory functions of the ZEB family during the development and progression of ovarian cancer. E-cadherin, vimentin, ZEB1 and ZEB2 were analyzed using immunohistochemistry in a series of ovarian tissues that included normal tissue, benign tumors, borderline tumors, malignant tumors and metastatic lesions. The correlation between E-cadherin and ZEB was analyzed. We also analyzed the association between the expression of the four factors and clinicopathological features in ovarian cancer. The results revealed that E-cadherin was weakly positive in normal ovarian epithelium. Cytoplasmic E-cadherin was significantly increased in benign tumors (P<0.01) and further increased in borderline tumors and ovarian cancers. However, cytoplasmic E-cadherin was markedly reduced in metastatic lesions (P<0.01). Membranous E-cadherin was increased in benign tumors, but decreased progressively in borderline, malignant and metastatic tumor tissues (P<0.05). The expression profile of vimentin was opposite to that of membranous E-cadherin. Membranous E-cadherin was negatively correlated with ZEB2 expression (r=-0.514). Additionally, cytoplasmic E-cadherin, ZEB1 and ZEB2 were associated with the FIGO stage of ovarian cancer. ZEB1 was also correlated with ascitic fluid volume. Our results suggest that epithelial-mesenchymal interconversions are dynamically regulated during the development and progression of ovarian tumors. ZEB2, but not ZEB1, may regulate the expression of membranous E-cadherin during these processes.
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Affiliation(s)
- D I Wu
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Lei Liu
- Department of Obstetrics and Gynecology, Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang 161006, P.R. China
| | - Chengcheng Ren
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Dan Kong
- Department of Gynecology, Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Pengqi Zhang
- Department of Pathology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Xiaoming Jin
- Department of Pathology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Tianzhen Wang
- Department of Pathology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Guangmei Zhang
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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Abstract
Background Podocalyxin-like 1 (PODXL) is a cell-adhesion glycoprotein associated with aggressive tumor phenotype and poor prognosis in several forms of cancer. The aim of this study was to investigate PODXL expression in gastric cancer by use of two different antibodies. Methods By tumor-tissue microarrays and immunohistochemistry we evaluated PODXL expression in tumor specimens from 337 patients who underwent surgery for gastric adenocarcinoma at Helsinki University Hospital. We used two different antibodies: HPA2110, which is a polyclonal antibody and an in-house monoclonal antibody called HES9, to investigate the association of PODXL expression with clinicopathologic variables and patient survival. Results PODXL staining was positive by the polyclonal antibody in 153 (57.5%) cases and by the monoclonal antibody in 212 (76%). Polyclonal antibody expression was associated with intestinal cancer type (p<0.001). Monoclonal antibody staining was associated with age over 66 (p = 0.001), with intestinal cancer (p<0.001), and with small tumor size (≤ 5 cm; p = 0.024). Both antibodies were associated with high S-phase fraction (p = 0.022; p = 0.010), and high tumor proliferation index (Ki-67; p = 0.003; p = 0.001). PODXL positivity by the polyclonal antibody indicated reduced gastric-cancer-specific 5-year survival of 24.0% (95% CI 16.9–31.1), compared to 43.3% (95% CI 33.7–52.9) for patients with PODXL negativity (p = 0.001). The result remained significant in multivariable analysis (HR = 3.17; 95% CI 1.37–7.34, p = 0.007). Conclusion In gastric cancer, PODXL expression by the polyclonal antibody HPA2110 is an independent marker of poor prognosis.
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Chen CH, Shyu MK, Wang SW, Chou CH, Huang MJ, Lin TC, Chen ST, Lin HH, Huang MC. MUC20 promotes aggressive phenotypes of epithelial ovarian cancer cells via activation of the integrin β1 pathway. Gynecol Oncol 2015; 140:131-7. [PMID: 26616226 DOI: 10.1016/j.ygyno.2015.11.025] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 11/20/2015] [Accepted: 11/21/2015] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Mucin (MUC) 20 has recently been implicated to play a role in human carcinogenesis. However, the role of MUC20 in epithelial ovarian cancer (EOC) remains to be elucidated. METHODS MUC20 expression was assessed in tissue microarray and tumor specimens of EOC patients by immunohistochemistry. Effects of MUC20 on cell viability, adhesion, migration, and invasion were analyzed in MUC20 overexpressing or knockdown EOC cells. Western blotting was performed to analyze signaling pathways modulated by MUC20. RESULTS MUC20 was overexpressed in EOC samples compared with benign tissues. High MUC20 expression was significantly associated with poor overall survival in patients with advanced-stage disease. MUC20 overexpression significantly enhanced EOC cell migration and invasion, but not viability. Mechanistic investigations showed that MUC20 increased cell adhesion to extracellular matrix (ECM) proteins and enhanced activation of integrin β1 and phosphorylation of focal adhesion kinase (FAK). The enhancement of cell motility and the integrin β1 signaling by MUC20 was significantly suppressed by integrin β1 blocking antibody. Furthermore, these effects of MUC20 on EOC cells were also demonstrated in MUC20 knockdown cells. CONCLUSIONS Our results suggest that MUC20 enhances aggressive behaviors of EOC cells by activating integrin β1 signaling and provide novel insights into the role of MUC20 in ovarian cancer metastasis.
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Affiliation(s)
- Chi-Hau Chen
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ming-Kwang Shyu
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
| | - Shu-Wei Wang
- Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chih-Hsing Chou
- Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Miao-Juei Huang
- Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tzu-Chi Lin
- Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Syue-Ting Chen
- Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ho-Hsiung Lin
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
| | - Min-Chuan Huang
- Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan.
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Pai P, Rachagani S, Lakshmanan I, Macha MA, Sheinin Y, Smith LM, Ponnusamy MP, Batra SK. The canonical Wnt pathway regulates the metastasis-promoting mucin MUC4 in pancreatic ductal adenocarcinoma. Mol Oncol 2015; 10:224-39. [PMID: 26526617 DOI: 10.1016/j.molonc.2015.10.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 10/09/2015] [Indexed: 01/15/2023] Open
Abstract
Aberrant Wnt signaling frequently occurs in pancreatic cancer (PC) and contributes to disease progression/metastases. Likewise, the transmembrane-mucin MUC4 is expressed de novo in early pancreatic intraepithelial neoplasia (PanINs) and incrementally increases with PC progression, contributing to metastasis. To determine the mechanism of MUC4 upregulation in PC, we examined factors deregulated in early PC progression, such as Wnt/β-catenin signaling. MUC4 promoter analysis revealed the presence of three putative TCF/LEF-binding sites, leading us to hypothesize that MUC4 can be regulated by β-catenin. Immunohistochemical (IHC) analysis of rapid autopsy PC tissues showed a correlation between MUC4 and cytosolic/nuclear β-catenin expression. Knock down (KD) of β-catenin in CD18/HPAF and T3M4 cell lines resulted in decreased MUC4 transcript and protein. Three MUC4 promoter luciferase constructs, p3778, p3000, and p2700, were generated. The construct p3778, encompassing the entire MUC4 promoter, elicited increased luciferase activity in the presence of stabilized β-catenin. Mutation of the TCF/LEF site closest to the transcription start site (i.e., -2629/-2612) and furthest from the start site (i.e., -3425/-3408) reduced MUC4 promoter luciferase activity. Transfection with dominant negative TCF4 decreased MUC4 transcript and protein levels. Chromatin immunoprecipitation confirmed enrichment of β-catenin on -2629/-2612 and -3425/-3408 of the MUC4 promoter in CD18/HPAF. Functionally, CD18/HPAF and T3M4 β-catenin KD cells showed decreased migration and decreased Vimentin, N-cadherin, and pERK1/2 expression. Tumorigenicity studies in athymic nude mice showed CD18/HPAF β-catenin KD cells significantly reduced primary tumor sizes and metastases compared to scrambled control cells. We show for the first time that β-catenin directly governs MUC4 in PC.
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Affiliation(s)
- Priya Pai
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198-5870, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198-5870, USA
| | - Imayavaramban Lakshmanan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198-5870, USA
| | - Muzafar A Macha
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198-5870, USA
| | - Yuri Sheinin
- Department of Pathology and Microbiology, UNMC, Omaha, NE 68198-5900, USA
| | - Lynette M Smith
- Department of Biostatistics, UNMC College of Public Health, UNMC, Omaha, NE 68198-4375, USA
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198-5870, USA; Fred and Pamela Buffett Cancer Center, UNMC, Omaha, NE 68198, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, UNMC, Omaha, NE 68198-5950, USA; Fred and Pamela Buffett Cancer Center, UNMC, Omaha, NE 68198, USA.
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Das S, Rachagani S, Sheinin Y, Smith LM, Gurumurthy CB, Roy HK, Batra SK. Mice deficient in Muc4 are resistant to experimental colitis and colitis-associated colorectal cancer. Oncogene 2015; 35:2645-54. [PMID: 26364605 DOI: 10.1038/onc.2015.327] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Revised: 05/10/2015] [Accepted: 06/06/2015] [Indexed: 12/18/2022]
Abstract
MUC4, a large transmembrane mucin normally expressed in the small and large intestine, is differentially expressed during inflammatory and malignant conditions of the colon. However, the expression pattern and the role of MUC4 in colitis and colorectal cancer (CRC) are inconclusive. Therefore, the aim of this study was to understand the role of Muc4 during inflammatory and malignant conditions of the colon. Here, we generated Muc4(-/-) mice and addressed its role in colitis and colitis-associated CRC using dextran sodium sulfate (DSS) and azoxymethane (AOM)-DSS experimental models, respectively. Muc4(-/-) mice were viable, fertile with no apparent defects. Muc4(-/-) mice displayed increased resistance to DSS-induced colitis compared with wild-type (WT) littermates that was evaluated by survival rate, body weight loss, diarrhea and fecal blood score, and histological score. Reduced infiltration of inflammatory cells, that is, CD3(+) lymphocytes and F4/80(+) macrophages was observed in the inflamed mucosa along with reduction in the mRNA levels of inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α and anti-microbial genes Lysozyme M and SLPI in the colon of Muc4(-/-) mice compared with WT littermates. Compensatory upregulation of Muc2 and Muc3 mucins under basal and DSS treatment conditions partly explains the resistance observed in Muc4(-/-) mice. Accordingly, Muc4(-/-) mice exhibited significantly reduced tumor burden compared with WT mice assessed in a colitis-induced tumor model using AOM/DSS. An increased percentage of Ki67(+) nuclei was observed in the tumors from WT compared with Muc4(-/-) mice suggesting Muc4 to be critical in intestinal cell proliferation during tumorigenesis. Taken together, we conclusively demonstrate for the first time the role of Muc4 in driving intestinal inflammation and inflammation-associated tumorigenesis using a novel Muc4(-/-) mouse model.
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Affiliation(s)
- S Das
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - S Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Y Sheinin
- Department of Pathology, University of Nebraska Medical Center, Omaha, NE, USA
| | - L M Smith
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA
| | - C B Gurumurthy
- Mouse Genome Engineering Core Facility, Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
| | - H K Roy
- Center for Digestive Disorders, Boston University School of Medicine, Boston, MA, USA
| | - S K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
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EMT-Inducing Molecular Factors in Gynecological Cancers. BIOMED RESEARCH INTERNATIONAL 2015; 2015:420891. [PMID: 26356073 PMCID: PMC4556818 DOI: 10.1155/2015/420891] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 01/14/2015] [Indexed: 12/27/2022]
Abstract
Gynecologic cancers are the unregulated growth of neoplastic cells that arise in the cervix, ovaries, fallopian tubes, uterus, vagina, and vulva. Although gynecologic cancers are characterized by different signs and symptoms, studies have shown that they share common risk factors, such as smoking, obesity, age, exposure to certain chemicals, infection with human immunodeficiency virus (HIV), and infection with human papilloma virus (HPV). Despite recent advancements in the preventative, diagnostic, and therapeutic interventions for gynecologic cancers, many patients still die as a result of metastasis and recurrence. Since mounting evidence indicates that the epithelial-mesenchymal transition (EMT) process plays an essential role in metastatic relapse of cancer, understanding the molecular aberrations responsible for the EMT and its underlying signaling should be given high priority in order to reduce cancer morbidity and mortality.
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Exploring the role and diversity of mucins in health and disease with special insight into non-communicable diseases. Glycoconj J 2015; 32:575-613. [PMID: 26239922 DOI: 10.1007/s10719-015-9606-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 06/18/2015] [Indexed: 12/11/2022]
Abstract
Mucins are major glycoprotein components of the mucus that coats the surfaces of cells lining the respiratory, digestive, gastrointestinal and urogenital tracts. They function to protect epithelial cells from infection, dehydration and physical or chemical injury, as well as to aid the passage of materials through a tract i.e., lubrication. They are also implicated in the pathogenesis of benign and malignant diseases of secretory epithelial cells. In Human there are two types of mucins, membrane-bound and secreted that are originated from mucous producing goblet cells localized in the epithelial cell layer or in mucous producing glands and encoded by MUC gene. Mucins belong to a heterogeneous family of high molecular weight proteins composed of a long peptidic chain with a large number of tandem repeats that form the so-called mucin domain. The molecular weight is generally high, ranging between 0.2 and 10 million Dalton and all mucins contain one or more domains which are highly glycosylated. The size and number of repeats vary between mucins and the genetic polymorphism represents number of repeats (VNTR polymorphisms), which means the size of individual mucins can differ substantially between individuals which can be used as markers. In human it is only MUC1 and MUC7 that have mucin domains with less than 40% serine and threonine which in turn could reduce number of PTS domains. Mucins can be considered as powerful two-edged sword, as its normal function protects from unwanted substances and organisms at an arm's length while, malfunction of mucus may be an important factor in human diseases. In this review we have unearthed the current status of different mucin proteins in understanding its role and function in various non-communicable diseases in human with special reference to its organ specific locations. The findings described in this review may be of direct relevance to the major research area in biomedicine with reference to mucin and mucin associated diseases.
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50
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Rodrigues LU, Rider L, Nieto C, Romero L, Karimpour-Fard A, Loda M, Lucia MS, Wu M, Shi L, Cimic A, Sirintrapun SJ, Nolley R, Pac C, Chen H, Peehl DM, Xu J, Liu W, Costello JC, Cramer SD. Coordinate loss of MAP3K7 and CHD1 promotes aggressive prostate cancer. Cancer Res 2015; 75:1021-34. [PMID: 25770290 DOI: 10.1158/0008-5472.can-14-1596] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Prostate cancer subtypes are poorly defined and functional validation of drivers of ETS rearrangement-negative prostate cancer has not been conducted. Here, we identified an ETS(-) subtype of aggressive prostate cancer (ERG(-)MAP3K7(del)CHD1(del)) and used a novel developmental model and a cell line xenograft model to show that cosuppression of MAP3K7 and CHD1 expression promotes aggressive disease. Analyses of publicly available prostate cancer datasets revealed that MAP3K7 and CHD1 were significantly codeleted in 10% to 20% of localized tumors and combined loss correlated with poor disease-free survival. To evaluate the functional impact of dual MAP3K7-CHD1 loss, we suppressed Map3k7 and/or Chd1 expression in mouse prostate epithelial progenitor/stem cells (PrP/SC) and performed tissue recombination experiments in vivo. Dual shMap3k7-shChd1 PrP/SC recombinants displayed massive glandular atypia with regions of prostatic intraepithelial neoplasia and carcinoma apparent. Combined Map3k7-Chd1 suppression greatly disrupted normal prostatic lineage differentiation; dual recombinants displayed significant androgen receptor loss, increased neuroendocrine differentiation, and increased neural differentiation. Clinical samples with dual MAP3K7-CHD1 loss also displayed neuroendocrine and neural characteristics. In addition, dual Map3k7-Chd1 suppression promoted E-cadherin loss and mucin production in recombinants. MAP3K7 and CHD1 protein loss also correlated with Gleason grade and E-cadherin loss in clinical samples. To further validate the phenotype observed in the PrP/SC model, we suppressed MAP3K7 and/or CHD1 expression in LNCaP prostate cancer cells. Dual shMAP3K7-shCHD1 LNCaP xenografts displayed increased tumor growth and decreased survival compared with shControl, shMAP3K7, and shCHD1 xenografts. Collectively, these data identify coordinate loss of MAP3K7 and CHD1 as a unique driver of aggressive prostate cancer development.
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Affiliation(s)
- Lindsey Ulkus Rodrigues
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Cancer Biology, Wake Forest University, Winston-Salem, North Carolina
| | - Leah Rider
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Cera Nieto
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Lina Romero
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Anis Karimpour-Fard
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Massimo Loda
- Department of Pathology, Dana Farber Cancer Institute, Boston, Massachusetts
| | - M Scott Lucia
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Min Wu
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Lihong Shi
- Department of Cancer Biology, Wake Forest University, Winston-Salem, North Carolina
| | - Adela Cimic
- Department of Pathology, Wake Forest University, Winston-Salem, North Carolina
| | | | - Rosalie Nolley
- Department of Urology, Stanford University School of Medicine, Stanford, California
| | - Colton Pac
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Haitao Chen
- Center for Genetic Epidemiology, Fudan University, Shanghai, China
| | - Donna M Peehl
- Department of Urology, Stanford University School of Medicine, Stanford, California
| | - Jianfeng Xu
- Center for Cancer Genomics, Wake Forest University, Winston-Salem, North Carolina. Center for Genomics and Personalized Medicine Research, Wake Forest University, Winston-Salem, North Carolina
| | - Wennuan Liu
- Center for Cancer Genomics, Wake Forest University, Winston-Salem, North Carolina. Center for Genomics and Personalized Medicine Research, Wake Forest University, Winston-Salem, North Carolina
| | - James C Costello
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Scott D Cramer
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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