title: Ectopic overexpression of filamin C scaffolds MEK1/2 and ERK1/2 to promote the progression of human hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) invasion and metastasis are mediated by a complicated signal transduction network and downstream cytoskeletal and adhesion molecules. In this study, a microarray-based analysis revealed a dramatic increase in filamin C (FLNC), which is commonly expressed in muscle rather than in liver cells, in the two metastatic HCC cell lines MHCC97L and HCCLM3. Clinicopathological studies showed that increased FLNC expression was associated with microvascular invasion and poor prognosis. Specific hypomethylation was identified within the FLNC promoter region in HCC cell lines and patient tumor samples, which might contribute to the ectopic overexpression of FLNC. FLNC downregulation inhibited cell migration and impaired cell proliferation and promoted apoptosis. Mechanistic studies suggested that FLNC interacts with mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) and extracellular signal-regulated kinase 1/2 (ERK1/2) and that FLNC downregulation inhibited MEK1/2 and ERK1/2 activation. Xenographic tumor transplantation experiments in nude mice further confirmed the role of FLNC in HCC progression and metastasis. Our results reveal a novel mechanism by which the cytoskeletal protein FLNC enhances the mitogen-activated protein kinase signaling pathway during tumorigenesis.
authors.affiliation: Key Laboratory of Breast Cancer Prevention and Therapy, Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Research Center of Basic Medical Sciences, Department of Medical Microbiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China; Department of Gynaecology and Obstetrics, Jiaxing Maternity and Child Health Care Hospital, Jiaxing, Zhejiang Province, China.
authors.forename: Baicai
authors.initials: B
authors.lastname: Yang
authors.affiliation: Key Laboratory of Breast Cancer Prevention and Therapy, Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Research Center of Basic Medical Sciences, Department of Medical Microbiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Breast Cancer Prevention and Therapy, Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Research Center of Basic Medical Sciences, Department of Medical Microbiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Breast Cancer Prevention and Therapy, Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Research Center of Basic Medical Sciences, Department of Medical Microbiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Kaiwen
authors.initials: K
authors.lastname: Hei
authors.affiliation: Key Laboratory of Breast Cancer Prevention and Therapy, Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Research Center of Basic Medical Sciences, Department of Medical Microbiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhuang
authors.affiliation: Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: School of Life Sciences, Chongqing University, Chongqing, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Wei
authors.affiliation: Key Laboratory of Breast Cancer Prevention and Therapy, Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Research Center of Basic Medical Sciences, Department of Medical Microbiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Ruibing
authors.initials: R
authors.lastname: Chen
authors.affiliation: Key Laboratory of Breast Cancer Prevention and Therapy, Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Research Center of Basic Medical Sciences, Department of Medical Microbiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. Electronic address: zhangning@tmu.edu.cn.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Breast Cancer Prevention and Therapy, Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Research Center of Basic Medical Sciences, Department of Medical Microbiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. Electronic address: liym@tmu.edu.cn.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D064448:Filamins; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D064448:Filamins; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases
keywords: Apoptosis; Metastasis; Methylation; Microarray; Proliferation