title: Steroid Receptor Coactivator 1 Promotes Human Hepatocellular Carcinoma Progression by Enhancing Wnt/β-Catenin Signaling.
abstract: Steroid receptor coactivator 1 (SRC-1) is a transcriptional coactivator not only for steroid receptors, such as androgen receptor and estrogen receptor, but also for other transcription factors. SRC-1 has been shown to play an important role in the progression of breast cancer and prostate cancer. However, its role in liver cancer progression remains unknown. In this study, we report that SRC-1 was overexpressed in 25 (62.5%) of 40 human hepatocellular carcinoma (HCC) specimens. Down-regulation of SRC-1 decreased HCC cell proliferation and impaired tumor maintenance in HCC xenografts. Knockdown of SRC-1 reduced protein levels of the proliferation marker proliferating cell nuclear antigen (PCNA) and the oncogene c-Myc. Knockout of SRC-1 in mice reduced diethylnitrosamine/CCl4-induced tumor formation in the liver and the expression of c-Myc and PCNA in liver tumors. SRC-1 promoted c-Myc expression, at least in part, by directly interacting with β-catenin to enhance Wnt/β-catenin signaling. Consistent with these results, the expression of SRC-1 was positively correlated with PCNA expression in human HCC specimens, and the expression levels of c-Myc in SRC-1-positive HCC specimens were higher than in SRC-1-negative HCC specimens. In addition, SRC-1 and SRC-3 were co-overexpressed in 47.5% of HCC specimens, and they cooperated to promote HCC cell proliferation. Simultaneous down-regulation of SRC-1 and SRC-3 dramatically inhibited HCC cell proliferation. Our results demonstrate that SRC-1 promotes HCC progression by enhancing Wnt/β-catenin signaling and suggest that SRC-1 is a potential therapeutic molecular target for HCC.
authors.affiliation: From the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China, the Engineering Research Center of Molecular Diagnostics, Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Zhangwei
authors.initials: Z
authors.lastname: Tong
authors.affiliation: From the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China, the Department of Hepatobiliary Pancreas and Vessel Surgery, Chenggong Hospital of Xiamen University, Xiamen, Fujian 361003, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: From the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: From the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Pingli
authors.initials: P
authors.lastname: Mo
authors.affiliation: From the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.affiliation: From the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China, the Department of Pathology, Chenggong Hospital of Xiamen University, Xiamen, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
authors.affiliation: From the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Ren
authors.affiliation: the Department of Hepatobiliary Pancreas and Vessel Surgery, Chenggong Hospital of Xiamen University, Xiamen, Fujian 361003, China.
authors.forename: Wengang
authors.initials: W
authors.lastname: Li
authors.affiliation: the Cancer Research Center at Shantou University Medical College, Shantou, Guangdong 515041, China, and.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: the Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.affiliation: From the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China, the Engineering Research Center of Molecular Diagnostics, Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China, cdyu@xmu.edu.cn.
authors.forename: Chundong
authors.initials: C
authors.lastname: Yu
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D056920:Nuclear Receptor Coactivator 1 / Q000096:biosynthesis / Q000235:genetics*; D056921:Nuclear Receptor Coactivator 3 / Q000096:biosynthesis / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C489427:MYC protein, human; D018809:Proliferating Cell Nuclear Antigen; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin; C538866:NCOA3 protein, human; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3
keywords: Myc (c-Myc); Wnt signaling; cell proliferation; hepatocellular carcinoma; steroid receptor coactivator (SRC-1); transcriptional coactivator