PMID- 26082485 OWN - NLM STAT- MEDLINE DCOM- 20151019 LR - 20210205 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 290 IP - 30 DP - 2015 Jul 24 TI - Steroid Receptor Coactivator 1 Promotes Human Hepatocellular Carcinoma Progression by Enhancing Wnt/beta-Catenin Signaling. PG - 18596-608 LID - 10.1074/jbc.M115.640490 [doi] AB - 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 beta-catenin to enhance Wnt/beta-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/beta-catenin signaling and suggest that SRC-1 is a potential therapeutic molecular target for HCC. CI - (c) 2015 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Tong, Zhangwei AU - Tong Z AD - 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. FAU - Li, Ming AU - Li M AD - 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. FAU - Wang, Wei AU - Wang W AD - 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. FAU - Mo, Pingli AU - Mo P AD - 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. FAU - Yu, Li AU - Yu L AD - 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. FAU - Liu, Kun AU - Liu K AD - 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. FAU - Ren, Wenjing AU - Ren W AD - 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. FAU - Li, Wengang AU - Li W AD - the Department of Hepatobiliary Pancreas and Vessel Surgery, Chenggong Hospital of Xiamen University, Xiamen, Fujian 361003, China. FAU - Zhang, Hao AU - Zhang H AD - the Cancer Research Center at Shantou University Medical College, Shantou, Guangdong 515041, China, and. FAU - Xu, Jianming AU - Xu J AD - the Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030. FAU - Yu, Chundong AU - Yu C AD - 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. LA - eng GR - R01 CA112403/CA/NCI NIH HHS/United States GR - R01 CA193455/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150616 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (MYC protein, human) RN - 0 (Proliferating Cell Nuclear Antigen) RN - 0 (Proto-Oncogene Proteins c-myc) RN - 0 (beta Catenin) RN - EC 2.3.1.48 (NCOA3 protein, human) RN - EC 2.3.1.48 (Nuclear Receptor Coactivator 1) RN - EC 2.3.1.48 (Nuclear Receptor Coactivator 3) SB - IM MH - Animals MH - Carcinoma, Hepatocellular/*genetics/pathology MH - Cell Proliferation/genetics MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Liver Neoplasms/*genetics/pathology MH - Mice MH - Nuclear Receptor Coactivator 1/biosynthesis/*genetics MH - Nuclear Receptor Coactivator 3/biosynthesis/metabolism MH - Proliferating Cell Nuclear Antigen/biosynthesis/metabolism MH - Proto-Oncogene Proteins c-myc/*biosynthesis/metabolism MH - Wnt Signaling Pathway/*genetics MH - Xenograft Model Antitumor Assays MH - beta Catenin/genetics/metabolism PMC - PMC4513118 OTO - NOTNLM OT - Myc (c-Myc) OT - Wnt signaling OT - cell proliferation OT - hepatocellular carcinoma OT - steroid receptor coactivator (SRC-1) OT - transcriptional coactivator EDAT- 2015/06/18 06:00 MHDA- 2015/10/20 06:00 PMCR- 2016/07/24 CRDT- 2015/06/18 06:00 PHST- 2015/01/23 00:00 [received] PHST- 2015/06/18 06:00 [entrez] PHST- 2015/06/18 06:00 [pubmed] PHST- 2015/10/20 06:00 [medline] PHST- 2016/07/24 00:00 [pmc-release] AID - S0021-9258(20)42338-5 [pii] AID - M115.640490 [pii] AID - 10.1074/jbc.M115.640490 [doi] PST - ppublish SO - J Biol Chem. 2015 Jul 24;290(30):18596-608. doi: 10.1074/jbc.M115.640490. Epub 2015 Jun 16.