title: SIRT1 facilitates hepatocellular carcinoma metastasis by promoting PGC-1α-mediated mitochondrial biogenesis.
abstract: SIRT1 is a multifaceted NAD+-dependent protein deacetylase known to act as a tumor promoter or suppressor in different cancers. Here, we describe a novel mechanism of SIRT1-induced hepatocellular carcinoma (HCC) metastasis. SIRT1 overexpression was frequently detected in human HCC specimens and was associated with microvascular invasion (P = 0.0039), advanced tumor node metastasis (TNM) stages (P = 0.0016), HCC recurrence (P = 0.021) and poor outcomes (P = 0.039). Lentivirus-mediated knockdown of SIRT1 in MHCC97H cells reduced invasion and metastasis in vitro and in vivo. SIRT1 depletion attenuated mitochondrial biogenesis and adenosine triphosphate (ATP) production but did not affect epithelial-mesenchymal transition. Elevated SIRT1 expression strongly correlated with the upregulation of PGC-1α in HCC specimens, and ectopic expression of SIRT1 increased PGC-1α levels. In cell assays and an orthotopic transplantation model, PGC-1α overexpression reversed the inhibitory effects of SIRT1 depletion on invasion and metastasis by enhancing mitochondrial biogenesis. These findings reveal the involvement of SIRT1 in HCC metastasis and provide a rationale for exploring therapeutic targets against the SIRT1/PGC-1α axis.
authors.affiliation: Department of Hepatobiliary Surgery, Second Affiliated Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, China.
authors.forename: Shangcheng
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Hepatobiliary Surgery, Second Affiliated Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, Second Affiliated Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, China.
authors.forename: Min
authors.initials: M
authors.lastname: Feng
authors.affiliation: Department of Military Nursing, School of Nursing, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xiaoya
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, Second Affiliated Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Han
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, China.
authors.forename: Huifeng
authors.initials: H
authors.lastname: Pi
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, Second Affiliated Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Hepatobiliary Surgery, Second Affiliated Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Nan
authors.initials: N
authors.lastname: You
authors.affiliation: Department of Hepatobiliary Surgery, Second Affiliated Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Yewang
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Hepatobiliary Surgery, Second Affiliated Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Guohua
authors.initials: G
authors.lastname: Zuo
authors.affiliation: Department of Hepatobiliary Surgery, Second Affiliated Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, Second Affiliated Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Deng
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, China.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Hepatobiliary Surgery, Second Affiliated Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Liang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: PGC-1α; SIRT1; hepatocellular carcinoma; metastasis; mitochondrial biogenesis