title: Metformin inhibits the prometastatic effect of sorafenib in hepatocellular carcinoma by upregulating the expression of TIP30.
abstract: We previously found that a low dose of sorafenib had a prometastatic effect on hepatocellular carcinoma (HCC), which was caused by downregulation of TIP30 expression. More recently, metformin has been shown to have potential as a preventive and therapeutic agent for different cancers, including HCC. This study evaluated whether the combination of sorafenib and metformin is sufficient to revert the expression of TIP30, thereby simultaneously reducing lung metastasis and improving survival. Our data show that the combination of sorafenib and metformin inhibits proliferation and invasion in vitro, prolongs median survival, and reduces lung metastasis of HCC in vivo. This effect is closely associated with the upregulation of TIP30, partly through activating AMP-activated protein kinase. Thioredoxin, a prometastasis factor, is negatively regulated by TIP30 and plays an essential role during the process of HCC metastasis. Overall, our results suggest that metformin might be a potent enhancer for the treatment of HCC by using sorafenib.
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Zhigui
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
authors.forename: Manqing
authors.initials: M
authors.lastname: Cao
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Abin
authors.initials: A
authors.lastname: You
authors.affiliation: Academy of Medical Image, Tianjin Medical University, Tianjin, China.
authors.forename: Junrong
authors.initials: J
authors.lastname: Gao
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Hongyuan
authors.initials: H
authors.lastname: Zhou
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Huikai
authors.initials: H
authors.lastname: Li
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Cui
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Fang
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Tianqiang
authors.initials: T
authors.lastname: Song
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
authors.forename: Huichuan
authors.initials: H
authors.lastname: Sun
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Ti
authors.initials: T
authors.lastname: Zhang
mesh_terms: D000123:Acetyltransferases / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000556:secondary; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects; D015398:Signal Transduction; D000077157:Sorafenib; D013879:Thioredoxins / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D010671:Phenylurea Compounds; D014157:Transcription Factors; D009536:Niacinamide; D013879:Thioredoxins; D008687:Metformin; D000077157:Sorafenib; D000123:Acetyltransferases; C111246:HTATIP2 protein, human
keywords: Hepatocellular carcinoma; human TIP30 protein; metformin; sorafenib; thioredoxins