title: miR-203 inhibits augmented proliferation and metastasis of hepatocellular carcinoma residual in the promoted regenerating liver.
abstract: Liver resection is still the most commonly used therapeutic treatment for hepatocellular carcinoma (HCC), and liver regeneration promotes HCC growth in the regenerating liver. The high recurrence/metastasis of HCC is the main cause of death for HCC patients after liver resection. However, how the augmented growth and metastasis of residual HCC induced by the promoted liver regeneration following liver resection can be abolished remains unclear. In this study, a rat model with liver cirrhosis and diffused HCC was established by administration of diethylnitrosamine. Recombinant miR-203 adenovirus was administered to induce hepatic miR-203 overexpression and 30% partial hepatectomy (PH) followed. The effect of miR-203 on the proliferation, invasion and metastasis of the residual HCC in the remnant cirrhotic liver with promoted regeneration was investigated. We found that the basic spontaneous regeneration of the non-tumorous liver by 30% PH promoted proliferation, invasion and lung metastasis of the hepatic residual HCC. miR-203 overexpression further promoted the regeneration of the non-tumorous liver by upregulating Ki67 expression and enhancing IL-6/SOCS3/STAT3 pro-proliferative signals. Importantly, miR-203 overexpression markedly inhibited the proliferation, invasion and metastasis of hepatic residual HCC through suppressing expression of Ki67, CAPNS1 and lung metastasis. Moreover, it was found that miR-203 overexpression reversed the epithelial-mesenchymal transition induced by hepatectomy through targeting IL-1β, Snail1 and Twist1. In conclusion, our results suggested that miR-203 overexpression inhibited the augmented proliferation and lung metastasis of the residual HCC induced by the promoted liver regeneration following PH partly by regulating epithelial-mesenchymal transition.
authors.affiliation: Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Xiao-Bo
authors.identifier: http://orcid.org/0000-0003-1361-6851
authors.initials: XB
authors.lastname: Zheng
authors.affiliation: Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.|Department of Hepatobiliary Surgery, The Affiliated Hospital of Kunming University of Science and Technology (the First People's Hospital of Yunnan Province), Kunming, China.
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Chen
authors.affiliation: Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Liang-Liang
authors.initials: LL
authors.lastname: Xu
authors.affiliation: Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Yi
authors.affiliation: Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Tang
authors.affiliation: Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Ming-Qing
authors.initials: MQ
authors.lastname: Xu
mesh_terms: D000818:Animals; D002154:Calpain / Q000096:biosynthesis; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics*; D004052:Diethylnitrosamine / Q000633:toxicity; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D006498:Hepatectomy; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000378:metabolism
chemical_list: C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D015850:Interleukin-6; D019394:Ki-67 Antigen; C000604042:MIRN203 microRNA, rat; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; D000071250:Snail Family Transcription Factors; C491410:Socs3 protein, rat; C494088:Stat3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D051879:Twist-Related Protein 1; C497754:Twist1 protein, rat; C000604452:snai1 protein, rat; D004052:Diethylnitrosamine; D002154:Calpain; C587939:Capns1 protein, rat
keywords: Hepatectomy; hepatocellular carcinoma; liver regeneration; miR-203 overexpression; proliferation and metastasis