title: Distinct anti-oncogenic effect of various microRNAs in different mouse models of liver cancer.
abstract: Deregulation of microRNAs (miRNAs) is a typical feature of human hepatocellular carcinoma (HCC). However, the in vivo relevance of miRNAs along hepatocarcinogenesis remains largely unknown. Here, we show that liver tumors induced in mice by c-Myc overexpression or AKT/Ras co-expression exhibit distinct miRNA expression profiles. Among the downregulated miRNAs, eight (miR-101, miR-107, miR-122, miR-29, miR-365, miR-375, miR-378, and miR-802) were selected and their tumor suppressor activity was determined by overexpressing each of them together with c-Myc or AKT/Ras oncogenes in mouse livers via hydrodynamic transfection. The tumor suppressor activity of these microRNAs was extremely heterogeneous in c-Myc and AKT/Ras mice: while miR-378 had no tumor suppressor activity, miR-107, mir-122, miR-29, miR-365 and miR-802 exhibited weak to moderate tumor suppressor potential. Noticeably, miR-375 showed limited antineoplastic activity against c-Myc driven tumorigenesis, whereas it strongly inhibited AKT/Ras induced hepatocarcinogenesis. Furthermore, miR-101 significantly suppressed both c-Myc and AKT/Ras liver tumor development. Altogether, the present data demonstrate that different oncogenes induce distinct miRNA patterns, whose modulation differently affects hepatocarcinogenesis depending on the driving oncogenes. Finally, our findings support a strong tumor suppressor activity of miR-101 in liver cancer models regardless of the driver oncogenes involved, thus representing a promising therapeutic target in human HCC.
authors.affiliation: School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, P.R. China.|Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA.
authors.forename: Junyan
authors.initials: J
authors.lastname: Tao
authors.affiliation: Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.|Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, Hawaii, USA.
authors.forename: Junfang
authors.initials: J
authors.lastname: Ji
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA.|Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, P.R. China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA.|Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, P.R. China.
authors.forename: Ning
authors.initials: N
authors.lastname: Ding
authors.affiliation: Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA.|Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Xin Wei
authors.initials: XW
authors.lastname: Wang
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.affiliation: Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Guisheng
authors.initials: G
authors.lastname: Song
authors.affiliation: School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, P.R. China.|Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D018631:ras Proteins
keywords: AKT; HCC; Ras; c-Myc; mouse liver cancer