Distinct anti-oncogenic effect of various microRNAs in different mouse models of liver cancer

// Junyan Tao 1, 2, * , Junfang Ji 3, 4, * , Xiaolei Li 2, 5, * , Ning Ding 2, 6, * , Heng Wu 7 , Yan Liu 2, 5 , XinWei Wang 3 , Diego F. Calvisi 8 , Guisheng Song 7 , Xin Chen 1, 2 1 School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, P.R. China 2 Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA 3 Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA 4 Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, Hawaii, USA 5 Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, P.R. China 6 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, P.R. China 7 Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA 8 Institute of Pathology, University of Greifswald, Greifswald, Germany * These authors have contributed equally to this work Correspondence to: Xin Chen, e-mail: xin.chen@ucsf.edu Guisheng Song, e-mail: gsong@umn.edu Keywords: HCC, c-Myc, AKT, Ras, mouse liver cancer Received: October 19, 2014 Accepted: January 19, 2015 Published: February 09, 2015 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.