Distinct anti-oncogenic effect of various microRNAs in different mouse models of liver cancer
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Junyan Tao1,2,*, Junfang Ji3,4,*, Xiaolei Li2,5,*, Ning Ding2,6,*, Heng Wu7, Yan Liu2,5, XinWei Wang3, Diego F. Calvisi8, Guisheng Song7, Xin Chen1,2
1School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, P.R. China
2Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA
3Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
4Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, Hawaii, USA
5Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, P.R. China
6Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, P.R. China
7Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
8Institute of Pathology, University of Greifswald, Greifswald, Germany
*These authors have contributed equally to this work
Xin Chen, e-mail: firstname.lastname@example.org
Guisheng Song, e-mail: email@example.com
Keywords: HCC, c-Myc, AKT, Ras, mouse liver cancer
Received: October 19, 2014 Accepted: January 19, 2015 Published: February 09, 2015
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.
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