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

被引:48
作者
Tao, Junyan [1 ,2 ,3 ]
Ji, Junfang [4 ,5 ]
Li, Xiaolei [2 ,3 ,6 ]
Ding, Ning [2 ,3 ,7 ]
Wu, Heng [8 ]
Liu, Yang [2 ,3 ,6 ]
Wang, XinWei [4 ]
Calvisi, Diego F. [9 ]
Song, Guisheng [8 ]
Cheng, Xin [1 ,2 ,3 ]
机构
[1] Hubei Univ Chinese Med, Sch Pharm, Wuhan, Hubei, Peoples R China
[2] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Ctr Liver, San Francisco, CA 94143 USA
[4] NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA
[5] Univ Hawaii Manoa, Univ Hawaii Canc Ctr, Canc Biol Program, Honolulu, HI 96822 USA
[6] Fourth Mil Med Univ, Xijing Hosp, Dept Hepatobiliary Surg, Xian 710032, Shaanxi, Peoples R China
[7] Peking Univ Canc Hosp & Inst, Dept Gastrointestinal Surg, Minist Educ, Key Lab Carcinogenesis & Translat Res, Beijing, Peoples R China
[8] Univ Minnesota, Sch Med, Dept Med, Minneapolis, MN 55455 USA
[9] Ernst Moritz Arndt Univ Greifswald, Inst Pathol, Greifswald, Germany
关键词
HCC; c-Myc; AKT; Ras; mouse liver cancer; HEPATOCELLULAR-CARCINOMA; C-MYC; TRANSGENIC MICE; STEM-CELLS; HEPATITIS; SURVIVAL; TUMORIGENICITY; IDENTIFICATION; AMPLIFICATION; MANAGEMENT;
D O I
10.18632/oncotarget.3166
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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, miR365, 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.
引用
收藏
页码:6977 / 6988
页数:12
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