Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model

Kota et al.  Cell 137, 1005–1017, 2009

Speaker: Shuo-Fu Lin (林碩甫)                                             Time: 13:10~14:00, Nov. 11, 2009

Commentator: Prof. Cheng-Chan Lu (呂政展 教授)              Place: Room 601

Abstract

      MicroRNAs (miRNAs) play fundamental roles in the regulation of gene expression by pairing within the 3′ untranslated regions (UTRs) of targeted transcripts¹. Although specific miRNAs are often overexpressed in cancer cells, most miRNAs are downregulated in tumors². There are numerous examples linking dysregulated expression of miRNAs to cancer, and miRNAs are increasingly viewed as potential therapeutic targets. Previous studies have demonstrated that hyperactivity of Myc, which commonly occurs in diverse tumor types, leads to widespread miRNA repression³. The miRNA whose expression is most perturbed in the MYC-induced hepatocarinoma is miR-26a³. In this study, the authors demonstrated that ectopic expression of a single miRNA, miR-26a, can reverse disease progression in a mouse model of hepatocellular carcinoma (HCC). First, they found that dysregulated expression of miRNAs in mouse and human liver tumors. They also showed that miR-26a regulates the expression of the cyclins D2 and E2 and induces a G1 arrest of human liver cancer cells. Hence, reduced expression of this miRNA is likely to perturb the normal cell-cycle control of hepatocytes. To further investigate the therapeutic potential of miR-26a for HCC, the authors exploited tet-o-MYC; LAP-tTA mice as a mouse model of hepatocarcinoma, in which expression of human MYC is induced by tetracycline. Mice harboring the inducible human MYC transgene develop hepatic cancer following administration of the tetracycline analog doxycycline. Systemic administration of adeno-associated virus (AAV) vectors expressing miR-26a resulted in inhibition of cancer cell proliferation, induction of tumor-specific apoptosis, and dramatic protection from disease progression without toxicity in the mouse model of HCC. Therefore, the use of a natural miRNA to suppress cell proliferation holds promise and may lead to a new therapeutic strategy for the treatment of liver cancer.

References

1.      Bartel  DP & Chen, CZ. 2004. Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nat. Rev. Genetics 5: 396-400.

2.      Gaur A et al. 2007. Characterization of MicroRNA Expression Levels and Their Biological Correlates in Human Cancer Cell Lines. Cancer Res. 67:2456-2468.

3.      Chang TC. et al. 2007. Widespread microRNA repression by Myc contributes to tumorigenesis. Nat. Genet. 40, 43-50