Talk abstracts

Talk on Monday 04:00-04:15pm submitted by Shu-hao Hsu

Loss of microRNA-122 in mice causes hepatic inflammation and hepatocarcinogenesis

Shu-hao Hsu (Department of Molecular and Cellular Biochemistry), Bo Wang (Department of Molecular and Cellular Biochemistry), Stefan Costinean (Department of Pathology), Huban Kutay, Shoumei Bai (Comprehensive Cancer Center), Lianbo Yu (Center for Biostatistics), Samson T. Jacob, Kalpana Ghoshal (Comprehensive Cancer Center)

Abstract:
Background: miR-122 is the most abundant liver-specific microRNA [1] that modulates hepatic lipid metabolism [2,3] and hepatitis C viral replication [4]. We have previously shown that it is downregulated in hepatocellular carcinoma (HCC) of both rodent and human origin [5], and it inhibits tumorigenic properties of HCC cells both in vitro and ex vivo [5,6]. Here, we have addressed the biological functions of miR-122 using liver specific (LKO) and germline (KO) miR-122 knockout mice.
Results and conclusions: Hepatic miR-122 level was depleted by 99% in adult LKO mice, and was abolished in KO mice. Both LKO and KO have increased hepatic triglyceride and reduced serum total, HDL- and LDL-associated cholesterol. Increased CK19- and A6-postitve cells as well as elevated serum alkaline phosphatase indicate abnormality in the biliary system in mutant mice. These mice developed hepatic inflammation in early adult life, which progressed to bridging inflammation and fibrosis with age. Sylamer analysis [7] of hepatic gene expression profile in LKO mice showed significant upregulation of mRNAs harboring miR-122 cognate sites in their 3’-UTRs. Ingenuity Pathway Analysis revealed genes involved in cancer and metabolic pathways are top scored networks among the dysregulated genes in LKO livers. Upregulation of Ccng1, Ccnd1, Afp, Igf2, c-Myc and Ctnnb1 (&beta-catenin) correlated with increased proliferation and dedifferentiation of miR-122 deficient hepatocytes. After one year, both LKO and KO mice developed spontaneous liver tumors, including HCC and cholangiocarcinoma, and exhibited liver damage. Taken together, these observations suggest that miR-122 deficiency causes steatosis, inflammation and fibrosis that lead to hepatocarcinogenesis. These results also provide rationale for examining therapeutic efficacy of miR-122 mimic against hepatocellular cancer.

References:
1. Lagos-Quintana, M. et al. Curr Biol 12 (9), 735-739 (2002).
2. Krutzfeldt, J. et al. Nature 438 (7068), 685-689 (2005).
3. Esau, C. et al. Cell Metab 3 (2), 87-98 (2006).
4. Jopling, C.L., Norman, K.L., & Sarnow, P. Cold Spring Harb Symp Quant Biol 71, 369-376 (2006).
5. Kutay, H. et al. J Cell Biochem 99 (3), 671-678 (2006).
6. Tsai, W.C. et al. Hepatology 49 (5), 1571-1582 (2009).
7. van Dongen, S., Abreu-Goodger, C., & Enright, A.J. Nat Methods 5 (12), 1023-1025 (2008).

Keywords: microRNA-122, knockout mice, hepatocarcinogenesis