Hepatotoxic Effects of Long-Term Inhibition of MiR-122 in Mice
Xiaofang Yang, Jun Xie, Guangping Gao, Zhong Jiang, Xiaofei Wang. UMass Memorial Medical Center, Worcester, MA; UMass Medical School, Worcester, MA
Background: MicroRNAs (miRs) play important pathophysiological roles. MiR-122 is a predominant and conserved liver-specific miRNA. Knockdown of miR-122 in mice lowered serum cholesterol and reduced hepatitis C viral load. Studies also linked low miR-122 level to the development of hepatocellular carcinoma (HCC). MiR-122 antisense oligonucleotides are in phase II clinical trial for HCV treatment, but the paradoxical effects from long-term miR-122 inhibition need to be addressed.
Design: A total of 212 C57/b6 mice were randomly divided into 3 groups and injected with 6x1011 copies of recombinant Adeno-associated virus vectors expressing miR-122 inhibitor (miR-I), scramble (SCR), or phosphate buffered saline (PBS). After 1, 6 and 13 months of injection, liver was harvested. Microscopic examination was performed on H&E stained sections after formalin fixation. Reticulin stain was performed for all hepatic nodule(s).
Results: The incidence of hepatocellular adenoma (figure 1) and HCC (figure 2) was significantly increased in miR-I group, compared to both controls. The size of nodules measures up to 0.8 cm in greatest dimension. Other pathologic changes including macrovesicular steatosis, mitotic activity, apoptosis, mononuclear infiltrates, and swelling were also higher in miR-I group, especially after 13-month of treatment. No significant fibrosis or cholestasis was identified. Inflammation was minimal to moderate and predominately perivascular. Steatosis is mainly within the nodule and in the background in some cases. Mitosis (up to 16/10 HPF) and apoptosis were identified exclusively in the nodules especially HCCs.
Conclusions: Long term inhibition of miR-122 causes significant hepatocellular injuries including increased occurrence of adenoma, HCC, steatosis, inflammation, and swelling. These date suggest that miR-122 plays an essential role in tumor suppression, fat metabolism, and anti-inflammation.
Wednesday, March 6, 2013 1:00 PM
Poster Session VI # 124, Wednesday Afternoon