The objective of this new R01 application is to advance our understanding of the role of miR-122 in hepatocarcinogenesis. HCC is the fifth most common cancer and the third common cause of cancer related death. The incidence of HCC is on the rise in USA, with little hope for cure or treatment through chemotherapy, radiation or other traditional cancer treatments. Its major risk factors are infection with hepatitis B and C viruses, and exposure to toxic chemicals, including alcohol, all of which cause chronic liver injury and inflammation. Using an animal model for hepatocarcinogenesis we were the first to demonstrate down regulation of miR-122, the most abundant liver-specific microRNA (~70% of the total miRNA) in the liver, during the initiation and progression of HCC and also in human primary HCCs. Suppression of miR-122 is a signature of HCCs with poor prognosis and metastasis. Studies with HCC cells in culture have shown that miR-122 functions as a tumor suppressor in vitro and in nude mice. To understand the biological functions of miR-122, especially in hepatocarcinogenesis, we have generated conditional knockout mice (supported by an R21 grant to the PI). These mice express 100 fold less miR-122 when crossed to AlbCre mice and spontaneously develop hepatitis in the liver with age, which is facilitated after feeding choline-deficient diet that promotes hepatocarcinogenesis. More importantly, miR-122 deleted (KO) mice are more susceptible to HCCs when exposed to diethylnitrosamine, a potent liver carcinogen. Based on these observations we hypothesize that miR-122 plays a critical role in maintaining liver function, and loss of miR-122 predisposes to liver disease including cancer.
The specific aims of the proposal are:
Aim 1. Investigate the role of miR-122 in a mouse model of nonalcoholic fatty liver disease (NAFLD) related HCC induced by feeding choline-deficient diet. 1a) The susceptibility of miR-122 / (KO) and miR-122fl/fl (control) mice to CDAA diet will be examined by comparing liver damage (apoptosis, steatosis or fatty liver, inflammation, fibrosis) and liver tumors (formation of adenomas and carcinomas) between these mice, and 1b) the involvement of miR-122 targets will be assessed.
Aim 2. Investigate the role of miR-122 in diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Pathological/molecular changes of mice injected with DEN will be monitored as described in Aim 1.
Aim 3. Examine the therapeutic potential of miR-122 alone or in combination with chemotherapeutic agents to inhibit tumor growth in vivo in the DEN model. Mice will be injected weekly for 4 weeks with miR-122 mimetics loaded in galactosylated nanoparticles (to specifically target it to HCC cells) at early stages of tumor development (visualized by MRI) and the regression in the tumor growth will be compared to those in mice treated with the scrambled RNA nanoparticles. This study will elucidate the function of the most abundant liver-specific microRNA in maintaining normal liver physiology and also its therapeutic efficacy against hepatocellular carcinomas in an animal model.
Layman's Abstract The urgent need for new treatments for hepatocellular cancer (HCC) is warranted because incidence of HCC is increasing considerably in the United States, their dismal prognosis and the poor response of this cancer to treatment regimen currently available. This project focuses on the role of the loss of function of miR-122 in the development and progression of hepatocellular carcinoma (HCC), one of the most common human malignancies. Our previous studies have shown downregulation of miR-122 in HCCs of both human and rodent origin. Now we intend to show that the loss of function of this liver specific miR plays a causal role in the initiation and progression of HCC. If this is the case, these studies will open the way to the development of novel miR-122 therapy for this incurable disease. Thus, establishing role of miR-122 mimetic in an animal model (in preclinical trial) would be a major milestone in the treatment of this deadly disease in the near future.
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