Abstract
Backgrounds and Aims: Hepatocellular Carcinoma (HCC) is the leading cause of cancer-related mortality across the world. Non-viral etiological factors including obesity and metabolic syndrome have now become prevalent cause of hepatocellular carcinoma. Sonic Hedgehog (SHH) pathway is activated in hepatocellular carcinoma but its role in regulation of lipogenic molecules during the hepatocarcinogenesis is not known. The aim of present study is to explore the role of SHH pathway in fatty changes associated with hepatocarcinogenesis at different stages and to further correlate the expression of SHH with lipogenic pathways.Results: Our results demonstrated significant increase in lipidosis and fibrosis in DEN+CCl4 treated animals. It was simultaneously associated with the enhanced expression level of SHH, E2F1, adiponectin, and lipogenic molecules in DEN+CCl4 treated animals. These results were also corroborated with the similar findings in higher stage patients’ biospecimens.Methods: N-Nitrosodiethylamine (DEN) and Carbon TetraChloride (CCl4) induced hepatocellular acrcinoma model in male Wistar rats were established to study the expression level of SHH pathway and associated fatty changes during different stages of hepatocarcinogenesis. The expression levels of SHH, E2F1, and lipogenic molecules were checked at different stages of hepatocellular carcinoma. These results were further compared with biospecimens of hepatocellular carcinoma patients of different stages.Conclusions: Our results revealed an unknown aspect of SHH pathway in hepatocarcinogenesis via its control over lipogenesis. It gives insight into the lipogenic properties of DEN+CCl4 induced rodent hepatocarcinogenesis model and how SHH pathway operate to arbitrate this response.
Highlights
Hepatocellular Carcinoma (HCC) is the most common primary liver cancer and the third leading cause of cancer-related death worldwide
Our results revealed an unknown aspect of Sonic Hedgehog (SHH) pathway in hepatocarcinogenesis via its control over lipogenesis
In the present study we identified the role of Sonic Hedgehog (SHH) pathway in fatty changes associated with DEN + CCl4 induced hepatocellular carcinoma model at different stages and substantiated the findings with clinical-samples
Summary
Hepatocellular Carcinoma (HCC) is the most common primary liver cancer and the third leading cause of cancer-related death worldwide. In most cases hepatocellular carcinoma is refractory to the available chemotherapeutic drugs [1, 2]. The etiology of hepatocellular carcinoma is diverse including viral www.Genes&Cancer.com infections (HBV and HCV), metabolic syndrome, alcohol consumption, aflatoxin exposure, and hereditary factor (alpha-1 antitrypsin deficiency). Metabolic Syndrome (MetS) is a group of metabolic factor abnormalities (biochemical and physiological) associated with the global epidemic diseases like obesity, diabetes, and cardiovascular disease [3]. Metabolic syndrome is considered a well documented risk-factor for Non-alcoholic Fatty Liver Diseases (NAFLD), which is a metabolic liver disease and can in turn lead to Non-Alcoholic Steatohepatitis (NASH) and fibrosis. Fibrosis can lead to cirrhosis which subsequently can progress into hepatocellular carcinoma
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