In-depth analysis of High-mobility group A proteins in NASH-HCC

Liver cancer is the sixth most common type of cancer worldwide and the fourth leading cause of cancer-related death. In contrast to other cancer types, the mortality of liver and biliary tract cancer increases dramatically, but the molecular causes are largely unknown. Therefore, understanding the underlying molecular mechanisms and identifying new therapeutic targets is important. In the past decades, infections with HBV and HCV or intoxications with alcohol or aflatoxins were the main causes of HCCs. Nowadays the global obesity epidemic is closely associated with the rising prevalence of NASH-HCC. Dysregulated epigenetic factors are promising therapeutic targets for liver cancer patients. High mobility group-A proteins are small non-histone chromatin-associated proteins involved in the modulation of transcription. Previously we have shown the mechanism by which HMGA proteins regulate transcription. Here we investigate the role of HMGAs in liver cancer. We use RNA-seq and corresponding clinicopathological data from publically available databases and tissue microarrays for expression and survival analysis of human HCC patients. To elucidate the underlying epigenetic mechanisms we perform in-depth analysis combining immunohistochemistry, metabolomics, and proteomics of hepatocyte-specific single and double-knockout mice in a NASH mouse model, resembling the human pathology. Furthermore, to analyze the impact on cellular transformation and signaling we perform in-vitro assays using human and murine HCC cell lines. In this study, we report that aberrant expression of HMGAs correlates with poor overall survival and advanced tumor grade of HCC patients. This indicates that the dysregulation of epigenetic factors potentially might contribute to NASH-HCC development.

Publication History

Article published online:
26 January 2022