Alternative splicing in hepatocellular carcinoma.

ABSTRACT Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancer cases, with over 850,000 new diagnoses per year globally. Recent trends in the U.S. reveal that liver cancer mortality has continued to rise in both men and women, while 5-year survival remains below 20%. Understanding key mechanisms that drive chronic liver disease progression to HCC can reveal new therapeutic targets and biomarkers for early detection of HCC. In that regard, many studies have underscored the importance of alternative splicing as a source of novel HCC prognostic markers and disease targets. Alternative splicing of RNA provides functional diversity to the genome, and endows cells with the ability to rapidly remodel the proteome. Genes that control fundamental processes, such as metabolism, cell proliferation and apoptosis are globally altered in HCC by alternative splicing. The focus of this review is to highlight the major splicing factors, RNA binding proteins, transcriptional targets and signaling pathways that are of key relevance to HCC. We highlight primary research from the last 3-5 years involving functional interrogation of alternative splicing in rodent and human liver, employing both large-scale transcriptomic and focused mechanistic approaches. As this is a rapidly advancing field, we anticipate that it will be transformative for the future of basic liver biology, as well as HCC diagnosis and management.