Impact of Alternative Splicing Variants on Liver Cancer Biology.

Abstract

Simple SummaryAmong the top ten deadly solid tumors are the two most frequent liver cancers, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma, whose development and malignancy are favored by multifactorial conditions, which include aberrant maturation of pre-mRNA due to abnormalities in either the machinery involved in the splicing, i.e., the spliceosome and associated factors, or the nucleotide sequences of essential sites for the exon recognition process. As a consequence of cancer-associated aberrant splicing in hepatocytes- and cholangiocytes-derived cancer cells, abnormal proteins are synthesized. They contribute to the dysregulated proliferation and eventually transformation of these cells to phenotypes with enhanced invasiveness, migration, and multidrug resistance, which contributes to the poor prognosis that characterizes these liver cancers.The two most frequent primary cancers affecting the liver, whose incidence is growing worldwide, are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which are among the five most lethal solid tumors with meager 5-year survival rates. The common difficulty in most cases to reach an early diagnosis, the aggressive invasiveness of both tumors, and the lack of favorable response to pharmacotherapy, either classical chemotherapy or modern targeted therapy, account for the poor outcome of these patients. Alternative splicing (AS) during pre-mRNA maturation results in changes that might affect proteins involved in different aspects of cancer biology, such as cell cycle dysregulation, cytoskeleton disorganization, migration, and adhesion, which favors carcinogenesis, tumor promotion, and progression, allowing cancer cells to escape from pharmacological treatments. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the available information regarding the impact of AS on liver carcinogenesis and the development of malignant characteristics of HCC and iCCA, whose understanding is required to develop novel therapeutical approaches aimed at manipulating the phenotype of cancer cells.