Loss of ARF/INK4A Promotes Liver Progenitor Cell Transformation Toward Tumorigenicity Supporting Their Role in Hepatocarcinogenesis.

Liver progenitor cells (LPCs) contribute to liver regeneration during chronic damage and are implicated as cells of origin for liver cancers including hepatocellular carcinoma (HCC). The locus, which encodes the tumor suppressors alternate reading frame protein (ARF) and INK4A, was identified as one of the most frequently altered genes in HCC. This study demonstrates that inactivation of enhances tumorigenic transformation of LPCs. The level of ARF and INK4A expression was determined in a panel of transformed and nontransformed wild-type LPC lines. Moreover, the transforming potential of LPCs with inactivated was shown to be enhanced in LPCs derived from and mice and in wild-type LPCs following CRISPR-Cas9 suppression of . ARF and INK4A abundance is consistently reduced or ablated following LPC transformation. and LPCs displayed hallmarks of transformation such as anchorage-independent and more rapid growth than control LPC lines with unaltered . Transformation was not immediate, suggesting that the loss of alone is insufficient. Further analysis revealed decreased p21 expression as well as reduced epithelial markers and increased mesenchymal markers, indicative of epithelial-to-mesenchymal transition, following inactivation of the gene were required for tumorigenic transformation. Loss of ARF and INK4A enhances the propensity of LPCs to undergo a tumorigenic transformation. As LPCs represent a cancer stem cell candidate, identifying as a driver of LPC transformation highlights ARF and INK4A as viable prognostic markers and therapeutic targets for HCC.