Relevance of MEK/ERK signaling in biliary differentiation in murine liver cancer

Introduction Activation of oncogenic RAS signaling is commonly observed in human cholangiocarcinoma (CC), but less frequently in hepatocellular carcinoma (HCC). In mice, activation of oncogenic RAS together with genetic inactivation of two important tumor suppressor genes (RPK; Rblox/lox;p53lox/lox;Kras/lsl-KrasG12D) in the liver results in rapid development of aggressive cholangiocarcinoma characterized by activation of PI3K/AKT and MEK/ERK signaling. To date, the relevance of these RAS-dependent signaling pathways in CC is not fully understood.

Methods To investigate RAS-dependent signaling pathways, animals with activation of oncogenic Kras (RPK) and genetic inactivation of either PI3K-activated AKT (RPK;Pdk1lox/lox) or MEK/ERK signaling (RPK;Map2k1lox/lox;Map2k2-/-) were generated. All mice harbored a liver-specific inducible CreER (AlbCreER) and tumor development was induced by tamoxifen. Tumors were analyzed by histopathology and determination of mRNA and protein expression levels.

Results Genetic inactivation of PI3K/AKT or MEK/ERK signaling both result in delayed tumor development and prolonged survival of RPK mice. While tumors in RPK;Pdk1lox/lox animals were more well differentiated than those in RPK control mice, RPK;Map2k1lox/lox;Map2k2-/- tumors were more poorly differentiated despite longer time to tumor development. Strikingly, genetic inactivation of MEK/ERK signaling resulted in a change in tumor differentiation towards the hepatocyte lineage, with 33% HCC and 29% mixed HCC/CC. This differentiation shift correlated with an activation of Wnt/beta-catenin signaling, a commonly activated pathway in human HCC.

Conclusion In cholangiocarcinoma, RAS-dependent signaling pathways seem to have distinct functions in tumorigenesis. While activation of PI3K/AKT signaling was associated with more poorly differentiated tumors, MEK/ERK signaling was relevant driver of biliary differentiation in murine CC.

Publication History

Article published online:
26 January 2022