LKB1 signaling is activated in CTNNB1 ‐mutated HCC and positively regulates β‐catenin‐dependent CTNNB1‐mutated HCC

ABSTRACTHepatocellular carcinomas (HCCs) are known to be highly heterogenous. Within the extensive histopathological and molecular heterogeneity of HCC, tumors with mutations inCTNNB1, encoding β‐catenin, (CTNNB1‐mutated HCC) constitute a very homogeneous group. We previously characterized a distinctive metabolic and histological phenotype forCTNNB1‐mutated HCC. They were found to be well‐differentiated, almost never steatotic, and often cholestatic, with a microtrabecular or acinar growth pattern. Here, we investigated whether LKB1, which controls energy metabolism, cell polarity, and cell growth, mediates the specific phenotype ofCTNNB1‐mutated HCC. The LKB1 protein was overexpressed inCTNNB1‐mutated HCC and oncogenic activation of β‐catenin in human HCC cells induced the post‐transcriptional accumulation of the LKB1 protein encoded by theLKB1 (STK11) gene. Hierarchical clustering, based on the expression of a murine hepatic liverLkb1 (Stk11) signature in a human public dataset, identified a HCC cluster, composed of almost all theCTNNB1‐mutated HCC, that expresses a hepatic liverLKB1 program. This was confirmed by RT ‐qPCR of an independent cohort ofCTNNB1‐mutated HCC and the suppression of theLKB1‐related profile upon β‐catenin silencing ofCTNNB1‐mutated human hepatoma cell lines. Previous studies described an epistatic relationship between LKB1 andCTNNB1 in which LKB1 acts upstream ofCTNNB1. We thus also analyzed the consequences ofLkb1 dele...
Source: The Journal of Pathology - Category: Pathology Authors: Tags: Original Paper Source Type: research