LKB1 signaling is activated in CTNNB1 -mutated HCC and positively regulates β-catenin-dependent CTNNB1 -mutated HCC - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Pathology Année : 2019

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

Résumé

CTNNB1‐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 of CTNNB1‐mutated HCC. The LKB1 protein was overexpressed in CTNNB1‐mutated HCC and oncogenic activation of β‐catenin in human HCC cells induced the post‐transcriptional accumulation of the LKB1 protein encoded by the LKB1 (STK11) gene. Hierarchical clustering, based on the expression of a murine hepatic liver Lkb1 (Stk11) signature in a human public dataset, identified a HCC cluster, composed of almost all the CTNNB1‐mutated HCC, that expresses a hepatic liver LKB1 program. This was confirmed by RT‐qPCR of an independent cohort of CTNNB1‐mutated HCC and the suppression of the LKB1‐related profile upon β‐catenin silencing of CTNNB1‐mutated human hepatoma cell lines. Previous studies described an epistatic relationship between LKB1 and CTNNB1 in which LKB1 acts upstream of CTNNB1. Thus, we also analyzed the consequences of Lkb1 deletion on the zonation of hepatic metabolism, known to be the hallmark of β‐catenin signaling in the liver. Lkb1 was required for the establishment of metabolic zonation in the mouse liver by positively modulating β‐catenin signaling. We identified positive reciprocal cross talk between the canonical Wnt pathway and LKB1, both in normal liver physiology and during tumorigenesis that likely participates in the amplification of the β‐catenin signaling by LKB1 and the distinctive phenotype of the CTNNB1‐mutated HCC.
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Dates et versions

hal-02365767 , version 1 (15-11-2019)

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Sara Charawi, Pierre-Alexandre Just, Mathilde Savall, Shirley Abitbol, Massiré Traore, et al.. LKB1 signaling is activated in CTNNB1 -mutated HCC and positively regulates β-catenin-dependent CTNNB1 -mutated HCC. Journal of Pathology, 2019, 247 (4), pp.435-443. ⟨10.1002/path.5202⟩. ⟨hal-02365767⟩
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