作者
Adeola O. Adebayo Michael,Sungjin Ko,Junyan Tao,Akshata Moghe,Hong Yang,Meng Xu,Jacquelyn O. Russell,Tirthadipa Pradhan-Sundd,Silvia Liu,Sucha Singh,Minakshi Poddar,Jayvir S. Monga,Pin Liu,Michael Oertel,Sarangarajan Ranganathan,Aatur D. Singhi,Sandra Rebouissou,Richard Moreau,Silvia Ribback,Diego F. Calvisi,Natalia Qvartskhava,Boris Görg,Dieter Häussinger,Xin Chen,Satdarshan P.S. Monga
摘要
Based on their lobule location, hepatocytes display differential gene expression, including pericentral hepatocytes that surround the central vein, which are marked by Wnt-β-catenin signaling. Activating β-catenin mutations occur in a variety of liver tumors, including hepatocellular carcinoma (HCC), but no specific therapies are available to treat these tumor subsets. Here, we identify a positive relationship between β-catenin activation, its transcriptional target glutamine synthetase (GS), and p-mTOR-S2448, an indicator of mTORC1 activation. In normal livers of mice and humans, pericentral hepatocytes were simultaneously GS and p-mTOR-S2448 positive, as were β-catenin-mutated liver tumors. Genetic disruption of β-catenin signaling or GS prevented p-mTOR-S2448 expression, while its forced expression in β-catenin-deficient livers led to ectopic p-mTOR-S2448 expression. Further, we found notable therapeutic benefit of mTORC1 inhibition in mutant-β-catenin-driven HCC through suppression of cell proliferation and survival. Thus, mTORC1 inhibitors could be highly relevant in the treatment of liver tumors that are β-catenin mutated and GS positive.