한빛사 논문
Adeola O. Adebayo Michael,1,2,16,17 Sungjin Ko,1,2,16 Junyan Tao,1,2 Akshata Moghe,2,3 Hong Yang,1,4 Meng Xu,5,6 Jacquelyn O. Russell,1,2 Tirthadipa Pradhan-Sundd,1,2 Silvia Liu,1,2 Sucha Singh,1,2 Minakshi Poddar,1,2 Jayvir S. Monga,1 Pin Liu,7 Michael Oertel,1,2 Sarangarajan Ranganathan,2,8 Aatur Singhi,2,9 Sandra Rebouissou,10,11,12,13 Jessica Zucman-Rossi,10,11,12,13 Silvia Ribback,14 Diego Calvisi,14 Natalia Qvartskhava,15 Boris Görg,15 Dieter Häussinger,15 Xin Chen,6 and Satdarshan P. Monga1,2,3,18,*
1 Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
2 Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
3 Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
4 Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
5 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China
6 Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA
7 Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
8 Division of Pediatric Pathology, Department of Pathology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
9 Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
10 Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Paris 75010, France
11 Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, 75010 Paris, France
12 Université Paris 13, Sorbonne Paris Cité, UFR SMBH, 93000 Bobigny, France
13 Université Paris Diderot, IUH, 75010 Paris, France
14 Institute of Pathology, University of Greifswald, Greifswald, Germany
15 Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
16 These authors contributed equally
17 Present address: Georgia Institute of Technology, Atlanta, GA, USA
18 Lead Contact
*Correspondence : Satdarshan P. Monga
Abstract
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.
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