Oncotarget

Priority Research Papers:

Aberrant amino acid signaling promotes growth and metastasis of hepatocellular carcinomas through Rab1A-dependent activation of mTORC1 by Rab1A

Bi-Hong Xu, Xiao-Xing Li, Yang Yang, Mei-Yin Zhang, Hui-Lan Rao, Hui-Yun Wang and X.F. Steven Zheng _

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Oncotarget. 2015; 6:20813-20828. https://doi.org/10.18632/oncotarget.5175

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Abstract

Bi-Hong Xu1,*, Xiao-Xing Li1,*, Yang Yang1, Mei-Yin Zhang1, Hui-Lan Rao2, Hui-Yun Wang1,3 and X.F. Steven Zheng1,3

1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

2 Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China

3 Rutgers Cancer Institute of New Jersey and Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA

* These authors have contributed equally to this work

Correspondence to:

X.F. Steven Zheng, email:

Hui-Yun Wang, email:

Keywords: signal transduction, Rab1A, mTORC1, cancer, rapamycin

Received: June 20, 2015 Accepted: July 28, 2015 Published: August 13, 2015

Abstract

mTORC1 is a master regulator of cell growth and proliferation, and an established anticancer drug target. Aberrant mTORC1 signaling is common in hepatocellular carcinoma (HCC), but the underlying mechanism remains elusive. Rab1A is a newly identified mTORC1 activator that mediates an alternative amino acid (AA) signaling branch to Rag GTPases. Because liver is a physiological hub for nutrient sensing and metabolic homeostasis, we investigated the possible role of Rab1A in HCC. We found that Rab1A is frequently overexpressed in HCC, which enhances hyperactive AA-mTORC1 signaling, promoting malignant growth and metastasis of HCC in vitro and in vivo. Moreover, aberrant Rab1A expression is closely associated with poor prognosis. Strikingly, aberrant Rab1A overexpression leads to increased rapamycin sensitivity, indicating that inappropriate activation of AA signaling is a cancer-driving event in HCC. Our findings further suggest that Rab1A is a valuable biomarker for prognosis and personalized mTORC1-targeted therapy in liver cancer.


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