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.
Highlights
hepatocellular carcinoma (HCC) is the predominant form of liver cancer
Genome data from two previous studies deposited in The Cancer Genome Atlas (TCGA) suggest that Rab1A gene is amplified in many HCC cases [22, 23]
These results indicate that HCC cell lines resemble those seen with human tumors, and are useful in vitro models for studying aberrant Rab1A expression
Summary
HCC is the predominant form of liver cancer. It is one of the most common malignancies in the world and the third leading cause of cancer-related death [1, 2]. MTOR is a PI3K-related kinase conserved throughout the eukaryotic kingdom. MTOR kinase inhibitors are currently in many human cancer clinical trials [8]. Recent studies indicate that mTOR signaling is aberrantly activated in HCC [11, 12]. Recent evidence shows that oncogenic PI3K is often insufficient to promote mTORC1 activity in colorectal and breast cancer cells [18, 19], suggesting that other events such as amino acid signaling are involved. We have previously conducted a genomic rapamycin screen for mTORC1 signaling pathway components in yeast [20], and identified Rab1A, a small GTPase previously known for its role in ER-to-Golgi trafficking, as a critical mediator of AA signaling to activate mTORC1 [21]. Our results demonstrate that Rab1A is a new oncogenic protein with potentially significant prognostic and therapeutic values
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
