Rag GTPases suppress PRL-3 degradation and predict poor clinical diagnosis of cancer patients with low PRL-3 mRNA expression.

Ras-related GTP binding (Rag) GTPases are required to activate mechanistic target of rapamycin complex 1 (mTORC1), which plays a central role in cell growth and metabolism and is considered as one of the most important oncogenic pathways. Therefore, Rag GTPases have been speculated to play a pro-cancer role via mTOR induction. However, aside from stimulation of mTOR signaling, firm links connecting Rag GTPase activity and their downstream effectors with cancer progression, remain largely unreported. In this study, we reported a novel link between RagB/C and a known oncoprotein phosphatase of regenerating liver-3 (PRL-3) by screening 22 pairs of tumors and their adjacent normal tissues from gastric, liver and lung cancers, and validating our findings in cancer cell lines with ectopic RagB/C expression. RagB/C was found to enhance PRL-3 stability by modulating two major cellular protein degradation pathways: lysosomal-autophagy and ubiquitin-proteasome system (UPS). Functionally, we identified the correlation between RagB/C expression with poor clinical outcomes in breast or colon cancer patients who also showed low PRL-3 mRNA expression from data retrieved from TCGA datasets, highlighting the potential relevance of Rag GTPase and PRL-3 mRNA in combination as a prognostic clinical biomarker.