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.

Ras 相关 GTP 结合 (Rag) GTPases 需要激活雷帕霉素复合物 1 (mTORC1) 的机制靶标，其在细胞生长和代谢中起着核心作用，被认为是最重要的致癌途径之一。因此，推测 Rag GTPases 通过 mTOR 诱导发挥促癌作用。然而，除了刺激 mTOR 信号之外，将 Rag GTPase 活性及其下游效应子与癌症进展联系起来的牢固联系在很大程度上仍未报道。在这项研究中，我们通过筛选来自胃癌、肝癌和肺癌的 22 对肿瘤及其邻近正常组织，并验证了我们的在具有异位 RagB/C 表达的癌细胞系中的发现。发现 RagB/C 通过调节两种主要的细胞蛋白质降解途径来增强 PRL-3 的稳定性：溶酶体-自噬和泛素-蛋白酶体系统 (UPS)。在功能上，我们确定了 RagB/C 表达与乳腺癌或结肠癌患者不良临床结果之间的相关性，这些患者也从 TCGA 数据集检索的数据中显示出低 PRL-3 mRNA 表达，突出了 Rag GTPase 和 PRL-3 mRNA 在组合作为预后临床生物标志物。