Rab1A promotes proliferation and migration abilities via regulation of the HER2/AKT-independent mTOR/S6K1 pathway in colorectal cancer

Colorectal carcinoma (CRC) is one of the most common malignancies worldwide and the second leading cause of cancer-related deaths in the US. Recently, Rab1A has been reported to be an activator of mTORC1 and p-S6K1, which is downstream of mTORC1. However, the association between Rab1A and p-S6K1 in CRC remains elusive. In the present study, we first demonstrated that Rab1A was overexpressed in CRC tissues and Rab1A overexpression was positively related to lymph node invasion, degree of differentiation, venous invasion and tumor-node-metastasis (TNM) stage. In both TNM stage I-II and III-IV patients, Rab1A-positive patients had a shorter survival time than Rab1A-negative patients. Furthermore, in univariate and multivariate analyses, only Rab1A expression was verified as an independent prognostic factor for survival in CRC patients. The level of p-S6K1 was markedly high in CRC tissues and Rab1A expression level had a positive association with p-S6K1 level. In addition, high levels of both Rab1A and p-S6K1 were associated with a poorer prognosis compared with low expression of either Rab1A or p-S6K1 level. Moreover, high levels of both Rab1A and p-S6K1 were associated with a poorer prognosis than patients with high levels of either Rab1A or p-S6K1 alone. Finally, knockdown of Rab1A expression inhibited migration and proliferation of SW480 and HCT116 cell lines by targeting regulation of p-S6K1. Thus, our findings indicate that Rab1A plays an important role in CRC and may provide a therapeutic target for CRC, particularly for mTORC1-targeted therapy-resistant cancers.