The critical role of dysregulated RhoB signaling pathway in radioresistance of colorectal cancer.

Abstract

PURPOSE\nTo explore whether Rho protein was involved in the radioresistance of colorectal cancer and investigated the underlying mechanism.\n\n\nMETHODS AND MATERIALS\nRho GTPase expression was measured after radiation treatment in colon cancer cells. RhoB knockout cell lines were established by CRISPR/Cas9 system. In vitro assays and zebrafish embryos were used for analyzing radiosensitivity and invasive ability. Mass cytometry was for detecting RhoB downstream signaling factors. RhoB and FOXM1 expression were detected by immunohistochemistry in rectal cancer patients who participated in a radiotherapy trial.\n\n\nRESULTS\nRhoB expression was related to radiation resistance. Complete depletion of RhoB protein increased radiosensitivity and impaired radiation-enhanced metastatic potential in vitro and in zebrafish model. Probing signaling using mass cytometry-based single-cell analysis showed that Akt phosphorylation level was inhibited by RhoB depletion after radiation. FOXM1 was downregulated in RhoB knockout cells and the inhibition of FOXM1 led to lower survival rates, and attenuated migration and invasion abilities of the cells after radiation. In the patients with radiotherapy, RhoB overexpression was related to high FOXM1, late TNM stage, high distant recurrence and poor survival independent of other clinical factors.\n\n\nCONCLUSIONS\nRhoB plays a critical role in radioresistance of colorectal cancer through Akt and FOXM1 pathway.