RHBDD2 binds to GRP78/BiP and promotes chemoresistant and invasive phenotypes to rectal cancer tumors via modulating UPR and Adhesion genes

Abstract

Abstract/Resumen: The current standard of care for locally advanced rectal cancer (RC) is neoadjuvant radio-chemotherapy (NRC) with 5-fluorouracil (5Fu) as the main drug, followed by surgery and adjuvant chemotherapy. A group of patients will achieve a pathological complete response, while a significant percentage will not respond to the treatment. The unfolding protein response (UPR) is generally activated in tumors and results in resistance to radio-chemotherapy. We previously showed that RHBDD2 gene is overexpressed in the advanced stages of colorectal cancer (CRC) and would be involved in the UPR. Moreover, its expression is induced by 5Fu. We hypothesized that the overexpression of RHBDD2 in the advanced stages of CRC could have an impact on the regulation of the UPR pathway providing tumor cells with a stress-resistant phenotype. We stably overexpressed and silenced RHBDD2 expression in the Caco2 and HCT116 cell lines, respectively. Results indicated that RHBDD2 overexpression conferred to Caco2 cells resistance to 5Fu, favored cell migration, adhesion and proliferation and had a profound impact on the expression of the UPR genes BiP, PERK and CHOP (p<0.01), and on the adhesion genes FAK and PXN (p<0.01). Moreover, by immunoprecipitation, we determined that RHBDD2 binds to GRP78. GRP78, also called BiP, is a master regulator of the UPR, reducing ER stress levels and apoptosis. In paired tumor samples (before and after NRC treatment) of patient with RC, we found that tumors that maintained a high expression of RHBDD2 even after treatment were associated with patients who had developed local or distant metastases. The collected evidence positionsRHBDD2 as a promising predictor of response to neoadjuvant therapy in patients with RC.