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

PALMA S; RAFFA CI; FERRETTI VA; ABBA MC; LACUNZA E

Mar del Plata

Congreso; LXIV Reunión Anual de la Sociedad Agentina de Investigación Clínica; 2019

Sociedad Agentina de Investigación Clínica

The current standard of care forlocally advanced rectal cancer (RC) is neoadjuvant radio-chemotherapy (NRC)with 5-fluorouracil (5Fu) as the main drug, followed by surgery and adjuvantchemotherapy. A group of patients will achieve a pathological complete response,while a significant percentage will not respond to the treatment. The UnfoldingProtein Response (UPR) is generally activated in tumors and results inresistance to radio-chemotherapy. We previously showed that RHBDD2 gene is overexpressedin the advanced stages of colorectal cancer (CRC) and would be involved in theUPR. Moreover, its expression is induced by 5Fu. We hypothesized that theoverexpression of RHBDD2 in the advanced stages of CRC could have an impact onthe regulation of the UPR pathway providing tumor cells with a stress-resistantphenotype. We stably overexpressed and silenced RHBDD2 expression in the Caco2and HCT116 cell lines, respectively. Results indicated that RHBDD2overexpression conferred to Caco2 cells resistance to 5Fu, favored cellmigration, adhesion and proliferation and had a profound impact on theexpression of the UPR genes BiP, PERK and CHOP (p<0.01), and on the adhesiongenes FAK and PXN (p<0.01). Moreover, byimmunoprecipitation, we determined that RHBDD2 binds to GRP78. GRP78, also called BiP, is a masterregulator of the UPR, reducing ER stress levels and apoptosis. the master regulator of the UPR. In paired tumor samples (before andafter NRC treatment) of patient with RC, we found that tumors that maintained ahigh expression of RHBDD2 even after treatment were associated with patientswho had developed local or distant metastases. The collected evidence positionsRHBDD2 as a promising predictor of response to neoadjuvant therapy in patientswith RC.