RHBDD2: a cancer 5Fu responsive gene, as a potential prognostic and therapeutic marker in colorectal cancer treated with neoadjuvant chemotherapy.

PALMA S; ZWENGER A; GIGOLA G; LACUNZA E

Mar del Plata

Congreso; LXI Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica; 2016

Sociedad Argentina de Investigación Clínica

Colorectal cancer (CRC) is a molecular heterogeneous disease. Sequencing technologies have characterized this heterogeneity to define molecular subtypes that allow stratify patients so that they receive adequate and specific treatment. RHBDD2 gene was found overexpressed in the advanced stages of breast and CR cancers. Previous studies also demonstrated that RHBDD2 expression is induced under stress caused by agents such as DTT or 5Fu as an adaptive response. This led to its association with ER stress and the UPR pathway. In this study RHBDD2 expression was evaluated in CRC exposed to chemotherapeutic agents, in order to understand its role in tumor biology and establish its potential utility as a marker of chemoresistance or as a therapeutic target. RHBDD2 expression was analyzed in paired samples (before and after treatment) of advanced rectal cancer. In most of them an abrupt decrease in protein expression after the treatment was observed. However, in those where there was no reduction in the expression, a significant association with metastasis was found. Similar results were obtained in rat induced CR tumors. Furthermore, colon cancer cell lines were employed to evaluate the effect of 5Fu on the expression of RHBDD2 and the UPR genes. Results confirmed that 5Fu induced the transient expression of all of them, but with variation according to the molecular subtype of the cell line. Taken together, results allow us to infer that RHBDD2 is a protein related to the UPR that responds to stress caused by neoadjuvant treatment, establishing two groups of post-treatment response: with decreased expression and without decline, being the latter associated with a worse prognosis. This differential response could be associated to the intrinsic tumor subtype. Establish to which group are the tumors that do not show variation of RHBDD2 after treatment would give an important value to the protein as a marker for monitoring response to therapy and as a therapeutic target.