RHBDD2 GENE EXPRESSION PROFILE IN LOW AND HIGH-GRADE BRAIN TUMORS REVEALS ITS UP- REGULATION IN THE MALIGNANT SUBTYPES.

FERRETTI VA; PALMA S; FACCHINETTI MM; CURINO AC; ABBA MC; LACUNZA E

Buenos Aires

Congreso; REUNIÓN CONJUNTA DE SOCIEDADES DE BIOCIENCIAS; 2017

Abstract: The Rhomboid family is a heterogeneous group of mem-brane proteins involved in various functions such as cell signaling,development, apoptosis or stress response to endoplasmic reticu-lum (ER). Several members have been associated to neurodegen-erative diseases and cancer. In previous studies, we determinedthat the expression of the gene RHBDD2, a member of the family, isincreased in the advanced stages of breast and colorectal cancersand it is induced by the chemotherapeutic agent 5-fluorouracil (5-Fu)in colon cancer cells. We also showed that RHBDD2 is associatedto the ER stress pathway known as the unfolded protein response(UPR). In this sense, UPR is highly active in glioma tumors andits induction drives chemoresistance in glioma cells. We hypothe-sized that the overexpression of RHBDD2 in the advanced stagesof cancer and its induction against 5-Fu provides the tumor cellswith a stress-resistant phenotype. In an exploratory study, usinghuman brain tumor samples, cell lines, gene expression databas-es and bioinformatic analysis we determined the expression profileof RHBDD2 and UPR genes in different subtypes of brain tumors(Oligodendrogliomas, Astrocitomas and Glioblastomas). Using IHC,RTPCR and phenotypic assays we observed that RHBDD2 expres-sion varied across the different types of tumors, being higher in glio-blastomas (p<0.01). We also evidenced that silencing of RHBDD2expression in the cell line SHS5Y, widely used as a cell model ofDAergic neurons, contributed with a decrease in cell migration andproliferation (wound healing assay, p<0.05) and also affected the ex-pression of UPR related genes. Survival analysis in TCGA datasetsindicated a significant association (p<0.01) between high RHBDD2expression and short-term survival factors such as grade, age andtumor localization. Although more studies are being carried out, theperspectives of these results position RHBDD2 as an interesting tar-get to be considered for malignant glioma therapeutics.Keywords: RHBDD2, Gliomas, UPR, chemoresistance.