ITPR2, AN ER CALCIUM CHANNEL, REGULATES ER STRESS AND INFLAMMATORY RESPONSE IN PRE-CANCEROUS KIDNEY TUBULE CELLS

Abstract

Renal cell carcinoma (RCC) is the 16th most common cause of cancer death worldwide, with clear cell renal cell carcinoma (ccRCC) being the most lethal subtype. Despite advancements in diagnosis and management, ccRCC remains highly fatal. Additionally, over 70% of ccRCC cases exhibit defects in the VHL tumor suppressor gene. In previous study, we reported that endoplasmic reticulum (ER) stress is one of the key regulators of VHL mutant ccRCC progression by inducinginflammatory responses via IRE1α signaling. Interestingly, ITPR2, an ER membrane protein and a second messenger intracellular calcium release channel, was found downregulated in RCC tumors compared to healthy kidney tissue, yet recent studies identified ITPR2 as a susceptibility locus for ccRCC on chromosome 12p11.23, a region frequently amplified in VHL-related RCC. These outcomes indicate that ITPR2 somehow affects the ccRCC progression with various influences in different stages. That leads us to the hypothesis that the alteration of ITPR2 could impact on the ER stress response, which in turn influences inflammation and ccRCC development. Here, we generated ITPR2 knockdown in proximal tubule epithelial cell line (HK-2) with or without VHL knockdown and used calcium flow as the reporter for ITPR2 activation to investigate the role of this gene in ER stress and inflammation. Our results showed that loss of ITPR2 expression reduces the ER stress burden and ER stressinduced inflammation. Besides, we also found that double knockdown ITPR2 and VHL in HK-2 diminishes macrophages recruitment compared with VHL single knockdown HK-2 in in vitro extravasation assay. These findings offer insights into ccRCC pathogenesis and suggest a novel therapeutic approach for kidney cancer