ORM1 promotes tumor progression of kidney renal clear cell carcinoma (KIRC) through CALR-mediated apoptosis

Abstract

AbstractKidney renal clear cell carcinoma (KIRC) is the most prevalent type of kidney cancer and causes thousands of deaths each year. The prognosis for KIRC is poor. One critical factor is that the mechanism beneath KIRC is unclear. ORM1 is a reactant to acute inflammation. In this study, we demonstrated that methylation of ORM1 promoter was low and ORM1 was expressed significantly higher in KIRC. KIRC with higher ORM1 expression exhibited worse survival probability. Meanwhile, ORM1 was expressed higher in KIRC cell lines. When ORM1 was knocked down, cell proliferation ability was inhibited potently compared to the NC control. Cell migration as well as invasion ability were also suppressed dramatically. At molecular level, the expression of active caspase-3 and Bax was upregulated in ORM1-KD group while Bcl-2 downregulated. Moreover, CALR decreased following ORM1-KD and rescued expression of CALR increased Bcl-2 level but reduced the level of cleaved caspase-3 and Bax. Consistently, the apoptotic rate of 786-O and Caki-2 cells was upregulated in ORM1-KD but downregulated after CALR overexpression. The activity of caspase-3 was also regulated by ORM1-KD. In addition, the inhibition rate of sorafenib was enhanced in ORM1 KD group but reduced after overexpression of ORM1. Conclusively, ORM1 is clinically associated with progression of KIRC and regulates cell proliferation, migration, invasion, and apoptosis in KIRC. Moreover, ORM1 affects the efficiency of sorafenib in KIRC and regulates caspase-3 mediated cascades response through CALR molecule. This study provides us a new way to recognize the development and progression in KIRC.