Regulation of proto-oncogene Orai3 by miR18a/b and miR34a.

Graphical abstract Highlights • Integrative bioinformatics analysis identify miRs that potentially regulate Orai3. • miR18a and miR18b enhance Orai3 expression and function. • miR34a negatively regulates Orai3 expression by inducing translational block. • These miRs control Orai3 levels by acting on its 3′UTR. • Literature meta-analysis validates the relationship of these miRs and Orai3 in clinical samples. Abstract Store Operated Ca²⁺ Entry (SOCE) mediated by Orai channels is a ubiquitous Ca²⁺ influx pathway that regulates several cellular functions. We have earlier reported that Orai3, the mammalian specific Orai1 homolog, plays a critical role in breast cancer progression. More recently, Orai3 was demonstrated to regulate prostate and lung tumorigenesis. Although the tumorigenic potential of Orai3 is associated with increase in its expression, the molecular machinery regulating its expression remains largely unexplored. Here, by performing extensive bioinformatics analysis and functional studies, we identify and characterize micro-RNAs (miRNAs) that regulate Orai3 expression and function. We demonstrate that miR18a and miR18b positively regulate Orai3 whereas miR34a represses Orai3 expression and function. All these miRs exert their effect on Orai3 by virtue of their direct action on Orai3 3′UTR. These miRs provide novel opportunities for targeting Orai3 for better management of cancer. This study further opens up the possibility of targeting specific Orai homologs by different miRs in tissue and disease specific context. [ABSTRACT FROM AUTHOR]