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Regulation of proto-oncogene Orai3 by miR18a/b and miR34a
Ayushi Vashisht1, Jyoti Tanwar1, Rajender K Motiani1
1CSIR- Institute of Genomics and Integrative Biology, Mathura Road, New Delhi 110025, India.
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.
Insights
MicroRNAs (miRNAs) regulate Orai3, a protein linked to cancer progression. Specific miRNAs, miR18a/b and miR34a, directly control Orai3 expression, offering new therapeutic targets for cancer management.
Area of Science:
- Molecular Biology
- Cancer Research
- Ion Channel Function
Background:
- Store-operated calcium entry (SOCE) via Orai channels is crucial for cellular functions.
- Orai3, an Orai1 homolog, is implicated in breast, prostate, and lung tumorigenesis.
- The regulation of Orai3 expression in cancer remains largely uncharacterized.
Purpose of the Study:
- To identify and characterize micro-RNAs (miRNAs) that regulate Orai3 expression and function.
- To explore the role of specific miRNAs in controlling Orai3's contribution to tumorigenesis.
Main Methods:
- Extensive bioinformatics analysis.
- Functional studies to validate miRNA-Orai3 interactions.
- Analysis of Orai3 3'UTR for miRNA binding sites.
Main Results:
- Identified specific miRNAs (miR18a, miR18b, miR34a) that directly regulate Orai3.
- miR18a and miR18b were found to positively regulate Orai3 expression and function.
- miR34a was demonstrated to repress Orai3 expression and function.
Conclusions:
- Specific miRNAs directly modulate Orai3 expression and function by targeting its 3'UTR.
- These miRNAs represent novel therapeutic targets for managing Orai3-driven cancers.
- The findings open avenues for tissue- and disease-specific targeting of Orai homologs using miRNAs.
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