Hormone-responsive miR-8073 Predicts Conserved Regulation of DEAD-box RNA Helicase 3 X-linked/DEAD-box RNA Helicase 3 Y-linked in Gender-specific Cancer Models
Mahendran Botlagunta, Jaithra Sai Gullapalli, Sri Sanjana RondaAbstract
Background:
DEAD-box RNA helicases regulates RNA metabolism, therapeutic resistance, and tumor progression. Although X and Y linked DEAD box RNA helicases (DDX3X and DDX3Y) are highly conserved, their sex-associated post-transcriptional regulation in hormone-responsive cancers remains unclear.
Methods:
DDX3 localization in processing bodies was examined by co-expressing green fluorescent protein-tagged DDX3 and red fluorescent protein-tagged decapping messenger RNA (mRNA) 1A in SiHa cervical and DU145 prostate cancer cells. MicroRNA (miRNA) expression was profiled following 17β-estradiol and 5α-dihydrotestosterone (DHT) exposure. Candidate miRNAs targeting DDX3X/DDX3Y 3′ untranslated regions were evaluated using target-prediction, RNA-interaction, sequence-conservation, pathway-enrichment, regulatory-network, and The Cancer Genome Atlas analyses. A DDX3 × 3′ untranslated-region luciferase-reporter deletion strategy assessed functional activity.
Results:
DDX3 co-localized with decapping mRNA 1A-positive cytoplasmic foci. Target comparison identified 175 miRNAs predicted to bind both homologs. miRNA-8073 showed the strongest combined predicted interaction and 96.52% identity across the homologous target-site window. DHT increased miRNA-8073 expression approximately 11–12-fold at 24 h in DU145 cells. In cervical squamous cell carcinoma and endocervical adenocarcinoma data, miRNA-8073 correlated inversely with DDX3X (Spearman
Conclusions:
These integrated findings prioritize miRNA-8073 as a candidate hormone-responsive regulator of a conserved DDX3X/DDX3Y 3′ untranslated-region segment. Direct gain- and loss-of-function experiments, seed-site mutagenesis, and endogenous protein studies are required before establishing a miRNA-8073–DDX3– forkhead box M1 mechanism. Accordingly, the study provides a focused experimental and computational framework for subsequent mechanistic validation in biologically relevant sex-associated, hormone-responsive cancer models.