Role of Ca(2+)-Dependent Epithelial-Mesenchymal Transition in Malignant Progression of Colorectal Cancer: Special Focus on REG Iα/EDNRB.

BACKGROUND: Colorectal cancer (CRC) is a major global health problem, ranking as the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths. This study aimed to elucidate the role and underlying molecular mechanism of the Regenerating Islet-Derived Protein 1 Alpha (REG Iα)/Endothelin Receptor B (EDNRB) axis in CRC malignant progression. METHODS: A nude mouse xenograft model and human CRC cell lines were used to investigate the REG Iα/EDNRB axis. RNA-sequencing (RNA-seq) was employed to identify downstream targets following REG Iα knockdown. Interventions included siRNA-mediated knockdown of REG Iα, overexpression of EDNRB, and pharmacological inhibition with the Ca(2+) chelator BAPTA-AM. Cell proliferation, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT) were assessed using Western blotting, RT-qPCR, and Transwell assays. RESULTS: REG Iα was significantly upregulated in CRC tissues. Downregulation of REG Iα suppressed CRC cell proliferation, migration, and invasion while promoting apoptosis. Mechanistically, REG Iα silencing downregulated the expression of its target EDNRB and subsequently inhibited the Ca(2+)/CaMKII signaling pathway, triggering endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) accumulation to induce apoptosis. Importantly, overexpression of EDNRB rescued the malignant phenotypes suppressed by REG Iα knockdown, whereas BAPTA-AM treatment abolished this rescue effect. The REG Iα/EDNRB axis was further demonstrated to drive the EMT process, and these findings were validated in vivo. CONCLUSIONS: The REG Iα/EDNRB axis promotes the malignant progression of CRC by activating Ca(2+)-dependent epithelial-mesenchymal transition, suggesting that targeting this axis is a promising therapeutic strategy to inhibit CRC metastasis.