Transient receptor potential canonical 3 is required for HPV-induced malignant transformation of cervical epithelial cells.

Human Papillomavirus (HPV) types 16 and 18 are well-established causative agents in cervical cancer. However, the mechanism of malignant transformation remains unclear. Although epithelial-mesenchymal transition (EMT) is regulated by Ca(2+) signaling, the functions of transient receptor potential canonical (TRPC) channel in cervical cancer have not been reported. Herein, employing multiple biological approaches, we first revealed that HPV16 and HPV18 infections significantly upregulated the expression of TRPC3 that orchestrated Ras-MAPK and MEK-ERK pathways in the abnormal transformation of cervical epithelial cells. Our transcriptomic sequencing of HPV-infected cervical epithelial cells with depletion of TRPC3 suggested the significant influence of TRPC3 on genes involved in the process of epithelial-mesenchymal transition (EMT). Consistently, inhibition of TRPC3 successfully suppressed HPV-triggered cell viability and EMT. Moreover, we found TRPC3 maintained the viability of HPV - infected cells by suppressing excessive MAPK activation through regulating Ras GTPase - activating protein 4 (RASA4), which was validated by the detection of phosphorylated ERK1/2 (p-ERK1/2).These findings were further confirmed in the HPV-infected female BALB/c mice, highlighting TRPC3 as a key hub in mediating transformation This study advances the knowledge about the Ca(2+) signaling-related molecular mechanism underlying HPV-driven malignant transformation. Targeting TRPC3 may have broader therapeutic implications.