Unraveled roles of Cav1.2 in proliferation and stemness of ameloblastoma

Abstract

Background Transcriptome analysis has been known as a functional tool for cancer research recently. Mounting evidence indicated that calcium signaling plays several key roles in cancer progression. Despite numerous studies examining calcium signaling in cancer, calcium signaling studies in ameloblastoma are limited. Results In the present study, comparative transcriptome profiling of two representative odontogenic lesions, ameloblastoma and odontogenic keratocyst, revealed that Cav1.2 (CACNA1C, an L-type voltage-gated calcium channel) is strongly enriched in ameloblastoma. It was confirmed that the Ca2+ influx in ameloblastoma cells is mainly mediated by Cav1.2 through L-type voltage-gated calcium channel agonist and blocking reagent treatment. Overexpression and knockdown of Cav1.2 showed that Cav1.2 is directly involved in the regulation of the nuclear translocation of nuclear factor of activated T cell 1 (NFATc1), which causes cell proliferation. Furthermore, a tumoroid study indicated that Cav1.2-dependent Ca2+ entry is also associated with the maintenance of stemness of ameloblastoma cells via the enhancement of Wnt/β-catenin signaling activity. Conclusion In conclusion, Cav1.2 regulates the NFATc1 nuclear translocation to enhance ameloblastoma cell proliferation. Furthermore, Cav1.2 dependent Ca2+ influx contributes to the Wnt/β-catenin activity for the ameloblastoma cell stemness and tumorigenicity. Our fundamental findings could have a major impact in the fields of oral maxillofacial surgery, and genetic manipulation or pharmacological approaches to Cav1.2 can be considered as new therapeutic options.

Targeting BRD4 attenuates the stemness and aggressiveness of ameloblastoma

“…The activation of the canonical Wnt signaling pathway prevents β‐catenin from being degraded via ubiquitination and causes it to accumulate in the nucleus, where it promotes the transcription of target genes such as MYC , CCND1 , and AXIN2 (Kikuchi et al, 2011). It has been reported that activation of the canonical Wnt pathway promotes the migration and invasion of AM cells (S. Liu et al, 2021) and the tumorigenicity and stemness of the immortalized AM cell line AM‐1 (Li et al, 2022). However, as our results showed, β‐catenin did not accumulate in the nucleus in AM cells, suggesting that the canonical Wnt pathway was not constitutively activated in AM cells.…”