cPLA2α reversibly regulates different subsets of cancer stem cells transformation in cervical cancer

Cervical cancer stem cells (CCSCs) are considered major causes of chemoresistance/radioresistance and metastasis. Although several cell surface antigens have been identified in CCSCs, these markers vary among tumors because of CSC heterogeneity. However, whether these markers specifically distinguish CCSCs with different functions is unclear. Here, we demonstrated that CCSCs exist in two biologically distinct phenotypes characterized by different levels of cytosolic phospholipase A2 alpha (cPLA2 alpha) expression. Overexpression of cPLA2 alpha results in a CD44(+)CD24(-) phenotype associated with mesenchymal traits, including increased invasive and migration abilities, whereas CCSCs with cPLA2 alpha downregulation express CD133 and show quiescent epithelial characteristics. In addition, cPLA2 alpha regulates the reversible transition between mesenchymal and epithelial CCSC states through PKC zeta, an atypical protein kinase C, which governs cancer cell state changes and the maintenance of various embryonic stem cell characteristics, further inhibiting beta-catenin-E-cadherin interaction in membrane and promoting beta-catenin translocation into the nucleus to affect the transcriptional regulation of stemness signals. We propose that reversible transitions between mesenchymal and epithelial CCSC states regulated by cPLA2 alpha are necessary for cervical cancer metastasis and recurrence. Thus, cPLA2 alpha might be an attractive therapeutic target for eradicating different states of CCSCs to eliminate tumors more effectively.