cPLA2α reversibly regulates different subsets of cancer stem cells transformation in cervical cancer
cPLA2α reversibly regulates different subsets of cancer stem cells transformation in cervical cancer
复制标题
cPLA2α可逆地调节宫颈癌中癌症干细胞转化的不同亚群
DOI：
10.1002/stem.3157
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发表时间：
2020-02-26
期刊：
影响因子：
5.2
通讯作者：
Guo, Hua
中科院分区：
文献类型：
--
作者：
He, Yuchao;Xiao, Manyu;Guo, Hua
宫颈癌干细胞（CCSCs）被认为是化疗耐药/放射耐药和转移的主要原因。虽然已经在CCSC中鉴定了几种细胞表面抗原，但由于CSC的异质性，这些标记物在肿瘤之间存在差异。然而，这些标记物是否特异性区分具有不同功能的CCSC尚不清楚。在这里，我们证明了CCSC存在于两种生物学上不同的表型，其特征在于不同水平的胞质磷脂酶A2 α（cPLA 2 α）表达。cPLA 2 α的过表达导致与间充质性状相关的CD 44（+）CD 24（-）表型，包括增加的侵袭和迁移能力，而cPLA 2 α下调的CCSC表达CD 133并显示静止上皮特征。此外，cPLA 2 α通过PKC zeta（一种非典型蛋白激酶C）调节间充质和上皮CCSC状态之间的可逆转换，从而控制癌细胞状态变化和各种胚胎干细胞特性的维持，进一步抑制膜中β-连环蛋白-E-钙粘蛋白相互作用，促进β-连环蛋白易位入核，影响干性信号的转录调节。我们认为cPLA 2 α调控的间质和上皮CCSC状态之间的可逆转换是宫颈癌转移和复发所必需的。因此，cPLA 2 α可能是一个有吸引力的治疗靶点，用于根除不同状态的CCSC，以更有效地消除肿瘤。
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.