P4HA1调控EMT影响脑胶质瘤侵袭性研究

P4HA1 regulates EMT to affect glioma invasion

脯氨酰4-羟化酶亚基α1(prolyl 4-hydroxylase subunitα1,P4HA1)是脯氨酰4-羟化酶的限速亚基,为合成各种类型胶原所必需.有报道显示其在乳腺癌、前列腺癌等肿瘤中具有促进肿瘤细胞侵袭和转移的能力,但机制尚不明了.本课题组在前期研究中发现,低氧环境可诱导胶质瘤细胞中P4HA1表达上调,敲低P4HA1可抑制胶质瘤干细胞的内皮细胞转分化,从而破坏胶质瘤中血管形成.本研究进一步探讨了P4HA1促进胶质瘤细胞侵袭性进展机制,并发现P4HA1在胶质瘤细胞中与HIF1α的表达呈密切正相关,其表达上调可促进上皮间质转化(epithelial-mesenchymal transition,EMT),这一过程可能与其抑制E-钙黏蛋白、升高N-钙黏蛋白和波形蛋白表达密切相关,而上述蛋白表达变化有可能是由于P4HA1上调了SNAI1和SNAI2的表达所导致.同时,P4HA1还可促进人脑微血管内皮细胞(human brain microvascular endothelial cells,HBMECs)的迁移和管腔形成,推测P4HA1也有可能通过这一途径参与了胶质瘤的血管生成.由此本文推论,P4HA1的表达有可能受HIF1α调控,其表达升高有可能通过上调SNAI1和SNAI2诱导的EMT和通过诱导HBMECs的血管生成从而促进胶质瘤的侵袭性生长.

Prolyl 4-hydroxylase subunitα1(P4HA1)is the rate-limiting subunit of prolyl 4-hydroxylase,which is necessary for the synthesis of various types of collagen.There are reports that P4HA1 promotes tumor cell invasion and metastasis in breast cancer and prostate cancer,but the mechanism is unknown.In previous studies,we found that hypoxia can induce the expression of P4HA1 in glioma cells,and knockdown of P4HA1 can inhibit the differentiation of glioma stem cells into endothelial cells,thereby destroying the angiogenesis of gliomas.In this study,we further explored the mechanism by which P4HA1 promoted invasive progression of glioma cells.We found that P4HA1 was closely positively correlated with HIF1αexpression in glioma cells.Upregulation of P4HA1 expression promoted epithelial-mesenchymal transition(EMT)by inhibiting E-cadherin,increasing N-cadherin and vimentin,and the change in the expression of these proteins may be due to P4HA1 up-regulating SNAI1 and SNAI2.In addition,P4HA1 can also promote the migration and tube formation of human brain microvascular endothelial cells(HBMECs).It was speculated that P4HA1 may also participate in angiogenesis of gliomas through this pathway.Therefore,we reasoned that the expression of P4HA1 may be regulated by HIF1α,and the high expression of P4HA1 may promote the aggressive growth of gliomas by up-regulating EMT activated by SNAI1 and SNAI2 and by inducing angiogenesis of HBMECs.