Xin Ming-Jie, Yuan Yong
Medical College, Henan Vocational University of Science and Technology, Zhoukou 466000, Henan Province, China.
World J Gastrointest Oncol. 2025 Apr 15;17(4):102619. doi: 10.4251/wjgo.v17.i4.102619.
Centromere protein A (CENPA) exhibits an increased expression level in primary human rectal cancer tissues, but its role has not been investigated.
To clarify the specific role and mechanism of CENPA in rectal cancer progression.
CENPA protein expression in rectal cancer tissues and cell lines were detected. CENPA was overexpressed and knocked down in SW837 and SW480 cells, and proliferation, invasion, apoptosis and epithelial-mesenchymal transition (EMT) marker protein levels were examined. O6-methylguanine DNA methyltransferase (MGMT) promoter methylation was assessed with methylation-specific polymerase chain reaction. Co-immunoprecipitation assay verified the interaction between MGMT and protein tyrosine phosphatase nonreceptor type 4 (PTPN4). SW837 cells with CENPA knockdown were injected subcutaneously into mice, and tumor growth was examined.
CENPA was upregulated in rectal cancer tissues and cell lines. CENPA overexpression promoted proliferation, invasion and EMT, and inhibited apoptosis in rectal cancer cells. Whereas CENPA knockdown showed the opposite results. Moreover, CENPA inhibited MGMT expression by promoting DNA methyltransferase 1-mediated MGMT promoter methylation. MGMT knockdown abolished the CENPA knockdown-mediated inhibition of rectal cancer cell progression. MGMT increased PTPN4 protein stability by inhibiting PTPN4 ubiquitination degradation competing with ubiquitin-conjugating enzyme E2O for interacting with PTPN4. PTPN4 knockdown abolished the inhibitory effects of MGMT overexpression on rectal cancer cell progression. Moreover, CENPA knockdown inhibited xenograft tumor growth
CENPA knockdown inhibited rectal cancer cell growth and attenuated xenograft tumor growth through regulating the MGMT/PTPN4 axis.
着丝粒蛋白A（CENPA）在原发性人类直肠癌组织中的表达水平升高，但其作用尚未得到研究。
阐明CENPA在直肠癌进展中的具体作用和机制。
检测直肠癌组织和细胞系中CENPA蛋白的表达。在SW837和SW480细胞中过表达和敲低CENPA，并检测细胞增殖、侵袭、凋亡及上皮-间质转化（EMT）标志物蛋白水平。采用甲基化特异性聚合酶链反应评估O6-甲基鸟嘌呤DNA甲基转移酶（MGMT）启动子甲基化情况。通过免疫共沉淀实验验证MGMT与非受体型蛋白酪氨酸磷酸酶4（PTPN4）之间的相互作用。将敲低CENPA的SW837细胞皮下注射到小鼠体内，观察肿瘤生长情况。
CENPA在直肠癌组织和细胞系中上调。CENPA过表达促进了直肠癌细胞的增殖、侵袭和EMT，并抑制了细胞凋亡。而敲低CENPA则产生相反的结果。此外，CENPA通过促进DNA甲基转移酶1介导的MGMT启动子甲基化来抑制MGMT表达。敲低MGMT消除了敲低CENPA介导的对直肠癌细胞进展的抑制作用。MGMT通过抑制PTPN4泛素化降解，与泛素结合酶E2O竞争与PTPN4相互作用，从而增加PTPN4蛋白稳定性。敲低PTPN4消除了MGMT过表达对直肠癌细胞进展的抑制作用。此外，敲低CENPA抑制了异种移植瘤的生长。
敲低CENPA通过调节MGMT/PTPN4轴抑制直肠癌细胞生长并减弱异种移植瘤的生长。
