HOXA5 inhibits the proliferation of extrahepatic cholangiocarcinoma cells by enhancing MXD1 expression and activating the p53 pathway.
HOXA5 inhibits the proliferation of extrahepatic cholangiocarcinoma cells by enhancing MXD1 expression and activating the p53 pathway.
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DOI：
10.1038/s41419-022-05279-6
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发表时间：
2022-09-27
影响因子：
9
通讯作者：
Chen, Yongjun
中科院分区：
文献类型：
--
作者：
Xiong, Fei;Liu, Wenzheng;Wang, Xin;Wu, Guanhua;Wang, Qi;Guo, Tong;Huang, Wenhua;Wang, Bing;Chen, Yongjun
同源盒A5 （HOXA5）是哺乳动物的一种转录因子，可调节细胞分化、增殖、凋亡和肿瘤发生。然而，对于HOXA5是否以及如何调节胆管癌的恶性行为，我们知之甚少。利用甲基化芯片和亚硫酸氢盐测序PCR检测HOXA5的甲基化水平。免疫组化和Western blot检测组织样品中HOXA5的表达。通过CCK-8、EdU和裸鼠致瘤性试验评估肿瘤细胞的增殖情况。采用创面愈合实验和流式细胞术观察肿瘤细胞的侵袭、凋亡和细胞周期变化。采用CUT & Tag法、荧光素酶报告基因法和染色质免疫沉淀法检测HOXA5与MXD1启动子的相互作用。HOXA5启动子的高甲基化下调了HOXA5在肝外胆管癌（ECCA）组织中的表达，这与较差的总生存率相关。HOXA5过表达可显著抑制肿瘤的增殖和生长。在ECCA细胞中，HOXA5过表达通过直接结合MXD1启动子增强MXD1表达。MXD1过表达可抑制细胞增殖和肿瘤生长，而MXD1沉默可消除hoxa5介导的增殖抑制作用。HOXA5过表达以mxd1依赖的方式增加p53蛋白的表达。HOXA5和MXD1作为抑癌因子，通过增强p53信号，抑制ECCA细胞有丝分裂。我们的发现可能揭示了HOXA5/MXD1轴调控ECCA进展的分子机制，提示HOXA5/MXD1可能是ECCA的治疗靶点。
Homeobox A5 (HOXA5) is a transcription factor in mammalian and can regulate cell differentiation, proliferation, and apoptosis as well as tumorigenesis. However, little is known on whether and how HOXA5 can regulate the malignant behaviors of cholangiocarcinoma. The methylation levels of HOXA5 were evaluated by methylation microarray and bisulfite sequencing PCR. HOXA5 expression in tissue samples was examined by immunohistochemistry and Western blot. The proliferation of tumor cells was assessed by CCK-8, EdU, and nude mouse tumorigenicity assays. The invasion, apoptosis and cell cycling of tumor cells were evaluated by Wound healing assay and flow cytometry. The interaction between HOXA5 and the MXD1 promoter was examined by CUT & Tag assay, luciferase reporter assay and chromatin immunoprecipitation. Hypermethylation in the HOXA5 promoter down-regulated HOXA5 expression in extrahepatic cholangiocarcinoma (ECCA) tissues, which was correlated with worse overall survival. HOXA5 overexpression significantly inhibited the proliferation and tumor growth. HOXA5 overexpression enhanced MXD1 expression by directly binding to the MXD1 promoter in ECCA cells. MXD1 overexpression inhibited the proliferation and tumor growth while MXD1 silencing abrogated the HOXA5-mediated proliferation inhibition. HOXA5 overexpression increased p53 protein expression in an MXD1-dependent manner. HOXA5 and MXD1 acted as tumor suppressors to inhibit the mitosis of ECCA cells by enhancing the p53 signaling. Our findings may uncover molecular mechanisms by which the HOXA5/MXD1 axis regulates the progression of ECCA, suggesting that the HOXA5/MXD1 may be therapeutic targets for ECCA.
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