HOXA5 inhibits the proliferation and neoplasia of cervical cancer cells via downregulating the activity of the Wnt/β-catenin pathway and transactivating TP53
HOXA5 inhibits the proliferation and neoplasia of cervical cancer cells via downregulating the activity of the Wnt/β-catenin pathway and transactivating TP53
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HOXA 5通过下调Wnt/β-catenin通路活性和反式激活TP 53抑制宫颈癌细胞增殖和成瘤
DOI：
10.1038/s41419-020-2629-3
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发表时间：
2020-06-04
影响因子：
9
通讯作者：
Zheng, Peng-Sheng
中科院分区：
文献类型：
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作者：
Ma, Hong-Mei;Cui, Nan;Zheng, Peng-Sheng
HOXA5被认为是参与胚胎发育和细胞分化的调节因子和肿瘤抑制因子。然而，其在宫颈癌中的生物学作用尚不清楚。本研究免疫组化结果显示，HOXA5的表达随着宫颈病变程度的加深而逐渐降低。在体外和体内实验中，异位表达HOXA5抑制细胞增殖，降低细胞活力，抑制肿瘤形成。此外，HOXA5的表达可以将细胞周期从G0/G1期阻滞到S期。RNA-seq显示p21和cyclinD1参与了这一过程。此外，基因集富集分析和TOP/FOP报告基因实验均表明HOXA5可以抑制Wnt/ β -catenin通路的活性。通过双荧光素酶报告基因法和定量染色质免疫沉淀法进一步研究表明，HOXA5可以通过其HD结构域直接结合TP53启动子内的TAAT基序，并反激活TP53，从而上调p21。总之，我们的数据表明，HOXA5通过抑制Wnt/ β -catenin通路的活性和反激活TP53来抑制宫颈癌的增殖和肿瘤形成。
HOXA5 is considered a regulator involved in embryonic development and cellular differentiation and a tumor suppressor. Nevertheless, its biological role in cervical carcinoma is still unclear. In the present study, immunohistochemistry showed that HOXA5 expression gradually decreased as the degree of cervical lesions deepened. Ectopic expression of HOXA5 restrained cell proliferation, decreased cell viability, and inhibited tumor formation in vitro and in vivo. Furthermore, the expression of HOXA5 could arrest cell cycle from G0/G1 to S phase. RNA-seq revealed that p21 and cyclinD1 were involved in this process. Moreover, the gene set enrichment analysis and the TOP/FOP reporter assay both suggested that HOXA5 could restrain the activity of the Wnt/beta -catenin pathway. Further study using dual-luciferase reporter assay and quantitative chromatin immunoprecipitation assay demonstrated that HOXA5 could directly bind to the TAAT motif within the promoter of TP53 by its HD domain and transactivate TP53, which can upregulate p21. Altogether, our data suggest that HOXA5 inhibits the proliferation and neoplasia via repression activity of the Wnt/beta -catenin pathway and transactivating TP53 in cervical cancer.