Transcription factor homeobox D9 is involved in the malignant phenotype of cervical cancer through direct binding to the human papillomavirus oncogene promoter
Transcription factor homeobox D9 is involved in the malignant phenotype of cervical cancer through direct binding to the human papillomavirus oncogene promoter
复制标题
DOI：
10.1016/j.ygyno.2019.08.026
复制
发表时间：
2019-11-01
影响因子：
4.7
通讯作者：
Kawakami, Yutaka
中科院分区：
文献类型：
--
作者：
Hirao, Nobumaru;Iwata, Takashi;Kawakami, Yutaka
目的：目的探讨同源框D9（HOXD 9）通过P97启动子调控人乳头瘤病毒（HPV）16型E6/E7基因的表达与宫颈癌细胞的生存、增殖和转移的关系。100例宫颈癌（CC），CC细胞系SKG-I、SKG-II、SKG-IIIa、SKG-IIIb、HeLa和SiHa，和人肿瘤异种移植小鼠模型用于检查HOXD 9在CC中的作用。敲低实验采用H 0XD 9的RNA干扰。结果：所有CC细胞株均表达HOXD 9 mRNA和蛋白。HOXD 9基因在子宫癌组织中的表达明显高于正常宫颈组织。在患者样本中发现淋巴管间隙浸润和淋巴结转移与HOXD 9高水平表达呈正相关。小鼠异种移植模型中的H 0XD 9敲减细胞仅形成小肿瘤或不形成肿瘤。HOXD 9基因的敲低可显著降低CC细胞的增殖、迁移和侵袭能力，诱导细胞凋亡，增加P53蛋白表达，并通过与HPV 16 E6/E7基因的P97启动子直接结合而抑制HPV E6/E7表达。结论：HOXD 9通过与P97启动子直接结合，促进HPV 16 E6和E7的表达，从而促进CCr细胞的增殖、迁移和转移。我们的研究结果表明HOXD 9可能是CC的预后生物标志物和潜在的治疗靶点。(C)2019爱思唯尔公司All rights reserved.
Objective: To determine the involvement of homeobox D9 (HOXD9) in the survival, proliferation, and metastasis of cervical cancer cells through regulating the expression of human papillomavirus (HPV) 16 E6/E7 genes using the P97 promoter.Methods: One hundred cases of cervical cancer (CC), CC cell lines SKG-I, SKG-II, SKG-IIIa, SKG-IIIb, HeLa, and SiHa, and a human tumor xenograft mouse model were used to examine the roles of HOXD9 in CC. Knockdown experiments employed RNA interference of HOXD9. qPCR, functional assays, western blotting, DNA microarray, and luciferase and ChIP assays were applied for assessments.Results: All CC cell lines expressed HOXD9 mRNA and protein. In uterine CC, HOXD9 gene expression was significantly higher than in normal cervical tissues. A positive correlation of lymphovascular space invasion and lymph node metastasis with high levels of HOXD9 expression was found in patient samples. HOXD9-knockdown cells in the mouse xenograft model only formed small or no tumors. Knockdown of HOXD9 markedly reduced CC cell proliferation, migration and invasion, induced apoptosis, increased P53 protein expression, and suppressed HPV E6/E7 expression by directly binding to the P97 promoter of HPV16 E6/E7 genes. A positive correlation between HOXD9 and HPV16 E6 expression was found in CC patients.Conclusions: HOXD9 promotes HPV16 E6 and E7 expression by direct binding to the P97 promoter, which enhances proliferation, migration, and metastasis of CCr cells. Our results suggest that HOXD9 could be a prognostic biomarker and potential therapeutic target in CC. (C) 2019 Elsevier Inc. All rights reserved.