Overexpression of the telomerase holoenzyme induces EMT and tumorigenesis of HPV-immortalized keratinocytes.
Overexpression of the telomerase holoenzyme induces EMT and tumorigenesis of HPV-immortalized keratinocytes.
复制标题
端粒酶全酶的过度表达诱导 HPV 永生化角质形成细胞的 EMT 和肿瘤发生。
DOI：
10.1002/jmv.28681
复制
发表时间：
2023
影响因子：
12.7
通讯作者：
Yuan,Hang
中科院分区：
文献类型：
--
作者：
Wang,Aibing;Zhou,Dan;Krawczyk,Ewa;Li,Tuanjie;Simic,Vera;Lu,Jie;Liu,Xuefeng;Schlegel,Richard;Yuan,Hang
宫颈癌是女性生殖道最常见的恶性肿瘤，与宫颈持续感染高危人乳头瘤病毒（HPV）有关。两种HPV癌蛋白E6和E7共同使宫颈细胞永生化，是诱导致瘤性必不可少的，但不足以诱导致瘤性。在HPV相关宫颈发育不良向癌发展的过程中，细胞端粒酶逆转录酶（TERT）基因被激活，TERC基因被扩增。我们质疑这些端粒酶成分的增加是否可能介导致瘤表型的获得。因此，我们将TERT和TERC基因转导到锚定依赖性和非致瘤性的E6/E7永生化角化细胞中。由此产生的细胞显示出上皮-间充质转变的深刻形态学变化，以及相应的vimentin、N - cadherin、锌指E - Box结合同源盒1、蜗牛家族转录抑制因子1和基质金属肽酶2的表达增加，角蛋白和E - cadherin的表达减少。更重要的是，转导的细胞现在是不依赖于锚定的，并在免疫缺陷小鼠中形成肿瘤。我们的研究结果表明，在HPV永生化细胞中，端粒酶全酶的过表达足以诱导完全转化表型。
Cervical cancer is the most frequent malignancy of the female genital tract and is associated with persistent infection of the uterine cervix with high‐risk human papillomaviruses (HPV). The two HPV oncoproteins, E6 and E7, cooperatively immortalize cervical cells and are essential but insufficient for inducing tumorigenicity. During the progression of HPV‐associated cervical dysplasia to carcinoma, the cellular telomerase reverse transcriptase (TERT) gene is activated and the TERC gene amplified. We questioned whether these increases in telomerase components might mediate the acquisition of the tumorigenic phenotype. We therefore transduced the TERT and TERC genes into E6/E7 immortalized keratinocytes that were anchorage‐dependent and nontumorigenic. The resultant cells showed a profound morphological change characteristic of epithelial‐mesenchymal transition as well as a corresponding increase in expression of vimentin, N‐cadherin, Zinc finger E‐Box binding homeobox 1, snail family transcriptional repressor 1 and matrix Metallopeptidase 2 and decrease in keratin and E‐cadherin. More important, the transduced cells were now anchorage‐independent and formed tumors in immunodeficient mice. Our findings indicate that overexpression of the telomerase holoenzyme in HPV‐immortalized cells is sufficient to induce the complete transformed phenotype.