HIV-1 Proteins gp120 and Tat Promote Epithelial-Mesenchymal Transition and Invasiveness of HPV-Positive and HPV-Negative Neoplastic Genital and Oral Epithelial Cells.
HIV-1 Proteins gp120 and Tat Promote Epithelial-Mesenchymal Transition and Invasiveness of HPV-Positive and HPV-Negative Neoplastic Genital and Oral Epithelial Cells.
复制标题
HIV-1蛋白GP120和TAT促进了HPV阳性和HPV阴性的肿瘤生殖器和口服上皮细胞的上皮 - 间质转变以及侵入性。
DOI：
10.1128/spectrum.03622-22
复制
发表时间：
2022-12-21
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
人类免疫缺陷病毒（HIV）感染者中与人乳头瘤病毒（HPV）相关的肛门生殖器和口咽癌的发病率大大高于未感染HIV的个体。HIV也可能是hpv阴性的头颈癌、肝癌、肺癌和肾癌的危险因素。然而，hiv -1相关的上皮恶性肿瘤增加的分子机制尚不完全清楚。在这里，我们发现hpv -16永活的肛门AKC-2和宫颈CaSki上皮细胞经历长时间暴露于无细胞HIV-1病毒粒子或HIV-1病毒蛋白gp120，并响应上皮-间质转化（EMT）和增加的侵袭性。在用这些病毒蛋白培养的hpv -16感染的SCC-47和hpv -16阴性的HSC-3口腔上皮癌细胞中也观察到类似的反应。gp120诱导EMT，导致贴壁差的细胞脱离培养基质；这些细胞仍然具有再附着的能力，在此基础上它们共同表达e -钙粘蛋白和vimentin，表明EMT处于中间阶段。再附着的细胞也表达干细胞标志物CD133和CD44，这可能在癌细胞的侵袭和转移中起关键作用。抑制转化生长因子(TGF)-β1和MAPK信号传导及vimentin表达，恢复E-cadherin表达，可降低hiv诱导的EMT和hpv -16永活肛门上皮细胞和宫颈上皮细胞的侵袭活性。总的来说，我们的研究结果表明，这些方法以及抗逆转录病毒治疗（ART）的HIV病毒抑制可能有助于限制HIV-1感染在hpv相关或不依赖hpv的上皮瘤变加速中的作用。hpv -16永生化的生殖器和口腔上皮细胞以及hpv阴性的口腔癌细胞与无细胞的HIV-1病毒粒子或病毒蛋白gp120长时间接触，并通过变得更具侵袭性而做出反应。在hpv -16永生肛门上皮细胞和宫颈上皮细胞中，HIV-1诱导的EMT细胞表达干细胞标志物CD133和CD44。这些结果表明，HIV-1与肿瘤上皮细胞的相互作用可能导致其去分化为对凋亡和抗癌药物具有抗性的癌症干细胞。因此，这一途径可能在侵袭性癌症的发展中发挥关键作用。抑制TGF-β1和MAPK信号传导及vimentin表达，恢复E-cadherin表达，可降低hiv诱导的EMT和hpv -16永生肛门和颈部上皮细胞的侵袭性。综上所述，这些结果表明，这些方法可能被用来限制HIV-1感染在加速hpv相关或不依赖hpv的上皮瘤变中的作用。
The incidence of human papillomavirus (HPV)-associated anogenital and oropharyngeal cancer in human immunodeficiency virus (HIV)-infected individuals is substantially higher than in HIV-uninfected individuals. HIV may also be a risk factor for the development of HPV-negative head and neck, liver, lung, and kidney cancer. However, the molecular mechanisms underlying HIV-1-associated increase of epithelial malignancies are not fully understood. Here, we showed that HPV-16-immortalized anal AKC-2 and cervical CaSki epithelial cells that undergo prolonged exposure to cell-free HIV-1 virions or HIV-1 viral proteins gp120 and tat respond with the epithelial-mesenchymal transition (EMT) and increased invasiveness. Similar responses were observed in HPV-16-infected SCC-47 and HPV-16-negative HSC-3 oral epithelial cancer cells that were cultured with these viral proteins. EMT induced by gp120 and tat led to detachment of poorly adherent cells from the culture substratum; these cells remained capable of reattachment, upon which they coexpressed both E-cadherin and vimentin, indicative of an intermediate stage of EMT. The reattached cells also expressed stem cell markers CD133 and CD44, which may play a critical role in cancer cell invasion and metastasis. Inhibition of transforming growth factor (TGF)-β1 and MAPK signaling and vimentin expression, and restoration of E-cadherin expression reduced HIV-induced EMT and the invasive activity of HPV-16-immortalized anal and cervical epithelial cells. Collectively, our results suggest that these approaches along with HIV viral suppression with antiretroviral therapy (ART) might be useful to limit the role of HIV-1 infection in the acceleration of HPV-associated or HPV-independent epithelial neoplasia. IMPORTANCE HPV-16-immortalized genital and oral epithelial cells and HPV-negative oral cancer cells that undergo prolonged contact with cell-free HIV-1 virions or with viral proteins gp120 and tat respond by becoming more invasive. EMT cells induced by HIV-1 in cultures of HPV-16-immortalized anal and cervical epithelial cells express the stem cell markers CD133 and CD44. These results suggest that the interaction of HIV-1 with neoplastic epithelial cells may lead to their de-differentiation into cancer stem cells that are resistant to apoptosis and anti-cancer drugs. Thus, this pathway may play a critical role in the development of invasive cancer. Inhibition of TGF-β1 and MAPK signaling and vimentin expression, and restoration of E-cadherin expression reduced HIV-induced EMT and the invasiveness of HPV-16-immortalized anal and cervical epithelial cells. Taken together, these results suggest that these approaches might be exploited to limit the role of HIV-1 infection in the acceleration of HPV-associated or HPV-independent epithelial neoplasia.
登录
查看更多内容
DOI：
10.1186/1756-9966-33-40
发表时间：
2014-05-10
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Fujii R;Imanishi Y;Shibata K;Sakai N;Sakamoto K;Shigetomi S;Habu N;Otsuka K;Sato Y;Watanabe Y;Ozawa H;Tomita T;Kameyama K;Fujii M;Ogawa K
通讯作者：
Ogawa K
影响因子：
7.3
作者：
Gonzalez DM;Medici D
通讯作者：
Medici D
影响因子：
6.6
作者：
Angelica De la Fuente-Hernandez，Marcela;Claudia Alanis-Manriquez，Erika;Maldonado Lagunas，Vilma
通讯作者：
Maldonado Lagunas，Vilma
影响因子：
6.7
作者：
Chung, Charlotte Y.;Alden, Stephanie L.;Levine, Alan D.
通讯作者：
Levine, Alan D.
影响因子：
4.8
作者：
Glauser, Dominique A.;Schlegel, Werner
通讯作者：
Schlegel, Werner