Araújo Rita, Santos Joana M O, Fernandes Mara, Dias Francisca, Sousa Hugo, Ribeiro Joana, Bastos Margarida M S M, Oliveira Paula A, Carmo Diogo, Casaca Fátima, Silva Sandra, Medeiros Rui, Gil da Costa Rui M
Molecular Oncology and Viral Pathology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
Abel Salazar Institute of Biomedical Sciences of the University of Porto (ICBAS), Rua de Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal.
J Cancer Res Clin Oncol. 2018 Feb;144(2):241-248. doi: 10.1007/s00432-017-2549-5. Epub 2017 Nov 27.
Persistent human papillomavirus (HPV) infection is associated with the development of certain types of cancer and the dysregulation of microRNAs has been implicated in HPV-associated carcinogenesis. This is the case of microRNA-146a (miR-146a), which is thought to regulate tumor-associated inflammation. We sought to investigate the expression levels of miR-146a during HPV16-mediated carcinogenesis using skin samples from K14-HPV16 transgenic mice which develop the consecutive phases of the carcinogenesis process.
Female transgenic (HPV) and wild-type (HPV) mice were sacrificed at 24-26 weeks-old or 28-30 weeks-old. Chest and ear skin samples from HPV and HPV mice were histologically classified and used for microRNA extraction and quantification by qPCR.
Chest skin samples from 24 to 26 weeks-old HPV mice presented diffuse epidermal hyperplasia and only 22.5% showed multifocal dysplasia, while at 28-30 weeks-old all (100.0%) HPV animals showed epidermal dysplasia. All HPV ear skin samples showed carcinoma in situ (CIS). MiR-146a expression levels were higher in HPV compared to HPV mice (p = 0.006). There was also an increase in miR-146a expression in dysplastic skin lesions compared with hyperplasic lesions (p = 0.011). Samples showing CIS had a significant decrease in miR-146a expression when compared to samples showing epidermal hyperplasia (p = 0.018) and epidermal dysplasia (p = 0.009).
These results suggest that HPV16 induces the overexpression of miR-146a in the initial stages of carcinogenesis (hyperplasia and dysplasia), whereas decreases its expression at later stages (CIS). Taken together, these data implicate and suggest different roles of miR-146a in HPV-mediated carcinogenesis.
持续性人乳头瘤病毒（HPV）感染与某些类型癌症的发生有关，且微小RNA的失调与HPV相关的致癌作用有关。微小RNA-146a（miR-146a）就是这种情况，它被认为可调节肿瘤相关炎症。我们试图利用K14-HPV16转基因小鼠的皮肤样本研究miR-146a在HPV16介导的致癌过程中的表达水平，这些小鼠会经历致癌过程的连续阶段。
在24 - 26周龄或28 - 30周龄时处死雌性转基因（HPV）和野生型（HPV）小鼠。对HPV和HPV小鼠的胸部和耳部皮肤样本进行组织学分类，并用于通过qPCR提取和定量微小RNA。
24至26周龄的HPV小鼠胸部皮肤样本呈现弥漫性表皮增生，只有22.5%表现为多灶性发育异常，而在28 - 30周龄时，所有（100.0%）HPV动物均表现出表皮发育异常。所有HPV耳部皮肤样本均显示原位癌（CIS）。与HPV小鼠相比，HPV小鼠中miR-146a的表达水平更高（p = 0.006）。与增生性病变相比，发育异常的皮肤病变中miR-146a的表达也有所增加（p = 0.011）。与表现为表皮增生（p = 0.018）和表皮发育异常（p = 0.009）的样本相比，显示CIS的样本中miR-146a的表达显著降低。
这些结果表明，HPV16在致癌作用的初始阶段（增生和发育异常）诱导miR-146a的过表达，而在后期阶段（CIS）降低其表达。综上所述，这些数据表明miR-146a在HPV介导的致癌作用中具有不同的作用。
