Virginia Commonwealth University, Philips Institute for Oral Health Research, School of Dentistry, Richmond, Virginia, USA
Virginia Commonwealth University, Philips Institute for Oral Health Research, School of Dentistry, Richmond, Virginia, USA.
mSphere. 2020 Mar 18;5(2):e00049-20. doi: 10.1128/mSphere.00049-20.
Human papillomaviruses (HPVs) are small, double-stranded DNA viruses that are significant risk factors in the development of cancer, and HPV accounts for approximately 5% of all worldwide cancers. Recent studies using data from The Cancer Genome Atlas (TCGA) have demonstrated that elevated levels of estrogen receptor alpha (ERα) are associated with improved survival in oropharyngeal cancers, and these elevated receptor levels were linked with human papillomavirus-positive cancers (HPV+cancers). There has been a dramatic increase in HPV-related head and neck squamous cell carcinomas (HPV+HNSCCs) over the last 2 decades, and therapeutic options for this ongoing health crisis are a priority; currently, there are no antiviral therapeutics available for combatting HPV+cancers. During our TGCA studies on head and neck cancer, we had also discovered the overexpression of ERα in HPV+cancers. Here, we demonstrate that 17β-estradiol (estrogen) attenuates the growth/cell viability of HPV+cancers , but not HPV-negative cancer cells. In addition, N/Tert-1 cells (foreskin keratinocytes immortalized with human telomerase reverse transcriptase [hTERT]) containing human papillomavirus 16 (HPV16) have elevated levels of ERα and growth sensitivity after estrogen treatment compared with parental N/Tert-1 cells. Finally, we demonstrate that there are potentially two mechanisms contributing to the attenuation of HPV+ cell growth following estrogen treatment. First, estrogen represses the viral transcriptional long control region (LCR) downregulating early gene expression, including E6/E7. Second, expression of E6 and E7 by themselves sensitizes cells to estrogen. Overall, our results support the recent proposal that estrogen could be exploited therapeutically for the treatment of HPV-positive oral cancers. Human papillomaviruses cause around 5% of all human cancers, yet there are no specific antiviral therapeutic approaches available for combatting these cancers. These cancers are currently treated with standard chemoradiation therapy (CRT). Specific antiviral reagents are desperately required, particularly for HPV+HNSCC whose incidence is increasing and for which there are no diagnostic tools available for combatting this disease. Using data from The Cancer Genome Atlas (TCGA), we and others determined that the estrogen receptor alpha (ERα) is overexpressed in HPV+HNSCC and that elevated levels are associated with an improved disease outcome. This has led to the proposal that estrogen treatment could be a novel therapeutic approach for combatting HPV+cancers. Here, we demonstrate that estrogen attenuates the growth of HPV+epithelial cells using multiple mechanisms, supporting the idea that estrogen has potential as a therapeutic agent for the treatment of HPV+HNSCC.
人乳头瘤病毒（HPV）是一种小型双链 DNA 病毒，是癌症发展的重要危险因素，约占全球所有癌症的 5%。最近使用癌症基因组图谱（TCGA）数据进行的研究表明，雌激素受体 alpha（ERα）水平升高与口咽癌的生存改善有关，并且这些受体水平与 HPV 阳性癌症（HPV+cancers）相关。在过去的 20 年中，HPV 相关的头颈部鳞状细胞癌（HPV+HNSCCs）急剧增加，针对这一持续存在的健康危机的治疗选择是当务之急；目前，尚无针对 HPV+cancers 的抗病毒治疗方法。在我们对头颈癌的 TCGA 研究中，我们还发现 HPV+cancers 中 ERα 的过表达。在这里，我们证明 17β-雌二醇（雌激素）可减弱 HPV+cancers 的生长/细胞活力，但不会减弱 HPV 阴性癌细胞的活力。此外，与亲本 N/Tert-1 细胞相比，含有 HPV16 的 N/Tert-1 细胞（用人端粒酶逆转录酶 [hTERT] 永生化的包皮角质形成细胞）中 ERα 的水平升高，并且在雌激素处理后对生长的敏感性增加。最后，我们证明有两种潜在的机制可能导致雌激素处理后 HPV+细胞生长的减弱。首先，雌激素抑制病毒转录的长控制区（LCR），下调早期基因表达，包括 E6/E7。其次，E6 和 E7 的表达本身会使细胞对雌激素敏感。总的来说，我们的研究结果支持最近的观点，即雌激素可以被用于治疗 HPV 阳性口腔癌的治疗。人乳头瘤病毒导致约 5%的人类癌症，但目前尚无针对这些癌症的特定抗病毒治疗方法。这些癌症目前采用标准的放化疗（CRT）治疗。迫切需要特定的抗病毒试剂，特别是对于 HPV+HNSCC，其发病率正在增加，并且目前尚无针对该疾病的诊断工具。使用癌症基因组图谱（TCGA）的数据，我们和其他人确定 ERα 在 HPV+HNSCC 中过表达，并且水平升高与疾病结局改善相关。这导致了雌激素治疗可能是对抗 HPV+cancers 的一种新的治疗方法的提议。在这里，我们证明雌激素通过多种机制减弱 HPV+上皮细胞的生长，支持雌激素作为 HPV+HNSCC 治疗剂的潜力的观点。
