Departments of Microbiology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
Beijing Key Laboratory of Environment and Viral Oncology, Beijing University of Technology, Beijing, People's Republic of China.
BMC Cancer. 2019 Feb 11;19(1):138. doi: 10.1186/s12885-019-5347-4.
Human papillomavirus (HPV) is an etiological agent of cervical cancer. Yet co-factors are believed to be involved in HPV-mediated carcinogenesis. Polycyclic aromatic hydrocarbons (PAHs) are considered as one of these co-factors. Epidemiologic studies have associated high PAH exposure with increased risk for cancer development. To date, many studies focus on benzo[a]pyrene, however, the role of other PAHs should not be neglected. This study aimed to compare the potential of different PAHs as a co-factor in HPV-mediated carcinogenesis, and to investigate the possible mechanisms involved.
The effect of 17 PAHs on high-risk HPV (HPV16) were examined in this study. HPV16 E7 oncogene was expressed in primary cells extracted from baby rat kidney and treated with PAHs. The co-transforming ability of PAHs were measured by colony formation index according to the number and size of transformed colonies. Effects of PAHs on proliferation of HPV-null (C33A) and -infected (CaSki) were examined using CCK-8 assay. Wound healing assay and matrigel invasion chambers were used to investigate effects of PAHs on cell motility and invasivion of HPV-null (MCF7, C33A) and -infected (SiHa) cells.
Benzo[a]pyrene (BaP), dibenz[a,h]anthracene (DBA) and indeno[1,2,3-cd]pyrene (IDP) showed the greatest co-transforming potential in the baby rat kidney cell system. Short-term exposure to BaP, DBA, IDP and pyrene (PR) did not affect proliferation of C33A or CaSki cells, however, long-term exposure of these four PAHs led to dramatic increase in growth rate of CaSki cells by 120-140%. Besides, exposure of PAHs has an effect on cell motility and invasiveness of C33A and SiHa cells, but not for MCF7 cells. Exposure of BaP and DBA enhanced migration (1.26 to 1.40-fold) and invasion (1.68 to 1.94-fold) capacity of C33A cells. Intriguingly, exposure of all four types of PAHs boosted the migration (1.12 to 1.28-fold) and invasion (1.26 to 1.40-fold) capacity of SiHa cells.
Our results indicate that exposure to PAHs can be a key co-factor in HPV-related cancer development. They could act on all three stages, namely initiation, promotion and progression. Further study is needed to unveil the mechanisms by which PAHs interact with HPV to cause malignancy.
人乳头瘤病毒（HPV）是宫颈癌的病因。然而，据信还有其他共同因素参与 HPV 介导的癌变。多环芳烃（PAHs）被认为是这些共同因素之一。流行病学研究表明，高 PAH 暴露与癌症发展风险增加有关。迄今为止，许多研究都集中在苯并[a]芘上，但是其他 PAHs 的作用也不容忽视。本研究旨在比较不同 PAHs 作为 HPV 介导的癌变中的共同因素的潜力，并探讨可能涉及的机制。
本研究检测了 17 种 PAHs 对高危型 HPV（HPV16）的影响。在本研究中，在从幼鼠肾中提取的原代细胞中表达 HPV16 E7 癌基因，并用 PAHs 处理。根据转化集落的数量和大小，通过集落形成指数测量 PAHs 的共转化能力。使用 CCK-8 测定法检测 PAHs 对 HPV 阴性（C33A）和感染（CaSki）细胞增殖的影响。使用划痕愈合试验和基质胶侵袭室检测 PAHs 对 HPV 阴性（MCF7、C33A）和感染（SiHa）细胞迁移和侵袭的影响。
苯并[a]芘（BaP）、二苯并[a，h]蒽（DBA）和茚并[1,2,3-cd]芘（IDP）在幼鼠肾细胞系统中显示出最大的共转化潜力。BaP、DBA、IDP 和芘（PR）的短期暴露对 C33A 或 CaSki 细胞的增殖没有影响，但是这四种 PAHs 的长期暴露会导致 CaSki 细胞的生长速度显著增加 120-140%。此外，PAHs 的暴露对 C33A 和 SiHa 细胞的迁移和侵袭有影响，但对 MCF7 细胞没有影响。BaP 和 DBA 的暴露增强了 C33A 细胞的迁移（1.26 至 1.40 倍）和侵袭（1.68 至 1.94 倍）能力。有趣的是，四种类型的 PAHs 的暴露均增强了 SiHa 细胞的迁移（1.12 至 1.28 倍）和侵袭（1.26 至 1.40 倍）能力。
我们的结果表明，PAHs 的暴露可能是 HPV 相关癌症发展的关键共同因素。它们可以作用于起始、促进和进展三个阶段。需要进一步研究以揭示 PAHs 与 HPV 相互作用导致恶性肿瘤的机制。
