The relationship between human papillomavirus (HPV) and esophageal cancer (EC) has been controversial, which may be caused by the difference in geographic regions of sample origin. Thus, we conducted a case-control study to find that HPV increased the risk of esophageal cancer, and the HPV18 detection rate is the highest (24.2%) among patients with EC, suggesting that HPV18 could be the most risk subtype of HPV infected. We then identified high-risk HPV18 and N-methyl-N′-nitro-N-nitroso-guanidine (MNNG) to establish a model on the viral etiology cooperating with environmental carcinogens. Het-1A cells containing HPV18 were continuously exposed to MNNG or not; then the morphological phenotype and function assays were performed in 25th passage cells. MNNG promoted the proliferation and invasion abilities and inhibited apoptosis both in Het-1A-HPV18 and control group. However, the Het-1A-HPV18 had a stronger change in phenotypic features and formed more transformed foci in soft agar. Further, Western blot found p53 and p21 were down-regulated, and expression of c-Myc, MMP-2, and MMP-9 and Bcl-2/Bax ratio were up-regulated. Our results revealed that MNNG was easier to induce malignant transformation of Het-1A cells transfected with HPV18. It is good evidence for the close relationship between HPV and the etiology of EC, providing foundation for further study in molecular mechanism and specific intervention targets.

中文翻译：

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人乳头瘤病毒 18 感染促进烷化剂诱导的人食管细胞系恶性转化

人乳头瘤病毒（HPV）与食管癌（EC）之间的关系一直存在争议，这可能是由样本来源地理区域的差异引起的。因此，我们进行了病例对照研究，发现 HPV 增加了食管癌的风险，其中 HPV18 检出率在 EC 患者中最高（24.2%），表明 HPV18 可能是感染 HPV 风险最高的亚型。然后我们确定了高危HPV18和N-甲基-N'-硝基-N-亚硝基胍 (MNNG) 建立病毒病因与环境致癌物合作的模型。含HPV18的Het-1A细胞是否持续暴露于MNNG；然后在第25代细胞中进行形态学表型和功能测定。MNNG促进Het-1A-HPV18和对照组的增殖和侵袭能力并抑制细胞凋亡。然而，Het-1A-HPV18 的表型特征变化更大，在软琼脂中形成更多转化灶。此外，蛋白质印迹发现 p53 和 p21 下调，c-Myc、MMP-2 和 MMP-9 的表达和 Bcl-2/Bax 比率上调。我们的结果表明，MNNG 更容易诱导转染 HPV18 的 Het-1A 细胞发生恶性转化。这是HPV与EC病因密切相关的良好证据，