Wu De-Wei, Chuang Chun-Yi, Lin Wea-Long, Sung Wen-Wei, Cheng Ya-Wen, Lee Huei
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 115, Taiwan, Republic of China, School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan, Republic of China and Department of Otolaryngology and Department of Pathology, Chung Shan Medical University Hospital, Taichung 402, Taiwan, Republic of China.
School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan, Republic of China and Department of Otolaryngology and.
Carcinogenesis. 2014 Aug;35(8):1823-9. doi: 10.1093/carcin/bgu102. Epub 2014 Apr 29.
High-risk human papillomavirus (HPV) 16-infected oral cavity squamous cell carcinoma (OCSCC) differs significantly from non-HPV-infected OCSCC. However, the molecular pathogenesis of HPV-infected OCSCC remains unclear. Paxillin (PXN) has been reported to promote lung tumor progression by miR-218 targeting. In addition, expression of miR-218 has been shown to be reduced by HPV16 E6 in cervical cancer. We thus asked whether PXN can promote tumor progression by E6-reduced miR-218 in OCSCC, especially in HPV-infected OCSCC. Mechanistic studies demonstrated that PXN expression increased markedly upon E6-mediated reductions in miR-218, resulting in increased colony formation and invasion capabilities in HPV-infected OCSCC cells. Among tumor specimens, HPV16/18 infection was negatively associated with miR-218 expression and positively associated with PXN expression. Kaplan-Meier and Cox regression models demonstrated that patients with low-miR-218 tumors or high-PXN tumors exhibited shorter overall survival (OS) and relapse-free survival (RFS) than those with high-miR-218 tumors or low-PXN tumors. Interestingly, HPV-infected patients with low-miR-218, high-PXN tumors and both combinations exhibited the worst OS and RFS compared with patients in their counterparts. These observations in patients were consistent with the findings from the cell model. Therefore, we suggest that PXN might be targeted to suppress tumor progression and consequently to improve outcomes in OCSCC, especially in HPV-infected OCSCC.
高危型人乳头瘤病毒（HPV）16感染的口腔鳞状细胞癌（OCSCC）与非HPV感染的OCSCC有显著差异。然而，HPV感染的OCSCC的分子发病机制仍不清楚。据报道，桩蛋白（PXN）通过靶向miR-218促进肺癌进展。此外，在宫颈癌中，HPV16 E6可使miR-218的表达降低。因此，我们探讨了在OCSCC中，尤其是在HPV感染的OCSCC中，PXN是否可通过E6降低的miR-218促进肿瘤进展。机制研究表明，miR-218经E6介导降低后，PXN的表达显著增加，导致HPV感染的OCSCC细胞的集落形成和侵袭能力增强。在肿瘤标本中，HPV16/18感染与miR-218表达呈负相关，与PXN表达呈正相关。Kaplan-Meier和Cox回归模型表明，与高miR-218肿瘤或低PXN肿瘤患者相比，低miR-218肿瘤或高PXN肿瘤患者的总生存期（OS）和无复发生存期（RFS）较短。有趣的是，与相应患者相比，低miR-218、高PXN肿瘤及两者组合情况的HPV感染患者的OS和RFS最差。患者中的这些观察结果与细胞模型的结果一致。因此，我们认为PXN可能是抑制肿瘤进展从而改善OCSCC患者结局（尤其是HPV感染的OCSCC患者）的靶点。
