Up-regulation of FOXM1 by E6 oncoprotein through the MZF1/NKX2-1 axis is required for human papillomavirus-associated tumorigenesis.
Up-regulation of FOXM1 by E6 oncoprotein through the MZF1/NKX2-1 axis is required for human papillomavirus-associated tumorigenesis.
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DOI：
10.1016/j.neo.2014.09.010
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发表时间：
2014-11
期刊：
影响因子：
4.8
通讯作者：
Lee, Huei
中科院分区：
文献类型：
--
作者：
Chen, Po-Ming;Cheng, Ya-Wen;Wang, Yao-Chen;Wu, Tzu-Chin;Chen, Chih-Yi;Lee, Huei
目的：Foxhead box M1（FOXM 1）表达与人乳头瘤病毒（HPV）16/18感染的宫颈癌相关。然而，在HPV 16/18感染的癌症中诱导FOXM 1的潜在机制仍然难以捉摸。实验设计：在细胞和动物模型中阐明了E6/NKX 2 -1轴诱导的FOXM 1在肿瘤侵袭性中的机制作用。使用Kaplan-Meier和考克斯回归模型评估FOXM 1对HPV阳性口腔癌和肺癌的总生存期（OS）和无复发生存期（RFS）的预后价值。结果：在HPV阳性的宫颈癌、口腔癌和肺癌细胞中，E6介导的NKX 2 -1上调FOXM 1的表达。E6通过MZF 1/NKX 2 -1轴诱导FOXM 1，通过激活Wnt/β-catenin信号通路负责HPV介导的软琼脂生长、侵袭和干性。在裸鼠模型中，HPV 18 E6阳性GNM或HPV 16 E6阳性TL-1注射裸鼠中的转移性肺肿瘤结节在E6敲除、FOXM 1敲除或用FOXM 1抑制剂（硫链丝菌素）治疗的两种细胞类型中均显著减少。在这四个亚组患者中，在HPV 16/18阳性且肿瘤高表达FOXM 1的患者中观察到FOXM 1对OS和RFS的最差预后价值。结论：E6癌蛋白通过MZF 1/NKX 2 -1轴诱导FOXM 1可能是HPV 16/18介导的肿瘤进展和HPV阳性患者预后不良的原因。
PURPOSE: Foxhead box M1 (FOXM1) expression has been shown to be linked with human papillomavirus (HPV) 16/18–infected cervical cancer. However, the mechanism underlying the induction of FOXM1 in HPV 16/18–infected cancers remains elusive. EXPERIMENTAL DESIGN: The mechanistic actions of FOXM1 induced by the E6/NKX2-1 axis in tumor aggressiveness were elucidated in cellular and animal models. The prognostic value of FOXM1 for overall survival (OS) and relapse-free survival (RFS) in HPV-positive oral and lung cancers was assessed using Kaplan-Meier and Cox regression models. RESULTS: Herein, FOXM1 expression is upregulated by E6-mediated NKX2-1 in HPV-positive cervical, oral, and lung cancer cells. Induction of FOXM1 by E6 through the MZF1/NKX2-1 axis is responsible for HPV-mediated soft agar growth, invasiveness, and stemness through activating Wnt/β-catenin signaling pathway. In a nude mice model, metastatic lung tumor nodules in HPV 18 E6-positive GNM or HPV 16 E6-positive TL-1–injected nude mice were markedly decreased in both cell types with E6 knockdown, FOXM1 knockdown, or treatment with FOXM1 inhibitor (thiostrepton). Among the four subgroup patients, the worst FOXM1 prognostic value for OS and RFS was observed in HPV 16/18–positive patients with tumors with high-expressing FOXM1. CONCLUSIONS: Induction of FOXM1 by E6 oncoprotein through the MZF1/NKX2-1 axis may be responsible for HPV 16/18–mediated tumor progression and poor outcomes in HPV-positive patients.
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影响因子：
8
作者：
Lüscher-Firzlaff, JM;Westendorf, JM;Lüscher, B
通讯作者：
Lüscher, B
影响因子：
11.1
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11.2
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Huang C;Qiu Z;Wang L;Peng Z;Jia Z;Logsdon CD;Le X;Wei D;Huang S;Xie K
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