Human papillomavirus oncogenic E6 protein regulates human β-defensin 3 (hBD3) expression via the tumor suppressor protein p53.
Human papillomavirus oncogenic E6 protein regulates human β-defensin 3 (hBD3) expression via the tumor suppressor protein p53.
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DOI：
10.18632/oncotarget.8443
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发表时间：
2016-05-10
期刊：
影响因子：
--
通讯作者：
Jin G
中科院分区：
文献类型：
--
作者：
DasGupta T;Nweze EI;Yue H;Wang L;Jin J;Ghosh SK;Kawsar HI;Zender C;Androphy EJ;Weinberg A;McCormick TS;Jin G
人β-防御素-3（hBD 3）是一种上皮细胞来源的先天性免疫调节分子，在口腔异型增生病变中过表达，并促进肿瘤微环境。hBD 3的表达由表皮生长因子受体信号通路诱导。在这里，我们描述了一种新的途径，通过这种途径，高危型人乳头瘤病毒16型（HPV-16）癌蛋白E6诱导hBD 3在粘膜角质形成细胞中的表达。通过siRNA去除E6诱导了HPV-16阳性CaSki宫颈癌细胞和UM-SCC-104头颈癌细胞中的肿瘤抑制因子p53并减少了hBD 3。HPV-16相关口咽癌中的恶性细胞过表达hBD 3。HPV-16 E6诱导粘膜角质形成细胞hBD 3 mRNA表达、肽产生和基因启动子活性p53细胞水平的降低刺激hBD 3表达，而阿霉素激活p53抑制其在原代口腔角质形成细胞和CaSki细胞中的表达，表明p53抑制hBD 3表达。用电泳迁移率变动分析和染色质免疫沉淀法（ChIP）鉴定了hBD 3基因启动子中的p53结合位点。此外，p63蛋白亚型Δ Np 63 α，而不是TAp 63，刺激hBD 3基因的反式激活，并与hBD 3在头颈癌标本中共表达。因此，高危型HPV E6癌蛋白可能刺激肿瘤细胞中hBD 3的表达，以促进HPV相关头颈癌的肿瘤发生。
Human β-defensin-3 (hBD3) is an epithelial cell-derived innate immune regulatory molecule overexpressed in oral dysplastic lesions and fosters a tumor-promoting microenvironment. Expression of hBD3 is induced by the epidermal growth factor receptor signaling pathway. Here we describe a novel pathway through which the high-risk human papillomavirus type-16 (HPV-16) oncoprotein E6 induces hBD3 expression in mucosal keratinocytes. Ablation of E6 by siRNA induces the tumor suppressor p53 and diminishes hBD3 in HPV-16 positive CaSki cervical cancer cells and UM-SCC-104 head and neck cancer cells. Malignant cells in HPV-16-associated oropharyngeal cancer overexpress hBD3. HPV-16 E6 induces hBD3 mRNA expression, peptide production and gene promoter activity in mucosal keratinocytes. Reduction of cellular levels of p53 stimulates hBD3 expression, while activation of p53 by doxorubicin inhibits its expression in primary oral keratinocytes and CaSki cells, suggesting that p53 represses hBD3 expression. A p53 binding site in the hBD3 gene promoter has been identified by using electrophoretic mobility shift assays and chromatin immunoprecipitation (ChIP). In addition, the p63 protein isoform ΔNp63α, but not TAp63, stimulated transactivation of the hBD3 gene and was co-expressed with hBD3 in head and neck cancer specimens. Therefore, high-risk HPV E6 oncoproteins may stimulate hBD3 expression in tumor cells to facilitate tumorigenesis of HPV-associated head and neck cancer.
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影响因子：
3.5
作者：
Desdouets, C;Ory, C;SobczakThepot, J
通讯作者：
SobczakThepot, J
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28.2
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3.1
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10.3
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4.8
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