Attenuated TRAF3 Fosters Activation of Alternative NF-κB and Reduced Expression of Antiviral Interferon, TP53, and RB to Promote HPV-Positive Head and Neck Cancers.
Attenuated TRAF3 Fosters Activation of Alternative NF-κB and Reduced Expression of Antiviral Interferon, TP53, and RB to Promote HPV-Positive Head and Neck Cancers.
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DOI：
10.1158/0008-5472.can-17-0642
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发表时间：
2018-08-15
期刊：
影响因子：
11.2
通讯作者：
Van Waes C
中科院分区：
文献类型：
--
作者：
Zhang J;Chen T;Yang X;Cheng H;Späth SS;Clavijo PE;Chen J;Silvin C;Issaeva N;Su X;Yarbrough WG;Annunziata CM;Chen Z;Van Waes C
人乳头瘤病毒（HPV）与口咽部头颈部鳞状细胞癌（HNSCC）的流行性增加有关，HNSCC显示肿瘤抑制因子TP 53和RB 1的病毒失活以及快速的区域扩散。然而，基因组改变在调节促进这些癌症侵袭性表型的途径中的作用尚不清楚。最近，HPV+ HNSCC的一个子集已被证明具有新的遗传缺陷或TNF受体相关因子3（TRAF 3）表达降低。TRAF 3被认为是替代NF-κB途径激活的负调节剂和抗病毒I型IFN对其他DNA病毒应答的激活剂。TRAF 3改变如何影响HPV+ HNSCC的发病机制尚未得到广泛研究。在这里，我们报告TRAF 3缺陷型HPV+肿瘤和细胞系显示替代NF-κB通路组分和转录因子NF-κB2/RELB的表达增加。在内源性TRAF 3减少的HPV+细胞系中，TRAF 3过表达抑制NF-κB2/RELB表达、核定位和NF-κB报告基因活性，同时增加IFNA 1 mRNA和蛋白的表达，并使细胞对其生长抑制敏感。TRAF 3的过表达还增强了HPV+细胞中TP 53和RB肿瘤抑制蛋白的表达，并降低了HPV E6癌蛋白的表达。相应地，TRAF 3抑制细胞生长、集落形成、迁移以及对TNFα和顺铂诱导的细胞死亡的抵抗。相反，TRAF 3敲除增强表达更高TRAF 3水平的HPV+ HNSCC系的集落形成和增殖。总之，这些发现支持TRAF 3作为肿瘤抑制因子调节HPV+ HNSCC中已建立的癌症标志的功能作用。
Human papilloma viruses (HPV) are linked to an epidemic increase in oropharyngeal head and neck squamous cell carcinomas (HNSCC), which display viral inactivation of tumor suppressors TP53 and RB1 and rapid regional spread. However, the role of genomic alterations in enabling the modulation of pathways that promote the aggressive phenotype of these cancers is unclear. Recently, a subset of HPV+ HNSCC has been shown to harbor novel genetic defects or decreased expression of TNF receptor–associated factor 3 (TRAF3). TRAF3 has been implicated as a negative regulator of alternative NF-κB pathway activation and activator of antiviral type I IFN response to other DNA viruses. How TRAF3 alterations affect pathogenesis of HPV+ HNSCC has not been extensively investigated. Here, we report that TRAF3-deficient HPV+ tumors and cell lines exhibit increased expression of alternative NF-κB pathway components and transcription factors NF-κB2/RELB. Overexpression of TRAF3 in HPV+ cell lines with decreased endogenous TRAF3 inhibited NF-κB2/RELB expression, nuclear localization, and NF-κB reporter activity, while increasing the expression of IFNA1 mRNA and protein and sensitizing cells to its growth inhibition. Overexpression of TRAF3 also enhanced TP53 and RB tumor suppressor proteins and decreased HPV E6 oncoprotein in HPV+ cells. Correspondingly, TRAF3 inhibited cell growth, colony formation, migration, and resistance to TNFα and cisplatin-induced cell death. Conversely, TRAF3 knockout enhanced colony formation and proliferation of an HPV+ HNSCC line expressing higher TRAF3 levels. Together, these findings support a functional role of TRAF3 as a tumor suppressor modulating established cancer hallmarks in HPV+ HNSCC.