journal contribution posted on 2023-03-31, 01:24 authored by Jialing Zhang, Tony Chen, Xinping Yang, Hui Cheng, Stephan S. Späth, Paul E. Clavijo, Jianhong Chen, Christopher Silvin, Natalia Issaeva, Xiulan Su, Wendell G. Yarbrough, Christina M. Annunziata, Zhong Chen, Carter Van Waes
Supplementary Methods, related references, and Figures: S1, 2 Effects TRAF3 on alternate pathway proteins; S2, Effects TRAF3 on alternate pathway proteins; S3, Effects of TNF/LTB on NF-kB reporter activity and TRAF3 siRNA on alternate pathway; S4, Effects TRAF3 on cisplatin and anti-apoptotic genes; S5, TRAF3 loss with passage; S6-8, TRAF3 effects on IRF expression; S9, TRAF3 effects on TP53, RB, p21; S10, TRAF3 effects on E6; S11, Diagram illustrating the genetic and cellular mechanisms linked to deficient TRAF3 in HPV+ HNSCC.
National Institute on Deafness and Other Communication Disorders
ARTICLE ABSTRACTHuman 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.Significance: These findings report the functional role of TRAF3 as a tumor suppressor that modulates the malignant phenotype of HPV+ head and neck cancers. Cancer Res; 78(16); 4613–26. ©2018 AACR.