Defective TRAF3 modulates alternative NF-kB signaling and cytokine expression to promote cancer cell survival in HPV positive head and neck cancer (TUM10P.1049)

Abstract

Abstract Persistent infection of high-risk human papillomaviruses (HPV) is a known pathogen associated with head and neck squamous cell carcinoma (HNSCC), especially in tonsil, oropharynx and oral cavity. The incidence of HPV+ HNSCC has been increased recently in the Unites States, while the molecular mechanism of virus promoting HNSCC has not been fully understood. Recently, The Cancer Genome Atlas (TCGA) project revealed unique homozygous and heterozygous deletions and mutations of TNF receptor-associated factor 3 (TRAF3) in HPV associated HNSCC tumors. Low expression of TRAF3 was observed in HPV positive HNSCC samples and cell lines with TRAF3 deletions. These tumors had elevated expression of NF-kB subunits involved in alternative pathway, such as NF-kB2 and RelB, often associated with increased NIK, cIAP1 and cIAP2 expression. Overexpression of TRAF3 in HPV+ cell lines significantly suppressed alternative NF-kB subunit NF-kB2/RELB nuclear localization, while increasing expression of IFNα/β and IL10 implicated in anti-viral immunity. Further, overexpression of TRAF3 inhibited cell growth, colony formation, and migration, and sensitized cells to TNF-a and cisplatin induced cell death. Our data revealed that defective TRAF3 activated alternative NF-kB signaling and suppressed anti-viral cytokine expression, which promoted cancer cell survival and drug resistance, especially in HPV+ HNSCC.