Constitutive activation and overexpression of NF-?B/c-Rel in conjunction with p50 contribute to aggressive tongue tumorigenesis.

ABSTRACT: Tongue squamous cell carcinoma (TSCC) is a most aggressive head and neck cancer often associated with a poor survival rate. Yet, it always shows better prognosis in presence of HPV16 infection. NF-?B plays a pivotal role in carcinogenesis and chemo-radio resistance of cancer but its role in tongue cancer is not yet explored. In this study, a total of hundred tongue tissue biopsies comprising precancer, cancer and adjacent normal controls including two tongue cancer cell lines (HPV^+/-ve) were employed to examine expression and transactivation of NF-?B proteins, their silencing by siRNA and invasion assays to understand their contributions in tongue carcinogenesis. An exclusive prevalence (28%) of HR-HPV type 16 was observed mainly in well differentiated tumors (78.5%). Increased DNA binding activity and differential expression of NF-?B proteins was observed with p50 and c-Rel being the two major DNA binding partners forming the functional NF-?B complex that increased as a function of severity of lesions in both HPV^+/-ve tumors but selective participation of p65 in HPV16^+ve TSCCs induced well differentiation of tumors resulting in better prognosis. siRNA treatment against c-Rel or Fra-2 led to upregulation of p27 but strong inhibition of c-Rel, c-Jun, c-myc, HPVE6/E7 and Fra-2 which is exclusively overexpressed in HPV^-ve aggressive tumors. In conclusion, selective participation of c-Rel with p50 that in cross-talk with AP-1/Fra-2 induced poor differentiation and aggressive tumorigenesis mainly in HPV^-ve smokers while HPV infection induced expression of p65 and p27 leading to well differentiation and better prognosis preferably in non-smoking TSCC patients.

SUBMITTER: Gupta S 

PROVIDER: S-EPMC6152474 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature