// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Shilpi Gupta1, 2, *, Prabhat Kumar1, 2, *, Harsimrut Kaur2, Nishi Sharma3, Sunita Gupta4, Daman Saluja2, Alok C. Bharti5 and Bhudev Das1, 2 1Stem Cell and Cancer Research Lab, Amity Institute of Molecular Medicine and Stem Cell Research, Amity University Uttar Pradesh, Sector-125, Noida-201313, India 2Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi-110007, India 3Department of Otorhinolaryngology, Post Graduate Institute of Medical Education and Research, Dr. Ram Manohar Lohia Hospital, Delhi-110010, India 4Department of Oral Medicine and Radiology, Maulana Azad Institute of Dental Sciences, Delhi-110010, India 5Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi-110007, India *These authors contributed equally to this work Correspondence to: Bhudev Das, email: bcdas48@hotmail.com, bcdas@amity.edu Keywords: tongue squamous cell carcinoma; NF-κB/c-Rel; Fra-2; HPV; prognosis Received: April 17, 2018 Accepted: August 16, 2018 Published: August 31, 2018 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-κB 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-κB 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-κB proteins was observed with p50 and c-Rel being the two major DNA binding partners forming the functional NF-κB 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.