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