Constitutive activation and overexpression of NF-κB/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-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.

The role of NF-κB and miRNA in oral cancer and cancer stem cells with or without HPV16 infection

“…Interestingly enough, our group has recently shown a significant higher expression of c-Rel in HPV-ve tongue cancer instead of HPV+ve tumors which has been observed in oral cancer. This is intriguing but it indicate that expression of cancer associated genes may differ from cancer to cancer along with their grades/stages [ 60 ].…”

A novel role of MNT as a negative regulator of REL and the NF-κB pathway

“…Moreover, it has been described that REL induce MYC expression [41][42][43][44] . Considering the MYC-MNT antagonism, it would be possible that MNT would control MYC levels through the inhibition of REL functions.…”

Long Non-Coding RNAs Emerging as Potential Epigenetic Biomarkers for Tobacco and/or Alcohol-Induced Head and Neck Cancer

“…These lifestyle factors play a significant role in the aetiology of HNCs [10]. Globally, ~90% of HNCs are associated with avoidable well-known lifestyle factors such as tobacco chewing/ smoking and alcohol drinking [11][12][13][14][15][16][17][18][19]. Regardless of the fact that majority of research studies on HNCs and other diseases are primarily focused on the use of alcohol and tobacco as well-established classical factors, their rates of consumption in many countries specially in low and middle income countries remain high, requiring a better understanding of the mechanisms in HNCs that are exposed to these risk-factors [20].…”

“…Defective DNA repair can influence and modulate different genetic and epigenetic signalling pathways which effect transcriptional activation, DNA methylation, histone modifications, as well as the altered expression of noncoding RNAs (miRNAs, PIWI-RNAs and LncRNAs etc. ), which play critical roles in the genesis of different cancers including HNCs [14][15][16] [18].…”