title: The elevated activation of NFκB and AP-1 is correlated with differential regulation of Bcl-2 and associated with oral squamous cell carcinoma progression and resistance.
abstract: OBJECTIVE
  Oral cancer is the sixth most common cancer in the world. Failure of chemoradiation therapy is a major concern for treating oral cancer patients. The objective of this study is to determine the B cell lymphoma-2 (bcl-2) expression and its regulation by nuclear factor κB (NFκB) and activator protein 1 (AP-1) in oral cancer progression and chemoradiation resistance.
  
  
  METHODS
  In the present study, a total of 123 (n = 123) human samples were included. Briefly, 64 fresh samples were from adjacent normal (AN), primary oral tumors without treatment (PT), and tumors with resistance to chemoradiation therapy with local recurrence (RCRT). Fifty-nine samples were human tongue cancers and normal samples (TMA). Messenger RNA (mRNA) expression levels of bcl-2 and protein levels of bcl-2, NFκB, AP-1, and inactive GSK3α/β were measured by semiquantitative RT-PCR, immunohistochemistry, Western blot, and ChIP analysis.
  
  
  RESULTS
  Increased bcl-2 expression was observed in PT compared to AN. The RCRT tumors showed maximum expression of bcl-2 mRNA and protein over the PT and AN groups. Bcl-2 protein and mRNA expression were positively correlated with NFκB and AP-1 expression. AP-1 expression was strongly correlated with bcl-2 in the RCRT group of tumors. Further, inactive GSK3α/β showed a positive trend with bcl-2 expression in oral tongue cancer specimens.
  
  
  CONCLUSIONS
  Collectively, our results demonstrated cumulative effect of AP-1 and NFĸB for bcl-2 gene regulation in overall PT progression and chemoradiation resistance. The study provides evidence of increased bcl-2 mRNA/protein fueled by NFĸB in PT and AP-1 in RCRT. These regulations of bcl-2 by NFκB and AP-1 are important in OSCC progression and chemoradiation resistance.
authors.affiliation: Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe Ranchi, Jharkhand, 835205, India.
authors.forename: Manzar
authors.initials: M
authors.lastname: Alam
authors.affiliation: Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe Ranchi, Jharkhand, 835205, India.
authors.forename: Tanushree
authors.initials: T
authors.lastname: Kashyap
authors.affiliation: Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe Ranchi, Jharkhand, 835205, India.
authors.forename: Kamdeo K
authors.initials: KK
authors.lastname: Pramanik
authors.affiliation: Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe Ranchi, Jharkhand, 835205, India.
authors.forename: Abhay K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamil Nadu, 608 002, India.
authors.forename: Siddavaram
authors.initials: S
authors.lastname: Nagini
authors.affiliation: Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe Ranchi, Jharkhand, 835205, India. rajakishore.mishra@cuj.ac.in.
authors.forename: Rajakishore
authors.initials: R
authors.lastname: Mishra
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D059248:Chemoradiotherapy; D047369:Chromatin Immunoprecipitation; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D016328:NF-kappa B / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014062:Tongue Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C000595707:BCL2 protein, human; D014408:Biomarkers, Tumor; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D018808:Transcription Factor AP-1
keywords: AP-1; Bcl-2; Drug resistance; GSK3α; GSK3β; NFκB; OSCC; Oral cancer; Oral squamous cell carcinoma; Oral tumor resistance to chemoradiation therapy