Characterization of key transcription factors as molecular signatures of HPV-positive and HPV-negative oral cancers.
Prior studies established constitutively active AP-1, NF-κB, and STAT3 signaling in oral cancer. Differential expression/activation of specific members of these transcription factors has been documented in HPV-positive oral lesions that respond better to therapy. We performed a comprehensive analysis of differentially expressed, transcriptionally active members of these pivotal signaling mediators to develop specific signatures of HPV-positive and HPV-negative oral lesions by immunohistochemical method that is applicable in low-resource settings. We examined a total of 31 prospective and 30 formalin-fixed, paraffin-embedded tissues from treatment-naïve, histopathologically and clinically confirmed cases diagnosed as oral or oropharyngeal squamous cell carcinoma (OSCC/OPSCC). Following determination of their HPV status by GP5 + /GP6 +  PCR, the sequential sections of the tissues were evaluated for expression of JunB, JunD, c-Fos, p50, p65, STAT3, and pSTAT3(Y705), along with two key regulatory proteins pEGFR and p16 by IHC. Independent analysis of JunB and p65 showed direct correlation with HPV positivity, whereas STAT3 and pSTAT3 were inversely correlated. A combined analysis of transcription factors revealed a more restrictive combination, characterized by the presence of AP-1 and NF-κB lacking involvement of STAT3 that strongly correlated with HPV-positive tumors. Presence of STAT3/pSTAT3 with NF-κB irrespective of the presence or absence of AP-1 members was present in HPV-negative lesions. Expression of pSTAT3 strongly correlated with all the AP-1/NF-κB members (except JunD), its upstream activator pEGFRY1092, and HPV infection-related negative regulator p16. Overall, we show a simple combination of AP-1, NF-κB, and STAT3 members' expression that may serve as molecular signature of HPV-positive lesions or more broadly the tumors that show better prognosis.
Division of Molecular Oncology, Institute of Cytology & Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.|School of Biotechnology, Banaras Hindu University, Varanasi, Uttar Pradesh, India.|Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.
Gaurav
G
Verma
Division of Molecular Oncology, Institute of Cytology & Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.|School of Biotechnology, Banaras Hindu University, Varanasi, Uttar Pradesh, India.|Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.
Kanchan
K
Vishnoi
Division of Molecular Oncology, Institute of Cytology & Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.
Abhishek
A
Tyagi
Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.
Mohit
M
Jadli
Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.
Tejveer
T
Singh
Subharti Dental College, Meerut, Uttar Pradesh, India.
Ankit
A
Goel
Lady Harding Medical College, New Delhi, India.
Ankita
A
Sharma
Lady Harding Medical College, New Delhi, India.
Kiran
K
Agarwal
Division of Molecular Oncology, Institute of Cytology & Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.
Subhash Chandra
SC
Prasad
Department of Oncosurgery, Dr. Bheem Rao Ambedkar Institute-Rotary Cancer Hospital, All India Institute Of Medical Sciences, New Delhi, India.
Durgatosh
D
Pandey
Division of Molecular Oncology, Institute of Cytology & Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.
Shashi
S
Sharma
Division of Molecular Oncology, Institute of Cytology & Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.
Ravi
R
Mehrotra
School of Biotechnology, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
Sukh Mahendra
SM
Singh
Division of Molecular Oncology, Institute of Cytology & Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.|Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.
Alok Chandra
AC
Bharti
D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism; D009959:Oropharyngeal Neoplasms / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000378:metabolism*; D010766:Phosphorylation; D011446:Prospective Studies; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
C581727:JunB protein, human; D016328:NF-kappa B; C498143:RELA protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D014157:Transcription Factors
HPV-negative; HPV-positive; Head and neck cancer; immunohistochemistry; oral squamous cell carcinoma; oropharyngeal squamous cell carcinoma; transcription factors