Human oral cancers have altered expression of Bcl-2 family members and increased expression of the anti-apoptotic splice variant of Mcl-l

S. Mallick, R. Patil, R. Gyanchandani, S. Pawar, V. Palve, S. Kannan, K. A. Pathak, M. Choudhary, T. R. Teni

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Expression of Bcl-2 family proteins in tumours can modulate apoptosis, influencing tumour behaviour and treatment. To investigate their role in oral tumourigenesis, nine Bcl-2 family transcripts were examined in three oral cell lines and 25 oral tumours, using ribonuclease protection assay. Since Mcl-1 mRNA was elevated in these samples, Mcl-1 splice variants were assessed by RT-PCR and Mcl-1 protein was studied in normal, premalignant and malignant oral tissues and cell lines, by immunohistochemistry and/or immunoblotting. The cell lines exhibited significantly higher levels of 7/9 Bcl-2 family transcripts as compared to those in normal tongue, and significantly higher (p = 0.030, p = 0.004) anti-apoptotic versus pro-apoptotic transcripts. Elevated Mcl-1 mRJNA was observed in 11/25 (44%) tumours as compared to normal tissues with a fiveto ten-fold higher expression of full-length anti-apoptotic Mcl-1 transcript versus the pro-apoptotic short isoform. Strong cytoplasmic Mcl-1 immunoreactivity was detected predominantly in differentiated epithelia in 27/33 (82%) oral tumours, 18/20 (90%) leukoplakia, 25/30 (83%) submucous fibrosis and 3/3 oral cell lines, with weak staining in 8/15 (53%) normal mucosa samples. Mcl-1 positivity in malignant and premalignant tissues was comparable but significantly higher (p < 0.01) than that in normal mucosa. The expression of bcl-2 family genes, including Mcl-1 in tumours, did not correlate significantly with clinicopathological parameters. This is the first report delineating the in vivo expression patterns of Mcl-1 protein and Mcl-1 transcripts in oral cancers and premalignant lesions. The observed imbalance between expression of anti-apoptotic and pro-apoptotic Bcl-2 family genes may promote survival in the oral cell lines. Since the majority of oral tumours associated with tobacco-chewing evolve from premalignant lesions, the sustained expression of full-length anti-apoptotic Mcl-1 protein in these tissues suggests an important role for Mcl-1, early in oral cancer pathogenesis in protecting cells from apoptosis via neutralization of pro-apoptotic members and could be a potential therapeutic target for oral cancers.

Original languageEnglish (US)
Pages (from-to)398-407
Number of pages10
JournalJournal of Pathology
Volume217
Issue number3
DOIs
StatePublished - Feb 2009

Keywords

  • Apoptosis
  • Bcl-2 family members
  • Mcl-1
  • Oral cancer
  • Oral cavity
  • Oral cell lines
  • Oral lesions
  • Ribonuclease protection assay

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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