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Expression of Bcl-2 family proteins in tumours can modulate apoptosis, influencing tumour behaviour and treatment. To investigate their role in oral tumourigenesis, nineBcl-2family transcripts were examined in three oral cell lines and 25 oral tumours, using ribonuclease protection assay. SinceMcl-1mRNA was elevated in these samples,Mcl-1splice 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 7/9Bcl-2family transcripts as compared to those in normal tongue, and significantly higher (p= 0.030,p= 0.004) anti-apoptotic versus pro-apoptotic transcripts. ElevatedMcl-1mRNA was observed in 11/25 (44%) tumours as compared to normal tissues with a five- to ten-fold higher expression of full-length anti-apoptoticMcl-1transcript 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 ofbcl-2family genes, including Mcl-1 in tumours, did not correlate significantly with clinicopathological parameters. This is the first report delineating thein vivoexpression patterns of Mcl-1 protein andMcl-1transcripts in oral cancers and premalignant lesions. The observed imbalance between expression of anti-apoptotic and pro-apoptoticBcl-2family 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. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.