Human oral cancers have altered expression of Bcl‐2 family members and increased expression of the anti‐apoptotic splice variant of Mcl‐1

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 mRNA was observed in 11/25 (44%) tumours as compared to normal tissues with a five- to 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.

Gene expression profiling of archival tongue squamous cell carcinomas provides sub-classification based on DNA repair genes

“…To confirm that SCCHN tumours express the BCL2A1 protein, immunohistochemistry is needed, but could not be performed here due to lack of reliable antibodies. Previous studies have described the importance of other BCL2 family members in SCCHN (41,47) and our data implicate BCL2A1, which has an antiapoptotic function, as an important factor in tongue tumours.…”

Involvement of Mcl1 in diallyl disulfide-induced G2/M cell cycle arrest in HL-60 cells

“…Another study revealed that Mcl1 played an important role in apoptosis (25)(26)(27)(28). The findings of Yoon et al provided insight into a new regulatory circuit that controls cell death and survival by the coordinated actions of Mcl1 (29).…”

Myeloid cell leukemia-1 is a molecular indicator for malignant transformation of oral lichen planus

“…Mcl-1 has been reported to be a critical survival-promoting molecule in hematopoietic cells, and its overexpression is known to be associated with a variety of human hematopoietic and lymphoid cancers (22). The anti-apoptotic splice variant of Mcl-1 was also augmented in human oral cancer (23), and our previous study demonstrated that the overexpression of Mcl-1 may be strongly correlated with oral cancer development (24).…”