Overexpression of Mcl-1L Splice Variant Is Associated with Poor Prognosis and Chemoresistance in Oral Cancers

BACKGROUND Altered expression of Mcl-1, an anti-apoptotic member of the Bcl-2 family, has been linked to the progression and outcome of a variety of malignancies. We have previously reported the overexpression of Mcl-1 protein in human oral cancers. The present study aimed to evaluate the clinicopathological significance of the expression of three known Mcl-1 isoforms in oral tumors and the effect of targeting Mcl-1L isoform on chemosensitivity of oral cancer cells. METHODS The expression of Mcl-1 isoforms- Mcl-1L, Mcl-1S & Mcl-1ES was analyzed in 130 paired oral tumors and 9 oral cell lines using quantitative real-time PCR & protein by western blotting. The Mcl-1 mRNA levels were correlated with clinicopathological parameters and outcome of oral cancer patients. The effect of Mcl-1L shRNA or Obatoclax (a small molecule Mcl-1 inhibitor), in combination with Cisplatin on chemosensitivity of oral cancer cells was also assessed. RESULTS Anti-apoptotic Mcl-1L was predominantly expressed, over low or undetectable pro-apoptotic Mcl-1S and Mcl-1ES isoforms. The Mcl-1L transcripts were significantly overexpressed in all cancer cell lines and in 64% oral tumors versus adjacent normals (P<0.02). In oral cancer patients, high Mcl-1L expression was significantly associated with node positivity (P = 0.021), advanced tumor size (P = 0.013) and poor overall survival (P = 0.002). Multivariate analysis indicated Mcl-1L to be an independent prognostic factor for oral cancers (P = 0.037). Mcl-1L shRNA knockdown or its inhibition by Obatoclax in combination with Cisplatin synergistically reduced viability and growth of oral cancer cells than either treatment alone. CONCLUSION Our studies suggest that overexpression of Mcl-1L is associated with poor prognosis and chemoresistance in oral cancers. Mcl-1L is an independent prognostic factor and a potential therapeutic target in oral cancers.