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. 2014 Nov 19;9(11):e111927.
doi: 10.1371/journal.pone.0111927. eCollection 2014.

Overexpression of Mcl-1L splice variant is associated with poor prognosis and chemoresistance in oral cancers (V体育平台登录)

Vinayak Palve  1 , Sanchita Mallick  1 , Gauri Ghaisas  1 , Sadhana Kannan  2 , Tanuja Teni  1
Affiliations

Overexpression of Mcl-1L splice variant is associated with poor prognosis and chemoresistance in oral cancers

Vinayak Palve et al. PLoS One. .

Abstract

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 VSports手机版. .

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. V体育安卓版.

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 V体育ios版. 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 VSports最新版本. Mcl-1L is an independent prognostic factor and a potential therapeutic target in oral cancers. .

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

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Figure 1
Figure 1. Expression of Mcl-1 isoforms in oral cell lines.
(a) Expression of Mcl-1L & Mcl-1S mRNA in oral cell lines; Mcl-1 ES levels were undetectable (* P≤0.03) (b) Mcl-1L protein expression in oral cell lines.
Figure 2
Figure 2. Correlation of Mcl-1L mRNA expression in oral normal versus tumor tissues.
(a) Expression of Mcl-1L mRNA in normal vs. oral tumors of different subsites (* P≤0.02); (b) Mcl-1L protein expression in adjacent normal versus tumors.
Figure 3
Figure 3. Survival analysis of oral cancer patients.
(a-c) Kaplan–Meier estimates of overall survival of oral cancer patients with low or high expression of Mcl-1 isoforms; (d) Multivariate analysis of oral cancer patients.
Figure 4
Figure 4. Down regulation of Mcl-1L expression in oral cancer cell lines.
(a & b) shRNA mediated down regulation of Mcl-1L mRNA & protein in AW8507, UPCI:SCC040 & SCCC29B oral cancer cells as compared to the control.
Figure 5
Figure 5. Estimation of Cisplatin IC50 for seven oral cancer cell lines by MTT assay (a) and the effect of Mcl-1L knockdown and/or Cisplatin on induction of cell death by PI staining (b) (* & δ P<0.05, vs. individual treatments).
Figure 6
Figure 6. Effect of combination of BH3 mimetic Obatoclax and Cisplatin on cell viability & growth.
(a) Confocal microscopic representative images of AW8507 cells post different treatments; (b) Assessment of percent cell viability of oral cancer cells post different treatments by trypan blue dye exclusion assay (* P<0.05, vs. individual treatments); (c) Analysis of proliferation of oral cancer cells after different treatments by MTT assay. (* P<0.05, vs. individual treatments).
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