Palve Vinayak, Mallick Sanchita, Ghaisas Gauri, Kannan Sadhana, Teni Tanuja
Teni Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai-410210, India.
Epidemiology and Clinical Trial Unit (ECTU), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai-410210, India.
PLoS One. 2014 Nov 19;9(11):e111927. doi: 10.1371/journal.pone.0111927. eCollection 2014.
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.
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.
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.
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.
Bcl-2家族的抗凋亡成员Mcl-1的表达改变与多种恶性肿瘤的进展和预后相关。我们之前报道过Mcl-1蛋白在人类口腔癌中过表达。本研究旨在评估三种已知的Mcl-1亚型在口腔肿瘤中的表达的临床病理意义，以及靶向Mcl-1L亚型对口腔癌细胞化疗敏感性的影响。
使用定量实时PCR和蛋白质免疫印迹法分析了130对口腔肿瘤组织和9种口腔细胞系中Mcl-1亚型-Mcl-1L、Mcl-1S和Mcl-1ES的表达。Mcl-1 mRNA水平与口腔癌患者的临床病理参数和预后相关。还评估了Mcl-1L shRNA或Obatoclax（一种小分子Mcl-1抑制剂）与顺铂联合使用对口腔癌细胞化疗敏感性的影响。
抗凋亡的Mcl-1L占主导表达，而促凋亡的Mcl-1S和Mcl-1ES亚型表达较低或无法检测到。与相邻正常组织相比，Mcl-1L转录本在所有癌细胞系和64%的口腔肿瘤中均显著过表达（P<0.02）。在口腔癌患者中，高Mcl-1L表达与淋巴结阳性（P = 0.021）、肿瘤体积较大（P = 0.013）和总生存期较差（P = 0.002）显著相关。多因素分析表明Mcl-1L是口腔癌的独立预后因素（P = 0.037）。与单独使用任何一种治疗相比，Mcl-1L shRNA敲低或Obatoclax对其的抑制作用与顺铂联合使用可协同降低口腔癌细胞的活力和生长。
我们的研究表明，Mcl-1L过表达与口腔癌的不良预后和化疗耐药相关。Mcl-1L是口腔癌的独立预后因素和潜在治疗靶点。
