Cancer Research Center of Lyon, UMR INSERM 1052-CNRS 5286, Centre Léon Bérard, Lyon, France.
Department of Medicine, Centre Léon Bérard, Lyon, France.
J Natl Cancer Inst. 2018 Mar 1;110(3):250-7. doi: 10.1093/jnci/djx186.
We have previously shown that gene expression profiles of oral leukoplakia (OL) may improve the prediction of oral cancer (OC) risk. To identify new targets for prevention, we performed a systematic survey of transcripts associated with an increased risk of oral cancer and overexpressed in OC vs normal mucosa (NM).
We used gene expression profiles of 86 patients with OL and available outcomes from a chemoprevention trial of OC and NM. MET expression was evaluated using immunohistochemistry in 120 OL patients, and its association with OC development was tested in multivariable analysis. Sensitivity to pharmacological Met inhibition was tested invitro in premalignant and OC cell lines (n = 33) and invivo using the 4-NQO model of oral chemoprevention (n = 20 mice per group). All statistical tests were two-sided.
The overlap of 693 transcripts associated with an increased risk of OC with 163 transcripts overexpressed in OC compared with NM led to the identification of 23 overlapping transcripts, including MET. MET overexpression in OL was associated with a hazard ratio of 3.84 (95% confidence interval = 1.59 to 9.27, P = .003) of developing OC. Met activation was found in OC and preneoplastic cell lines. Crizotinib activity in preneoplastic and OC cell lines was comparable. ARQ 197 was more active in preneoplastic compared with OC cell lines. In the 4-NQO model, squamous cell carcinoma, dysplasia, and hyperkeratosis were observed in 75.0%, 15.0%, and 10.0% in the control group, and in 25.0%, 70.0%, and 5.0% in the crizotinib group (P < .001).
Together, these data suggest that MET activation may represent an early driver in oral premalignancy and a target for chemoprevention of OC.
我们之前已经表明，口腔白斑（OL）的基因表达谱可能会提高口腔癌（OC）风险的预测能力。为了确定新的预防靶点，我们对与 OC 风险增加相关且在 OC 与正常黏膜（NM）相比过表达的转录本进行了系统调查。
我们使用了 86 例 OL 患者的基因表达谱和 OC 及 NM 化学预防试验的可用结果。在 120 例 OL 患者中使用免疫组织化学法评估 MET 表达，并在多变量分析中检验其与 OC 发展的关系。在体外，在癌前病变和 OC 细胞系（n=33）中测试了对药理学 Met 抑制的敏感性，在 4-NQO 口腔化学预防模型中（每组 20 只小鼠）进行了体内测试。所有统计检验均为双侧检验。
与 OC 风险增加相关的 693 个转录本与 OC 中过表达的 163 个转录本的重叠，导致了 23 个重叠转录本的鉴定，其中包括 MET。OL 中 MET 的过度表达与 OC 发展的风险比为 3.84（95%置信区间=1.59 至 9.27，P=0.003）。在 OC 和癌前病变细胞系中发现了 Met 激活。在癌前病变和 OC 细胞系中，crizotinib 的活性相当。与 OC 细胞系相比，ARQ 197 在癌前病变细胞系中更具活性。在 4-NQO 模型中，对照组的鳞状细胞癌、发育不良和角化过度分别为 75.0%、15.0%和 10.0%，而 crizotinib 组分别为 25.0%、70.0%和 5.0%（P<0.001）。
综上所述，这些数据表明，MET 激活可能代表口腔癌前病变的早期驱动因素，也是 OC 化学预防的靶点。
