Vanderbilt-Ingram癌症中心研究人员已确定了肺癌中一个最常见的突变基因如何诱发肿瘤的发生。
研究人员发现肺癌的致病基因 有望研发出新疗法
研究者发现，一个由EPHA3基因编码的蛋白质通常抑制肿瘤的形成，而该基因的缺失经常出现在肺癌中，降低了肿瘤形成的抑制作用，从而引发肺癌的生成。相关研究发表在7月24日的《国家肿瘤研究所》期刊上，它有望为新疗法的形成提供线索，并将有助于癌症个体化治疗。
受体酪氨酸激酶家族（EPH受体）由大量的细胞表面的蛋白分子构成，它们在正常发育和疾病的细胞中提供细胞间的通讯。EPH受体的突变体与几种肿瘤类型有关联。
医学博士Jin Chen是医学、肿瘤生物学和细胞发育生物学方面的教授，她研究这些受体与癌症相关的作用。当实验室把研究重心放在EPHA2分子时（该分子的作用是促进乳腺癌和肿瘤血管形成），依据对肺癌进行的大量的基因组绘制，她决定研究一个不同的EPH受体。
Chen称：“2008年全基因组研究发表在《自然》期刊上，识别出诱发肺癌的26个潜在基因，其中一个便是EPHA3。”
这项研究连同其它的研究表明，EPHA3突变体目前存在于5％至10％的肺腺癌患者。然而，这些研究并没有揭示这些突变如何能促进肿瘤的形成或恶化。
Chen希望进一步研究，EPHA3突变是否真正促发肺癌或者仅是中性的递呈突变，以及突变如何能促进肿瘤的生长。
收集和分析受体中的15个不同的突变信息，研究人员发现，至少有2个对EPHA3蛋白发挥“负显性”抑制剂的作用，也就是说，等位基因中仅1个突变（人类中每一个基因有两个副本）能足以抑制EPHA3的功能。
Chen和同事确定，正常型或野生型基因EPHA3抑制了促使细胞存活的下游信号转导通路（Akt途径），因此，通常而言激活EPHA3能阻止细胞生成和存活，并诱使细胞程序性死亡（凋亡）。当一个EPHA3等位基因丢失（突变引起）时，受体不能被激活，Akt的途径仍然活跃，从而促进细胞生长和存活。
为了确定EPHA3突变对人体肺癌的影响，生物统计学家Yu Shyr博士和Fei Ye博士帮助Chen研究小组从现有病人数据（强关联于低生存率）中识别出突变标签。该小组还发现，肺癌患者的EPHA3在基因和蛋白水平上都降低。
虽然之前的研究将EPHA3突变关联到肺癌，但是，目前的研究是首次将EPHA3突变关联到具体点。
Chen称：“EPH家族属于一个大家族，没有人从台式机上真正获取它们的数据，如：细胞和生化方面的研究以及人体数据。”
总之研究表明，EPHA3突变在肺癌的重要部分发挥重要的驱动作用。研究小组识别出EPHA3突变体引起的生化和细胞方面的结果，这表明靶向下游通路（如Akt）的治疗或许有益于EPHA3突变的肿瘤患者。
Effects of Cancer-Associated EPHA3 Mutations on Lung Cancer
G. Zhuang, W. Song, K. Amato, Y. Hwang, K. Lee, M. Boothby, F. Ye, Y. Guo, Y. Shyr, L. Lin, D. P. Carbone, D. M. Brantley-Sieders, J. Chen.
Background Cancer genome sequencing efforts recently identified EPHA3, which encodes the EPHA3 receptor tyrosine kinase, as one of the most frequently mutated genes in lung cancer. Although receptor tyrosine kinase mutations often drive oncogenic conversion and tumorigenesis, the oncogenic potential of the EPHA3 mutations in lung cancer remains unknown.
Methods We used immunoprecipitation, western blotting, and kinase assays to determine the activity and signaling of mutant EPHA3 receptors. A mutation-associated gene signature was generated from one large dataset, mapped to another training dataset with survival information, and tested in a third independent dataset. EPHA3 expression levels were determined by quantitative reverse transcription-polymerase chain reaction in paired normal-tumor clinical specimens and by immunohistochemistry in human lung cancer tissue microarrays. We assessed tumor growth in vivo using A549 and H1299 human lung carcinoma cell xenografts in mice (n = 7–8 mice per group). Tumor cell proliferation was measured by bromodeoxyuridine incorporation and apoptosis by multiple assays. All P values are from two-sided tests.
Results At least two cancer-associated EPHA3 somatic mutations functioned as dominant inhibitors of the normal (wild type) EPHA3 protein. An EPHA3 mutation–associated gene signature that was associated with poor patient survival was identified. Moreover, EPHA3 gene copy numbers and/or expression levels were decreased in tumors from large cohorts of patients with lung cancer (eg, the gene was deleted in 157 of 371 [42%] primary lung adenocarcinomas). Reexpression of wild-type EPHA3 in human lung cancer lines increased apoptosis by suppression of AKT activation in vitro and inhibited the growth of tumor xenografts (eg, for H1299 cells, mean tumor volume with wild-type EPHA3 = 437.4mm3 vs control = 774.7mm3, P < .001). Tumor-suppressive effects of wild-type EPHA3 could be overridden in trans by dominant negative EPHA3 somatic mutations discovered in patients with lung cancer.
Conclusion Cancer-associated EPHA3 mutations attenuate the tumor-suppressive effects of normal EPHA3 in lung cancer.
文献链接：Effects of Cancer-Associated EPHA3 Mutations on Lung Cancer
