肺癌相关变异基因的作用机制引导新的治疗手段
2012-08-05 15:54:05   来源： 丁香园   作者：  评论：0 点击：

Vanderbilt-Ingram Cancer Center researchers have identified how one of the genes most commonly mutated in lung cancer may promote such tumors.
Vanderbilt-Ingram 肿瘤中心的研究人员已经明确了一个与肺癌相关的变异基因是怎样促发肺癌的。

The investigators found that the protein encoded by this gene, called EPHA3, normally inhibits tumor formation, and that loss or mutation of the gene - as often happens in lung cancer - diminishes this tumor-suppressive effect, potentially sparking the formation of lung cancer. The findings, published July 24 in the Journal of the National Cancer Institute, could offer direction for personalizing cancer treatments and development of new therapies.
研究人员发现的这一基因所编码的蛋白，被命名为 EPHA3，该蛋白正常情况下抑制肿瘤形成，而这一基因的缺失或变异---这种情况常常发生于肺癌患者---使得该基因的肿瘤抑制效应降低，从而潜在触发 肺癌形成。这一结果，7月24日发表在《国家肿瘤研究所》杂志上，它为肿瘤个体化治疗和发展新的治疗手段提供了方向。

The ephrin family of receptors (EPH receptors) comprises a large group of cell surface proteins that regulate cell-to-cell communication in normal development and disease. EPH receptor mutations have been linked to several different cancer types.
EPH受体家族有许多细胞表面蛋白家族成员，在正常发育以及患病时，这些细胞表面蛋白调控着细胞间的信息交换。已经有人认为，EPH受体变异与几种肿瘤相关。

Jin Chen, M.D., Ph.D., professor of Medicine, Cancer Biology and Cell & Developmental Biology, studies the cancer-associated roles of these receptors. While her lab has focused primarily on EPHA2 (and its role in promoting breast cancer and tumor blood vessel formation), she decided to look at a different ephrin receptor based on the findings of large genomic screens of lung tumors.
Jin Chen，是一位医学硕士，肿瘤生物学和细胞学博士，也是发育生物学教授，她研究EPH受体与肿瘤相关的作用。她的实验室一开始关注的是EPHA2基因 （该基因促进乳腺癌和肿瘤血管的形成），然而，基于大规模肺部肿瘤患者基因筛查的结果，她决定研究另一个EPH受体。

"A 2008 genome-wide study published in Nature identified 26 genes as potential drivers of lung cancer," Chen said. "One of them was EPHA3."
《自然》杂志上发表了一篇2008年基因组的研究，该项研究确认了能潜在触发肺癌的26个基因。Chen说：“其中之一是EPHA3”

That study and others suggested that mutations in EPHA3 were present in 5 percent to 10 percent of lung adenocarcinomas. However, the studies did not reveal how these mutations might promote tumor formation or progression.
这一研究以及其他的一些研究均认为：5%到10%的肺鳞状细胞癌患者存在EPHA3变异，但是这些研究都没有解释变异基因是如何促进肿瘤的形成和发展的

Chen wanted to investigate further whether mutations in EPHA3 were actually "drivers" of lung cancer or just neutral "passenger" mutations and how the mutations might promote tumor growth.
Chen 希望通过进一步研究，明确EPHA3基因变异是否是肺癌的触发因素，或者仅仅是一种无关紧要的变异，以及这种变异是如何促进肿瘤生长的。

The researchers generated and analyzed 15 different mutations in the receptor. They found that at least two functioned as "dominant negative" inhibitors of the EPHA3 protein - that is, having a mutation in just one allele (or "copy" - humans have two copies of each gene) was enough to inhibit the function of EPHA3.
研究人员构建和分析了该受体的15种不同变异型。他们发现至少有两种变异型是EPHA3蛋白的“显性负向”抑制子---这就是说，只要有一个等位基因变异，就会抑制 EPHA3基因的功能。

Chen and colleagues determined that normal or "wild type" EPHA3 inhibits a downstream signaling pathway (the Akt pathway) that promotes cell survival - so, normally, activation of EPHA3 acts as a "brake" on cell growth and survival and induces programmed cell death (apoptosis). When one EPHA3 allele is lost (due to a mutation), the receptor cannot be activated and the Akt pathway remains active, which promotes cell growth and survival.
Chen和同事们推断：正常或野生型的EPHA3抑制下游信号传导通路（Akt信号传导通路）——该通路促进细胞存 活。因此，正常情况下，EPHA3的作用是抑制细胞生长与存活，从而引起细胞凋亡。当EPHA3失去一个等位基因时（由于变异），该受体失活而使得Akt 信号传导通路持续激活，从而促进细胞的生长与存活

To determine the impact of EPHA3 mutations on human lung cancer cases, biostatisticians Yu Shyr, Ph.D., and Fei Ye, Ph.D., helped Chen's group identify a mutational signature from existing patient data that strongly correlated with poor patient survival. The team also found that both gene and protein levels of EPHA3 were decreased in patient lung tumors.
为了确定EPHA3 变异对人肺癌的影响，生物统计学家Yu Shyr博士和Fei Ye博士，帮助Chen的团队从还活着但生存率很低的病人数据中确定了变异特征。该团队还发现在肺癌患者中EPHA3的基因和蛋白水平均降低。

While previous studies had linked EPHA3 mutations to lung cancer, the current study is the first to "connect the dots."
尽管以前的研究已经认为EPHA3变异与肺癌相关，但是目前的研究却是第一次将两者直接联系起来。

"The EPH family is such a big family that nobody had really connected the data from bench top - from the cell and biochemical studies - to human data," Chen said.
“EPH 家族如此庞大，从来没有人真正的将它的细胞和生物化学的数据与人的数据相联系。”Chen 说

Together, the findings suggest that mutations in EPHA3 may be important drivers of a significant fraction of lung cancers. And the research team's identification of the biochemical and cellular consequences of EPHA3 mutations suggests that therapies that target a downstream pathway (such as Akt) might be beneficial for tumors with mutant EPHA3.
与此同时，这些研究结果显示，EPHA3 变异是许多类型肺癌的重要触发因素。研究团队明确了EPHA3基因变异所引起的生物化学效应和细胞学效应。其研究成果提示：以下游信号转导通路（例如Akt）为治疗靶点，可能对EPHA3变异的肿瘤患者有利。

Shyr is a professor of Biostatistics, Cancer Biology and Preventive Medicine and is Director of the Center for Quantitative Sciences; Ye is an assistant professor of Biostatistics.
Shyr 是生物统计学，肿瘤生物学和预防医学的教授，也是数量化科学中心的主任；Ye是生物统计学的助教。