随着肿瘤产生发展错误就会频频出现，而且每次一旦细胞分裂产生产生两个细胞，这些错误就会发生改变而且不断变得多样化；但在某些时候早期事件引发的癌症通常会被直接发现，就拿肠道癌来说，科学界在几乎30年来都认为是一种特殊的基因引发肠癌的发生。早在20世纪80年来来自英国癌症研究中心的科学家就发现了一种名为APC的腺瘤样息肉基因的错误拷贝，而且研究者在10例肠癌患者中就发现有8名患者携带APC的错误拷贝。
当APC错误在肠道内皮细胞中发生时就会引发接二连三的生长信号，从而促进细胞失控地，进而引发肠癌，而很多年来，研究者在多种疾病的研究中都肯定了APC错误的重要性。在正常的肠道细胞中，APC其中一项关键工作就是维持细胞中β连环蛋白的水平处于约束状态，一旦APC发生损伤，β连环蛋白水平就会增加，使得细胞暴露于多种生长信号中，从而细胞就会一直生长，这些信号被称为Wnt信号通路，其在肠癌的发病过程中扮演着重要角色。
肠道可以分为两部分—小肠组织和大肠组织，此前对小鼠进行研究发现，关闭肠道细胞中APC的功能就会引发小肠和大肠发生肿瘤。于是来自国外的研究人员就表示，为了观察是否APC的缺失会通过β连环蛋白来诱发肠癌，我们检测了是否工程化地含有错误的、活性版本β连环蛋白的细胞可以引发肿瘤。
研究者表示，我们在小鼠机体中测定了E-钙黏蛋白(E-cadherin)的水平，结果发现，相比小肠而言，大肠中的E-钙黏蛋白(E-cadherin)水平较高，而且E-钙黏蛋白(E-cadherin)的水平的增加的确可以帮助清理过多的β连环蛋白，从而抑制肠道中肿瘤的发生。β连环蛋白的错误在人类肠癌中并不常见，然而APC错误却在100例患者中的80例患者身上都会发生。
研究者David表示，是否改变E-钙黏蛋白的清理水平就可以帮助有效抑制肿瘤发生呢？研究者表示E-钙黏蛋白可以帮助有效抑制肠癌的发生。后期研究者们将进行更多深入的研究解析引发肠癌的分子机理，他们期望早日开发出治疗肠癌的新型个体化疗法。
doi:10.1038/nature11252
PMC:
PMID:
Comprehensive molecular characterization of human colon and rectal cancer
The Cancer Genome Atlas Network
To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale ysis of 276 samples, ysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic miatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, AD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative yses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.
1、Genes &Dev: "Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration."
2、The EMBO Journal: "E-cadherin can limit the transforming properties of activating beta-catenin mutations."
