Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumorigenesis.
Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumorigenesis.
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DOI：
10.1038/onc.2014.385
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发表时间：
2015-08-27
期刊：
影响因子：
8
通讯作者：
Dhawan P
中科院分区：
文献类型：
--
作者：
Bhat AA;Pope JL;Smith JJ;Ahmad R;Chen X;Washington MK;Beauchamp RD;Singh AB;Dhawan P
在正常结肠中，claudin-7 是高表达的claudin 蛋白之一，其在小鼠体内的敲低会导致上皮细胞稳态改变和新生儿死亡。值得注意的是，上皮稳态的失调会增强致癌转化和生长。然而，claudin-7 在结肠肿瘤发生调节中的作用仍知之甚少。使用大型结直肠癌 (CRC) 患者数据库和结肠癌小鼠模型，我们发现癌症样本中 Claudin-7 的表达显着下调。最值得注意的是，在低分化和高度转移的SW620结肠癌细胞中强制表达claudin-7可诱导上皮特征并抑制其在软琼脂中的生长和体内肿瘤的生长。相比之下，敲低HT-29或DLD-1细胞中的claudin-7可诱导上皮间质转化(EMT)、集落形成、无胸腺小鼠中的异种移植肿瘤生长和侵袭。重要的是，通过将DEG（使用claudin-7操作的细胞进行高通量转录组分析中的差异表达基因）与人类claudin-7特征基因重叠生成的claudin-7特征基因谱可以识别出高危CRC患者。此外，Rab25（一种结肠癌抑制剂和极化细胞运输的调节剂）构成了claudin-7过表达细胞中高度上调的DEG之一。值得注意的是，Rab25表达的沉默抵消了claudin-7表达的影响，不仅增加了增殖和细胞侵袭，而且还增加了p-Src和丝裂原激活蛋白激酶（细胞外信号调节激酶1/2）的表达，这些蛋白在claudin-7过表达时受到抑制。有趣的是，CRC 细胞系表现出 Claudin-7 表达降低，也表现出启动子 DNA 高甲基化，这是一种与转录沉默相关的修饰。总而言之，我们的数据证明了claudin-7作为结肠癌抑制剂的先前未描述的作用，并表明claudin-7的缺失以依赖于Rab25的方式增强EMT以促进结肠癌。
In normal colon, claudin-7 is one of the highly expressed claudin proteins and its knockdown in mice results in altered epithelial cell homeostasis and neonatal death. Notably, dysregulation of the epithelial homeostasis potentiates oncogenic transformation and growth. However, the role of claudin-7 in the regulation of colon tumorigenesis remains poorly understood. Using a large colorectal cancer (CRC) patient database and mouse models of colon cancer, we found claudin-7 expression to be significantly downregulated in cancer samples. Most notably, forced claudin-7 expression in poorly differentiated and highly metastatic SW620 colon cancer cells induced epithelial characteristics and inhibited their growth in soft agar and tumor growth in vivo. By contrast, knockdown of claudin-7 in HT-29 or DLD-1 cells induced epithelial-to-mesenchymal transition (EMT), colony formation, xenograft-tumor growth in athymic mice and invasion. Importantly, a claudin-7 signature gene profile generated by overlapping the DEGs (differentially expressed genes in a high-throughput transcriptome analysis using claudin-7-manipulated cells) with human claudin-7 signature genes identified high-risk CRC patients. Furthermore, Rab25, a colon cancer suppressor and regulator of the polarized cell trafficking constituted one of the highly upregulated DEGs in claudin-7 overexpressing cells. Notably, silencing of Rab25 expression counteracted the effects of claudin-7 expression and not only increased proliferation and cell invasion but also increased the expression of p-Src and mitogen-activated protein kinase–extracellular signal–regulated kinase 1/2 that were suppressed upon claudin-7 overexpression. Of interest, CRC cell lines, which exhibited decreased claudin-7 expression, also exhibited promoter DNA hypermethylation, a modification associated with transcriptional silencing. Taken together, our data demonstrate a previously undescribed role of claudin-7 as a colon cancer suppressor and suggest that loss of claudin-7 potentiates EMT to promote colon cancer, in a manner dependent on Rab25.