Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Oncogene. 2011 Jul 21;30(29):3234-47. doi: 10.1038/onc.2011.43. Epub 2011 Mar 7.
Claudin-2 is a unique member of the claudin family of transmembrane proteins, as its expression is restricted to the leaky epithelium in vivo and correlates with epithelial leakiness in vitro. However, recent evidence suggests potential functions of claudin-2 that are relevant to neoplastic transformation and growth. In accordance, here we report, on the basis of analysis of mRNA and protein expression using a total of 309 patient samples that claudin-2 expression is significantly increased in colorectal cancer and correlates with cancer progression. We also report similar increases in claudin-2 expression in inflammatory bowel disease-associated colorectal cancer. Most importantly, we demonstrate that the increased claudin-2 expression in colorectal cancer is causally associated with tumor growth as forced claudin-2 expression in colon cancer cells that do not express claudin-2 resulted in significant increases in cell proliferation, anchorage-independent growth and tumor growth in vivo. We further show that the colonic microenvironment regulates claudin-2 expression in a manner dependent on signaling through the EGF receptor (EGFR), a key regulator of colon tumorigenesis. In addition, claudin-2 expression is specifically decreased in the colon of waved-2 mice, naturally deficient in EGFR activation. Furthermore, genetic silencing of claudin-2 expression in Caco-2, a colon cancer cell line, prevents the EGF-induced increase in cell proliferation. Taken together, these results uncover a novel role for claudin-2 in promoting colon cancer, potentially via EGFR transactivation.
紧密连接蛋白-2 是紧密连接蛋白家族中独特的跨膜蛋白成员，因为其表达局限于体内的渗漏上皮组织，并且与体外上皮组织的渗漏性相关。然而，最近的证据表明紧密连接蛋白-2 具有与肿瘤转化和生长相关的潜在功能。因此，我们基于总共 309 个患者样本的 mRNA 和蛋白表达分析，报道了紧密连接蛋白-2 在结直肠癌中表达显著增加，并与癌症进展相关。我们还报道了在炎症性肠病相关的结直肠癌中紧密连接蛋白-2 表达的类似增加。最重要的是，我们证明了结直肠癌中紧密连接蛋白-2 的表达增加与肿瘤生长有关，因为在不表达紧密连接蛋白-2 的结肠癌细胞中强制表达紧密连接蛋白-2 导致细胞增殖、无锚定生长和体内肿瘤生长显著增加。我们进一步表明，结肠微环境以依赖于表皮生长因子受体（EGFR）信号的方式调节紧密连接蛋白-2 的表达，EGFR 是结肠肿瘤发生的关键调节剂。此外，在 EGFR 激活天然缺乏的 waved-2 小鼠的结肠中，紧密连接蛋白-2 的表达特异性降低。此外，在结肠癌细胞系 Caco-2 中基因沉默紧密连接蛋白-2 的表达可防止 EGF 诱导的细胞增殖增加。总之，这些结果揭示了紧密连接蛋白-2 在促进结肠癌中的新作用，可能通过 EGFR 反式激活。
