Department of Cancer Biology, Vanderbilt University Medical Center, , Nashville, Tennessee, USA.
Gut. 2014 Apr;63(4):622-34. doi: 10.1136/gutjnl-2012-304241. Epub 2013 Jun 13.
Claudin-1 expression is increased and dysregulated in colorectal cancer and causally associates with the dedifferentiation of colonic epithelial cells, cancer progression and metastasis. Here, we have sought to determine the role claudin-1 plays in the regulation of intestinal epithelial homeostasis.
We have used a novel villin-claudin-1 transgenic (Cl-1Tg) mouse as model (with intestinal claudin-1 overexpression). The effect of claudin-1 expression upon colonic epithelial differentiation, lineage commitment and Notch-signalling was determined using immunohistochemical, immunoblot and real-time PCR analysis. The frequently used mouse model of dextran sodium sulfate (DSS)-colitis was used to model inflammation, injury and repair.
In Cl-1Tg mice, normal colonocyte differentiation programme was disrupted and goblet cell number and mucin-2 (muc-2) expressions were significantly downregulated while Notch- and ERK1/2-signalling were upregulated, compared with the wild type-littermates. Cl-1Tg mice were also susceptible to colonic inflammation and demonstrated impaired recovery and hyperproliferation following the DSS-colitis. Our data further show that claudin-1 regulates Notch-signalling through the regulation of matrix metalloproteinase-9 (MMP-9) and p-ERK signalling to regulate proliferation and differentiation.
Claudin-1 helps regulate intestinal epithelial homeostasis through the regulation of Notch-signalling. An upregulated claudin-1 expression induces MMP-9 and p-ERK signalling to activate Notch-signalling, which in turn inhibits the goblet cell differentiation. Decreased goblet cell number decreases muc-2 expression and thus enhances susceptibility to mucosal inflammation. Claudin-1 expression also induces colonic epithelial proliferation in a Notch-dependent manner. Our findings may help understand the role of claudin-1 in the regulation of inflammatory bowel diseases and CRC.
Claudin-1 在结直肠癌中表达增加且失调，与结肠上皮细胞的去分化、癌症进展和转移有因果关系。在这里，我们试图确定 Claudin-1 在调节肠道上皮细胞稳态中的作用。
我们使用了一种新型的微绒毛蛋白- Claudin-1 转基因（Cl-1Tg）小鼠作为模型（肠道 Claudin-1 过表达）。通过免疫组织化学、免疫印迹和实时 PCR 分析，确定 Claudin-1 表达对结肠上皮细胞分化、谱系决定和 Notch 信号的影响。我们使用了常用的葡聚糖硫酸钠（DSS）-结肠炎小鼠模型来模拟炎症、损伤和修复。
在 Cl-1Tg 小鼠中，正常的结肠细胞分化程序被打乱，杯状细胞数量和粘蛋白-2（muc-2）表达显著下调，而 Notch 和 ERK1/2 信号被上调，与野生型同窝仔鼠相比。Cl-1Tg 小鼠也容易发生结肠炎症，并在 DSS-结肠炎后表现出恢复受损和过度增殖。我们的数据进一步表明，Claudin-1 通过调节基质金属蛋白酶-9（MMP-9）和 p-ERK 信号来调节增殖和分化，从而调节 Notch 信号。
Claudin-1 通过调节 Notch 信号来帮助调节肠道上皮细胞稳态。 Claudin-1 表达上调诱导 MMP-9 和 p-ERK 信号激活 Notch 信号，从而抑制杯状细胞分化。杯状细胞数量减少导致 muc-2 表达降低，从而增加粘膜炎症的易感性。Claudin-1 还以 Notch 依赖的方式诱导结肠上皮细胞增殖。我们的发现可能有助于理解 Claudin-1 在调节炎症性肠病和 CRC 中的作用。
