Myosin light chain kinase expression induced via tumor necrosis factor receptor 2 signaling in the epithelial cells regulates the development of colitis-associated carcinogenesis.
Myosin light chain kinase expression induced via tumor necrosis factor receptor 2 signaling in the epithelial cells regulates the development of colitis-associated carcinogenesis.
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DOI：
10.1371/journal.pone.0088369
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Watanabe M
中科院分区：
文献类型：
--
作者：
Suzuki M;Nagaishi T;Yamazaki M;Onizawa M;Watabe T;Sakamaki Y;Ichinose S;Totsuka M;Oshima S;Okamoto R;Shimonaka M;Yagita H;Nakamura T;Watanabe M
长期的炎症性肠病（IBD）可能导致结肠炎相关的致癌作用（CAC）。我们以前观察到，在CAC的发展过程中，结肠上皮细胞中NF-κB的活化与肿瘤坏死因子受体2（TNFR 2）表达的增加有关。然而，上皮NF-κB活化导致CAC的机制仍不清楚。肌球蛋白轻链激酶（MLCK）已被报道负责与TNF信号相关的上皮通透性。因此，我们关注MLCK表达通过TNFR 2信号传导对CAC发展的作用。在结肠炎背景下，促肿瘤发生细胞因子如IL-1β、IL-6和MIP-2的产生以及固有层的INF-γ和TNF的产生增加，并且进一步在肿瘤组织中与CAC模型的上皮细胞中上调的TNFR 2和MLCK表达相关。在TNF刺激的结肠上皮细胞中观察到MLCK表达的上调，其以剂量依赖性方式与TNFR 2的上调相关。沉默TNFR 2，而不是TNFR 1，导致与MLCK表达减少相关的上皮紧密连接（TJ）的恢复。抗体介导的TNF信号传导阻断也导致TJ恢复与MLCK表达抑制相关，有趣的是，通过抑制上皮细胞中的MLCK来抑制TNFR 2和MLCK表达也观察到类似的结果。MLCK的沉默也导致TNFR 2而非TNFR 1表达受抑制，表明恢复的TJ导致TNFR 2信号传导减少。MLCK的这种抑制以及TNFR 2信号传导的阻断导致TJ恢复、促肿瘤细胞因子减少和CAC发展减少。这些结果表明，MLCK可能是预防IBD相关肿瘤发展的潜在靶点。
It has been suggested that prolonged inflammatory bowel diseases (IBD) may lead to colitis-associated carcinogenesis (CAC). We previously observed that the NF-κB activation in colonic epithelial cells is associated with increased tumor necrosis factor receptor 2 (TNFR2) expression in CAC development. However, the mechanism by which epithelial NF-κB activation leading to CAC is still unclear. Myosin light chain kinase (MLCK) has been reported to be responsible for the epithelial permeability associated with TNF signaling. Therefore we focused on the role of MLCK expression via TNFR2 signaling on CAC development. Pro-tumorigenic cytokines such as IL-1β, IL-6 and MIP-2 production as well as INF-γ and TNF production at the lamina propria were increased in the setting of colitis, and further in tumor tissues in associations with up-regulated TNFR2 and MLCK expressions in the epithelial cells of a CAC model. The up-regulated MLCK expression was observed in TNF-stimulated colonic epithelial cells in a dose-dependent fashion in association with up-regulation of TNFR2. Silencing TNFR2, but not TNFR1, resulted in restoration of epithelial tight junction (TJ) associated with decreased MLCK expression. Antibody-mediated blockade of TNF signaling also resulted in restoration of TJ in association with suppressed MLCK expression, and interestingly, similar results were observed with suppressing TNFR2 and MLCK expressions by inhibiting MLCK in the epithelial cells. Silencing of MLCK also resulted in suppressed TNFR2, but not TNFR1, expression, suggesting that the restored TJ leads to reduced TNFR2 signaling. Such suppression of MLCK as well as blockade of TNFR2 signaling resulted in restored TJ, decreased pro-tumorigenic cytokines and reduced CAC development. These results suggest that MLCK may be a potential target for the prevention of IBD-associated tumor development.
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影响因子：
3.7
作者：
Chen C;Wang P;Su Q;Wang S;Wang F
通讯作者：
Wang F
影响因子：
24.5
作者：
Fish, SM;Proujansky, R;Reenstra, WW
通讯作者：
Reenstra, WW
影响因子：
32.4
作者：
Nagaishi, Takashi;Pao, Lily;Blumberg, Richard S.
通讯作者：
Blumberg, Richard S.
影响因子：
8.4
作者：
LAHM, H;PETRALMALEC, D;ODARTCHENKO, N
通讯作者：
ODARTCHENKO, N
DOI：
10.1073/pnas.94.19.10279
发表时间：
1997-09-16
影响因子：
11.1
作者：
Ohno, Y;Lee, J;Sanderson, IR
通讯作者：
Sanderson, IR