Claudin-1 promotes TNF-α-induced epithelial-mesenchymal transition and migration in colorectal adenocarcinoma cells.
Claudin-1 promotes TNF-α-induced epithelial-mesenchymal transition and migration in colorectal adenocarcinoma cells.
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DOI：
10.1016/j.yexcr.2016.10.005
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发表时间：
2016-11-15
影响因子：
3.7
通讯作者：
Dhawan P
中科院分区：
文献类型：
--
作者：
Bhat AA;Ahmad R;Uppada SB;Singh AB;Dhawan P
上皮-间质转化（EMT）是包括结直肠癌（CRC）在内的癌症进展和恶性肿瘤的重要机制。重要的是，炎症介质是局部肿瘤环境的关键组成部分，CRC进展和炎症之间的密切联系现已得到证实。我们和其他人已经报道了claudin-1表达失调在结肠癌发生中的关键作用，包括结肠炎相关结肠癌（CAC）。然而，claudin-1表达与炎症诱导的结肠癌进展之间的因果关系仍不清楚。在这里，我们证明，TNF-α，一种促炎细胞因子，调节claudin-1调节上皮间质转化（EMT）和迁移在结肠腺癌细胞。重要的是，在TNF-α（10 ng/ml）存在下培养的结肠癌细胞显示E-钙粘蛋白表达急剧下降，波形蛋白表达增加（与对照细胞相比）。有趣的是，TNF-α治疗也以时间依赖性方式上调（和离域）claudin-1表达，伴随着增殖和伤口愈合的增加。此外，类似于我们先前的观察，即CRC细胞中的claudin-1过表达诱导ERK 1/2和Src-活化，与结肠癌细胞存活和转化相关的信号传导，TNF-α处理诱导磷酸化-ERK 1/2和-Src表达的上调。shRNA介导的claudin-1表达的抑制在很大程度上消除了TNF-α诱导的EMT、增殖、迁移、p-Erk和p-Src表达的变化。总之，我们的数据表明TNF-α介导的claudin-1调节和结肠癌细胞的致瘤能力，并强调了claudin-1表达失调通过调节ERK和Src信号传导在炎症诱导的结直肠癌生长和进展中的关键作用。
Epithelial-mesenchymal transition (EMT) is an important mechanism in cancer progression and malignancy including colorectal cancer (CRC). Importantly, inflammatory mediators are critical constituents of the local tumor environment and an intimate link between CRC progression and inflammation is now validated. We and others have reported key role of the deregulated claudin-1 expression in colon carcinogenesis including colitis-associated colon cancer (CAC). However, the causal association between claudin-1 expression and inflammation-induced colon cancer progression remains unclear. Here we demonstrate, TNF-α, a pro-inflammatory cytokine, regulates claudin-1 to modulate epithelial to mesenchymal transition (EMT) and migration in colon adenocarcinoma cells. Importantly, colon cancer cells cultured in the presence of TNF-α (10 ng/ml), demonstrated a sharp decrease in E-cadherin expression and an increase in vimentin expression (versus control cells). Interestingly, TNF-α treatment also upregulated (and delocalized) claudin-1 expression in a time-dependent manner accompanied by increase in proliferation and wound healing. Furthermore, similar to our previous observation that claudin-1 overexpression in CRC cells induces ERK1/2 and Src- activation, signaling associated with colon cancer cell survival and transformation, TNF-α-treatment induced upregulation of phospho-ERK1/2 and -Src expression. The shRNA-mediated inhibition of claudin-1 expression largely abrogated the TNF-α-induced changes in EMT, proliferation, migration, p-Erk and p-Src expression. Taken together, our data demonstrate TNF-α mediated regulation of claudin-1 and tumorigenic abilities of colon cancer cells and highlights a key role of deregulated claudin-1 expression in inflammation-induced colorectal cancer growth and progression, through the regulation of the ERK and Src-signaling.
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影响因子：
3.7
作者：
Bhat AA;Sharma A;Pope J;Krishnan M;Washington MK;Singh AB;Dhawan P
通讯作者：
Dhawan P
影响因子：
7.8
作者：
Furuse, Mikio;Hata, Masaki;Furuse, Kyoko;Yoshida, Yoko;Haratake, Akinori;Sugitani, Yoshinobu;Noda, Tetsuo;Kubo, Akiharu;Tsukita, Shoichiro
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影响因子：
8
作者：
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通讯作者：
Dhawan P
影响因子：
8
作者：
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通讯作者：
Balkwill, FR
影响因子：
82.9
作者：
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通讯作者：
Balkwill, F