Abstract：
Colorectal cancer is one of the most prevalent and lethal malignancies, affecting approximately 900,000 individuals each year worldwide. Patients with colorectal cancer are found with elevated serum interleukin-6 (IL-6), which is associated with advanced tumor grades and is related to their poor survival outcomes. Although IL-6 is recognized as a potent inducer of colorectal cancer progression, the detail mechanisms underlying IL-6-induced colorectal cancer epithelial-mesenchymal transition (EMT), one of the major process of tumor metastasis, remain unclear. In the present study, we investigated the regulatory role of IL-6 signaling in colorectal cancer EMT using HCT116 human colorectal cancer cells. We noted that the expression of epithelial marker E-cadherin was reduced in HCT116 cells exposed to IL-6, along with the increase in a set of mesenchymal cell markers including vimentin and α-smooth muscle actin (α-SMA), as well as EMT transcription regulators-twist, snail and slug. The changes of EMT phenotype were related to the activation of Src, FAK, ERK1/2, p38 mitogen-activated protein kinase (p38MAPK), as well as transcription factors STAT3, κB and C/EBPβ. IL-6 treatment has promoted the recruitment of STAT3, κB and C/EBPβ toward the Twist promoter region. Furthermore, the Src-FAK signaling blockade resulted in the decline of IL-6 induced activation of ERK1/2, p38MAPK, κB, C/EBPβ and STAT3, as well as the decreasing mesenchymal state of HCT116 cells. These results suggested that IL-6 activates the Src-FAK-ERK/p38MAPK signaling cascade to cause the EMT of colorectal cancer cells. Pharmacological approaches targeting Src-FAK signaling may provide potential therapeutic strategies for rescuing colorectal cancer progression.
摘要：
结直肠癌是最常见和最致命的恶性肿瘤之一。每年影响全球约90万人。发现结直肠癌患者血清白细胞介素-6（IL-6）升高，这与晚期肿瘤分级相关，并与其不良生存结局相关。尽管IL-6被认为是结直肠癌进展的有效诱导剂，IL-6诱导结直肠癌上皮间质转化（EMT）的详细机制，肿瘤转移的主要过程之一，仍然不清楚。在本研究中,我们使用HCT116人结直肠癌细胞研究了IL-6信号在结直肠癌EMT中的调节作用.我们注意到，在暴露于IL-6的HCT116细胞中，上皮标记E-cadherin的表达降低，随着一组间充质细胞标记包括波形蛋白和α-平滑肌肌动蛋白（α-SMA）的增加，以及EMT转录调节因子扭曲，蜗牛和鼻涕.EMT表型的改变与Src的激活有关,FAK,ERK1/2,p38丝裂原活化蛋白激酶(p38MAPK),以及转录因子STAT3、κB和C/EBPβ。IL-6处理促进了STAT3，κB和C/EBPβ向Twist启动子区的募集。此外，Src-FAK信号传导阻滞导致IL-6诱导的ERK1/2、p38MAPK激活下降,κB,C/EBPβ和STAT3，以及HCT116细胞间充质状态的降低。这些结果表明IL-6激活Src-FAK-ERK/p38MAPK信号级联以引起结直肠癌细胞的EMT。靶向Src-FAK信号传导的药理学方法可能为挽救结直肠癌进展提供潜在的治疗策略。
