MUC1通过转变TGF-β抑癌信号促进肝癌发展的作用及分子机制

发布时间：2018-05-12 02:03

本文选题：MUC1 + TGF-β　；参考：《吉林大学》2015年博士论文

【摘要】：Mucin1(MUC1)作为癌基因可通过调控多种促增殖和抑制凋亡信号促进多种腺癌发生发展，但是MUC1是否能调控转化生长因子β (TGF-β)信号促进癌症进展还未见报道。我们前期研究发现，MUC1不仅影响肝癌的形成，同时能调控TGF-β信号通路分子的基因水平，提示了一个新的分子机制，即MUC1可能调控TGF-β信号促进癌症发展。TGF-β信号在正常细胞和癌前病变的组织中表现为肿瘤抑制作用，而在癌细胞中转变成促癌作用。然而，TGF-β在癌细胞中如何由抑癌作用转变成促癌作用的机制是一直未解决的科学问题。近年研究表明，JNK是TGF-β信号由抑癌向促癌转变的关键分子，但调控JNK的上游分子并不清楚。另外，MUC1能激活JNK抑制结肠癌细胞凋亡。因此，结合前期结果我们推测，MUC1可能通过激活JNK转变TGF-β抑癌信号促进肝癌发展。本研究中，我们在肝癌细胞系中进行MUC1基因沉默和过表达，，研究MUC1对肝癌细胞的增殖以及TGF-β信号的影响，通过阻断信号传导、基因干扰、荧光素酶报告分析及免疫沉淀等方法，研究JNK在MUC1调节的TGF-β信号中的作用，进一步通过体内实验以及临床肝癌病人肿瘤组织样本验证MUC1、TGF-β信号与JNK之间的关系。本研究结果表明，在肝癌细胞中MUC1直接结合并激活JNK活化JNK/AP1途径诱导自分泌TGF-β信号促进细胞迁移，并通过JNK将p-Smad3C/p21抑癌信号转变为p-Smad3L/c-Myc促癌信号促进细胞增殖，揭示MUC1是TGF-β信号由抑癌转变成促癌作用的新分子，TGF-β信号是MUC1发挥癌蛋白作用的新途径；阐明MUC1通过TGF-β信号不仅调控肿瘤细胞内部信号传导，而且通过诱导TGF-β分泌具有调控肿瘤微环境的潜能。本研究最终揭示MUC1是促进肝癌发展的重要癌基因，为肝癌靶向治疗提供有效靶点。
[Abstract]:Mucin1 mucl) as a oncogene can promote the development of many kinds of adenocarcinoma by regulating many kinds of signal of promoting proliferation and inhibiting apoptosis. However, whether MUC1 can regulate the signal of transforming growth factor 尾 TGF- 尾 has not been reported to promote the progression of cancer. Our previous studies have found that MUC1 not only affects the formation of liver cancer, but also regulates the gene level of TGF- 尾 signaling pathway molecules, suggesting a new molecular mechanism. That is, MUC1 may regulate TGF- 尾 signal to promote the development of cancer. TGF- 尾 signal in normal cells and precancerous lesions of tissues showed tumor inhibition, but in cancer cells to become carcinogenic. However, the mechanism of transforming TGF- 尾 from tumor suppressor to promoting cancer is an unsolved scientific problem. Recent studies have shown that JNK is a key molecule in the transition of TGF- 尾 signal from tumor suppressor to carcinogenic promoter, but the upstream molecules regulating JNK are not clear. In addition, MUC1 can activate JNK to inhibit the apoptosis of colon cancer cells. Therefore, we speculate that MUC1 may promote the development of liver cancer by activating JNK transforming TGF- 尾 tumor suppressor signal. In this study, we used MUC1 gene silencing and overexpression in hepatocellular carcinoma cell lines to study the effects of MUC1 on the proliferation and TGF- 尾 signal of hepatoma cells by blocking signal transduction, gene interference, luciferase report analysis and immunoprecipitation. To study the role of JNK in TGF- 尾 signal regulated by MUC1, and to further verify the relationship between MUC1 TGF- 尾 signal and JNK by in vivo experiments and tumor tissue samples of clinical liver cancer patients. The results showed that MUC1 directly binds and activates JNK activated JNK/AP1 pathway to induce autocrine TGF- 尾 signal to promote cell migration in hepatocellular carcinoma cells, and p-Smad3C/p21 suppressor signal is transformed into p-Smad3L/c-Myc signal to promote cell proliferation through JNK. It is revealed that MUC1 is a new molecule of transforming TGF- 尾 signal from tumor suppressor to carcinogenic promoting effect. TGF- 尾 signal is a new way for MUC1 to exert oncoprotein function, and MUC1 not only regulates the signal transduction in tumor cells by TGF- 尾 signal, but also shows that TGF- 尾 signal not only regulates the signal transduction in tumor cells. Moreover, TGF- 尾 secretion has the potential to regulate tumor microenvironment by inducing TGF- 尾 secretion. This study finally revealed that MUC1 is an important oncogene to promote the development of liver cancer and provide an effective target for the targeted therapy of liver cancer.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R735.7

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