本文選題：MUC1 + TGF-β��； 參考：《吉林大學(xué)》2015年博士論文

【摘要】：Mucin1(MUC1)作為癌基因可通過調(diào)控多種促增殖和抑制凋亡信號(hào)促進(jìn)多種腺癌發(fā)生發(fā)展，但是MUC1是否能調(diào)控轉(zhuǎn)化生長(zhǎng)因子β (TGF-β)信號(hào)促進(jìn)癌癥進(jìn)展還未見報(bào)道。我們前期研究發(fā)現(xiàn)，MUC1不僅影響肝癌的形成，同時(shí)能調(diào)控TGF-β信號(hào)通路分子的基因水平，提示了一個(gè)新的分子機(jī)制，即MUC1可能調(diào)控TGF-β信號(hào)促進(jìn)癌癥發(fā)展。TGF-β信號(hào)在正常細(xì)胞和癌前病變的組織中表現(xiàn)為腫瘤抑制作用，而在癌細(xì)胞中轉(zhuǎn)變成促癌作用。然而，TGF-β在癌細(xì)胞中如何由抑癌作用轉(zhuǎn)變成促癌作用的機(jī)制是一直未解決的科學(xué)問題。近年研究表明，JNK是TGF-β信號(hào)由抑癌向促癌轉(zhuǎn)變的關(guān)鍵分子，但調(diào)控JNK的上游分子并不清楚。另外，MUC1能激活JNK抑制結(jié)腸癌細(xì)胞凋亡。因此，結(jié)合前期結(jié)果我們推測(cè)，MUC1可能通過激活JNK轉(zhuǎn)變TGF-β抑癌信號(hào)促進(jìn)肝癌發(fā)展。 本研究中，我們?cè)诟伟┘?xì)胞系中進(jìn)行MUC1基因沉默和過表達(dá)，，研究MUC1對(duì)肝癌細(xì)胞的增殖以及TGF-β信號(hào)的影響，通過阻斷信號(hào)傳導(dǎo)、基因干擾、熒光素酶報(bào)告分析及免疫沉淀等方法，研究JNK在MUC1調(diào)節(jié)的TGF-β信號(hào)中的作用，進(jìn)一步通過體內(nèi)實(shí)驗(yàn)以及臨床肝癌病人腫瘤組織樣本驗(yàn)證MUC1、TGF-β信號(hào)與JNK之間的關(guān)系。本研究結(jié)果表明，在肝癌細(xì)胞中MUC1直接結(jié)合并激活JNK活化JNK/AP1途徑誘導(dǎo)自分泌TGF-β信號(hào)促進(jìn)細(xì)胞遷移，并通過JNK將p-Smad3C/p21抑癌信號(hào)轉(zhuǎn)變?yōu)閜-Smad3L/c-Myc促癌信號(hào)促進(jìn)細(xì)胞增殖，揭示MUC1是TGF-β信號(hào)由抑癌轉(zhuǎn)變成促癌作用的新分子，TGF-β信號(hào)是MUC1發(fā)揮癌蛋白作用的新途徑；闡明MUC1通過TGF-β信號(hào)不僅調(diào)控腫瘤細(xì)胞內(nèi)部信號(hào)傳導(dǎo)，而且通過誘導(dǎo)TGF-β分泌具有調(diào)控腫瘤微環(huán)境的潛能。本研究最終揭示MUC1是促進(jìn)肝癌發(fā)展的重要癌基因，為肝癌靶向治療提供有效靶點(diǎn)。
[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.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R735.7

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