本文選題：二乙基亞硝胺 + 前列環(huán)素　； 參考：《華中科技大學(xué)》2016年博士論文

【摘要】：肝細(xì)胞癌世界上排名第六的最常見癌癥,由于預(yù)后不良而成為癌癥死因中排名第三位的惡性腫瘤。由于缺乏可行的有效治療措施,對(duì)高危病人的預(yù)防已經(jīng)被作為一個(gè)可選的策略。肝癌可以發(fā)源于腫瘤起始細(xì)胞即腫瘤干細(xì)胞。肝癌的的主要風(fēng)險(xiǎn)因子是肝硬化,而且一系列的證據(jù)表明轉(zhuǎn)化生長因子和結(jié)締組織生長因子在肝硬化和肝癌的進(jìn)展中發(fā)揮重要作用,并且TGF-β在肝臟祖細(xì)胞惡化成為腫瘤起始細(xì)胞中也發(fā)揮至關(guān)重要的作用。本文中,我們發(fā)現(xiàn)在二乙基亞硝胺誘導(dǎo)的大鼠肝癌模型中肝臟祖細(xì)胞的激活大量增加,并且肝臟祖細(xì)胞中CTGF的表達(dá)也有明顯升高。但是當(dāng)我們同時(shí)給予DEN和CTGF合成抑制劑Iloprost后發(fā)現(xiàn)肝臟祖細(xì)胞的激活減少,其中CTGF的表達(dá)也同步降低。更重要的是,肝癌的發(fā)生率也出現(xiàn)明顯的下降。此外,DEN注射引起TGF-β和腫瘤起始細(xì)胞標(biāo)記物的表達(dá)增加,并且兩者之間呈正相關(guān)性。而給予CTGF合成抑制劑同樣可以降低TGF-β1和腫瘤起始細(xì)胞標(biāo)記物的表達(dá)。這也進(jìn)一步預(yù)示CTGF和TGF-β可能參與腫瘤起始細(xì)胞的產(chǎn)生進(jìn)而在肝癌的發(fā)生中發(fā)揮作用。為了模擬大鼠體內(nèi)的長期的TGF-β存在的環(huán)境,我們?cè)隗w外用長期(18周)低劑量TGF-β1(0.25ng/ml)處理大鼠肝臟祖細(xì)胞系WB-F344而建立WB-F344-TβLT細(xì)胞系。我們發(fā)現(xiàn)長期低劑量TGF-β處理可以損害肝臟祖細(xì)胞的分化能力而促進(jìn)肝臟祖細(xì)胞的惡性轉(zhuǎn)化,這與之前的一些研究結(jié)果具有一致性。進(jìn)而,我們準(zhǔn)備探討CTGF在這種長期的低劑量TGF-β1誘導(dǎo)的肝臟祖細(xì)胞的惡性轉(zhuǎn)化中的作用。所以,我們利用慢病毒構(gòu)建了敲減CTGF的大鼠肝臟祖細(xì)胞并研究了其在肝臟祖細(xì)胞中的生物學(xué)功能,結(jié)果顯示敲減CTGF后可以在一定程度上恢復(fù)肝臟祖細(xì)胞的分化能力,并且肝臟祖細(xì)胞的惡性程度明顯降低。我們前期的研究結(jié)果證實(shí)TGF-β1可以在肝臟祖細(xì)胞中誘導(dǎo)CTGF的表達(dá)。本文中,我們進(jìn)一步探討CTGF對(duì)TGF-β信號(hào)通路的影響,以及通過什么機(jī)制發(fā)揮作用。我們發(fā)現(xiàn)CTGF可以通過促進(jìn)TGF-β1-Smad3通路的激活,抑制TGF-β1-Smad1/5通路的激活水平介導(dǎo)促進(jìn)肝臟祖細(xì)胞的惡性轉(zhuǎn)化的作用。綜上所述,我們證實(shí)了大鼠肝癌發(fā)生過程中有肝臟祖細(xì)胞的參與,CTGF合成抑制劑可以起到保護(hù)肝臟,減少肝癌發(fā)生的作用。在TGF-β1所誘導(dǎo)的肝臟祖細(xì)胞的惡性轉(zhuǎn)化過程中,CTGF在其中也發(fā)揮促進(jìn)作用。另外,我們初步證明了TGF-β-CTGF的惡性循環(huán)可以增加肝癌的發(fā)生,促進(jìn)肝臟祖細(xì)胞的惡性轉(zhuǎn)化,并且通過調(diào)控肝臟祖細(xì)胞中不同TGF-β/Smad通路的激活水平來發(fā)揮作用。我們的研究首次確認(rèn)TGF-β-CTGF軸通過調(diào)節(jié)不同Smad的激活水平來促進(jìn)肝臟祖細(xì)胞的惡性轉(zhuǎn)化和肝癌的發(fā)生。
[Abstract]:Hepatocellular carcinoma (HCC), the sixth most common cancer in the world, is the third leading cause of cancer death due to poor prognosis. Prevention of high-risk patients has been an optional strategy due to the lack of feasible and effective treatment measures. Liver cancer can originate from tumor initiation cells, or tumor stem cells. The main risk factor for liver cancer is cirrhosis, and a series of evidence suggests that transforming growth factor and connective tissue growth factor play an important role in the progression of liver cirrhosis and liver cancer. TGF- 尾 also plays a crucial role in the progression of liver progenitor cells into tumor initiation cells. In this paper, we found that the activation of liver progenitor cells and the expression of CTGF in liver progenitor cells were significantly increased in the rat liver cancer model induced by diethylnitrosamine. However, when we were given both den and Iloprost, we found that the activation of liver progenitor cells was decreased, and the expression of CTGF was also decreased. More importantly, the incidence of liver cancer also showed a significant decline. In addition, the expression of TGF- 尾 and tumor initiation cell markers was increased after injection of den, and there was a positive correlation between the expression of TGF- 尾 and TGF- 尾. CTGF synthesis inhibitor also decreased the expression of TGF- 尾 1 and tumor initiation cell markers. This further indicates that CTGF and TGF- 尾 may be involved in the production of tumor initiation cells and thus play a role in the development of liver cancer. In order to simulate the long-term existence of TGF- 尾 in rats, we established WB-F344-T 尾 LT cell line by treating rat liver progenitor cell line WB-F344 with low-dose TGF- 尾 _ 1 0.25ng / ml for 18 weeks in vitro. We found that long-term low-dose TGF- 尾 treatment can damage the differentiation ability of liver progenitor cells and promote the malignant transformation of liver progenitor cells, which is consistent with some previous studies. Furthermore, we intend to explore the role of CTGF in the malignant transformation of liver progenitor cells induced by low dose TGF- 尾 1. Therefore, we used lentivirus to construct rat liver progenitor cells with CTGF knockout and to study its biological function in liver progenitor cells. The results showed that CTGF knockout could restore the differentiation ability of liver progenitor cells to some extent. The malignancy of liver progenitor cells was significantly decreased. Our previous study confirmed that TGF- 尾 1 could induce CTGF expression in liver progenitor cells. In this paper, we further investigate the effect of CTGF on TGF- 尾 signaling pathway and its mechanism. We found that CTGF can promote the malignant transformation of liver progenitor cells by promoting the activation of TGF- 尾 1-Smad3 pathway and inhibiting the activation level of TGF- 尾 1-Smad1 / 5 pathway. In conclusion, we confirmed that CTGF synthesis inhibitor can protect the liver and reduce the occurrence of liver cancer in rats. CTGF also plays a promoting role in the malignant transformation of liver progenitor cells induced by TGF- 尾 1. In addition, we preliminarily proved that the vicious cycle of TGF- 尾 -CTGF can increase the occurrence of liver cancer, promote the malignant transformation of liver progenitor cells, and play a role by regulating the activation level of different TGF- 尾 / Smad pathway in liver progenitor cells. Our study confirmed for the first time that the TGF- 尾 -CTGF axis promotes the malignant transformation of liver progenitor cells and the occurrence of liver cancer by regulating the activation levels of different Smad.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R735.7

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