本文選題：MiRNA　切入點(diǎn)：前列腺癌　出處：《華中科技大學(xué)》2014年博士論文

【摘要】：miRNAs是一類(lèi)近年研究發(fā)現(xiàn)的可以調(diào)控基因表達(dá)的內(nèi)源性非編碼短序列RNA,可以擔(dān)任癌基因或者抑癌基因的角色,參與腫瘤的發(fā)生、發(fā)展和轉(zhuǎn)歸。最近發(fā)現(xiàn),與正常前列腺組織相比,miR-128在原發(fā)前列腺腺癌組織中的表達(dá)明顯降低,在轉(zhuǎn)移性前列腺癌組織中的表達(dá)量更低。另一篇基因芯片相關(guān)的分析也顯示miR-128在前列腺腫癌組織中的表達(dá)比在正常前列腺組織中下調(diào)了大約40%。這些研究提示miR-128在前列腺癌中可能發(fā)揮著抑癌基因的功能,然而miR-128在前列腺癌中的具體作用和機(jī)制,目前尚無(wú)相關(guān)報(bào)道。本研究中,我們發(fā)現(xiàn),與正常前列腺上皮細(xì)胞NHP9相比,miR-128在不同背景的人前列腺癌細(xì)胞株中也表達(dá)下調(diào)；在前列腺癌細(xì)胞株中外源性過(guò)表達(dá)miR-128,能明顯抑制小鼠體內(nèi)前列腺癌移植瘤的形成,還能顯著抑制前列腺癌細(xì)胞的體外生長(zhǎng)、增殖和侵襲能力,使S期細(xì)胞百分比減少,而且miR-128過(guò)表達(dá)抑制了腫瘤干細(xì)胞相關(guān)的特性,包括：2D和3D干細(xì)樣克隆和懸浮球的形成能力。利用niR-128-sensor分離miR-128內(nèi)源性低表達(dá)和內(nèi)源性高表達(dá)的前列腺癌細(xì)胞,我們發(fā)現(xiàn)miR-128內(nèi)源性低表達(dá)的前列腺癌細(xì)胞比miR-128內(nèi)源性高表達(dá)的前列腺癌細(xì)胞擁有更高的成球能力和腫瘤再生潛能。miR-128負(fù)向調(diào)控與腫瘤干細(xì)胞“干性”相關(guān)的基因,包括BMI-1、NANOG和TGFBRl;在前列腺癌干/祖細(xì)胞中,這些干性相關(guān)基因高表達(dá),而miR-128低表達(dá)。進(jìn)一步發(fā)現(xiàn),BMI-1是miR-128直接的和功能性的靶基因；在CD44+DU145前列腺癌細(xì)胞中miR-128和BMI-1不僅表達(dá)反向,而且發(fā)揮著相反的生物學(xué)功能。這些研究說(shuō)明,miR-128以抑癌基因的角色參與前列腺癌腫瘤的形成,過(guò)表達(dá)miR-128通過(guò)下調(diào)BMI-1等“干性”相關(guān)基因,負(fù)向調(diào)控腫瘤干細(xì)胞特性,從而抑制前列腺癌的發(fā)展。本研究為前列腺癌發(fā)展的分子機(jī)制和臨床治療提供了新契機(jī),靶向miR-128有望成為治療前列腺癌的另一有效手段。
[Abstract]:MiRNAs is a kind of endogenous non-coding short sequence RNAs that can regulate gene expression, which can play the role of oncogene or tumor suppressor gene, participate in the occurrence, development and prognosis of tumor. Compared with the normal prostate tissue, the expression of mmiR-128 in the primary prostate adenocarcinoma was significantly lower than that in the normal prostate tissue. The expression of miR-128 was lower in metastatic prostate cancer than in normal prostate cancer. Another microarray analysis also showed that the expression of miR-128 was down-regulated in benign prostate cancer tissues. These studies suggest that the expression of miR-128 in prostate cancer tissues is lower than that in normal prostate tissues. These studies suggest that the expression of miR-128 in prostate cancer tissues is significantly lower than that in normal prostate tissues. Prostate cancer may function as a tumor suppressor gene. However, there are no reports on the role and mechanism of miR-128 in prostate cancer. In this study, we found that the expression of mmiR-128 was down-regulated in human prostate cancer cell lines with different backgrounds compared with normal prostatic epithelial cells (NHP9). Exogenous overexpression of miR-128 in prostate cancer cell line could significantly inhibit the formation of transplanted tumor of prostate cancer in mice, inhibit the growth, proliferation and invasion of prostate cancer cells in vitro, and decrease the percentage of S phase cells. Furthermore, overexpression of miR-128 inhibits the characteristics associated with tumor stem cells, including the ability to form small clones and suspension spheres in the presence of 2 D and 3 D dry samples. Prostate cancer cells with endogenous low expression and high expression of miR-128 are isolated by niR-128-sensor. We found that prostate cancer cells with low expression of miR-128 have higher globular ability and tumor regeneration potential than prostate cancer cells with high endogenous expression of miR-128. MiR-128 negatively regulates genes associated with "dryness" of tumor stem cells. These genes are highly expressed in prostate cancer stem / progenitor cells, but are low in miR-128. It is further found that BMI-1 is a direct and functional target gene of miR-128, and miR-128 and BMI-1 not only express reverse in CD44 DU145 prostate cancer cells. These studies suggest that miR-128 plays an important role in the formation of prostate cancer tumors, and that overexpression of miR-128 negatively regulates the characteristics of tumor stem cells by down-regulating "dry-related" genes such as BMI-1. In order to inhibit the development of prostate cancer, this study provides a new opportunity for the molecular mechanism of prostate cancer development and clinical treatment, targeted miR-128 is expected to become another effective means for the treatment of prostate cancer.
【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】：2014
【分類(lèi)號(hào)】：R737.25

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

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