miR-128下调BMI-1靶向抑制前列腺癌生长的机制研究

发布时间：2018-03-30 15:05

本文选题：MiRNA　切入点：前列腺癌　出处：《华中科技大学》2014年博士论文

【摘要】：miRNAs是一类近年研究发现的可以调控基因表达的内源性非编码短序列RNA,可以担任癌基因或者抑癌基因的角色,参与肿瘤的发生、发展和转归。最近发现,与正常前列腺组织相比,miR-128在原发前列腺腺癌组织中的表达明显降低,在转移性前列腺癌组织中的表达量更低。另一篇基因芯片相关的分析也显示miR-128在前列腺肿癌组织中的表达比在正常前列腺组织中下调了大约40%。这些研究提示miR-128在前列腺癌中可能发挥着抑癌基因的功能,然而miR-128在前列腺癌中的具体作用和机制,目前尚无相关报道。本研究中,我们发现,与正常前列腺上皮细胞NHP9相比,miR-128在不同背景的人前列腺癌细胞株中也表达下调；在前列腺癌细胞株中外源性过表达miR-128,能明显抑制小鼠体内前列腺癌移植瘤的形成,还能显著抑制前列腺癌细胞的体外生长、增殖和侵袭能力,使S期细胞百分比减少,而且miR-128过表达抑制了肿瘤干细胞相关的特性,包括：2D和3D干细样克隆和悬浮球的形成能力。利用niR-128-sensor分离miR-128内源性低表达和内源性高表达的前列腺癌细胞,我们发现miR-128内源性低表达的前列腺癌细胞比miR-128内源性高表达的前列腺癌细胞拥有更高的成球能力和肿瘤再生潜能。miR-128负向调控与肿瘤干细胞“干性”相关的基因,包括BMI-1、NANOG和TGFBRl;在前列腺癌干/祖细胞中,这些干性相关基因高表达,而miR-128低表达。进一步发现,BMI-1是miR-128直接的和功能性的靶基因；在CD44+DU145前列腺癌细胞中miR-128和BMI-1不仅表达反向,而且发挥着相反的生物学功能。这些研究说明,miR-128以抑癌基因的角色参与前列腺癌肿瘤的形成,过表达miR-128通过下调BMI-1等“干性”相关基因,负向调控肿瘤干细胞特性,从而抑制前列腺癌的发展。本研究为前列腺癌发展的分子机制和临床治疗提供了新契机,靶向miR-128有望成为治疗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.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R737.25

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