MiR-506在乳腺癌中的表达及通过靶向调节IQGAP1抑制乳腺癌发生发展的作用机制研究

发布时间：2018-04-20 22:24

本文选题：microRNA-506 + 乳腺癌　；参考：《吉林大学》2016年博士论文

【摘要】：乳腺癌是人类最常见的一类恶性肿瘤,发病率高居妇女癌症第二位。Micro RNA-506(mi R506)与多种肿瘤的发生发展密切相关,且在肿瘤组织中表达异常。然而,mi RNA-506调节乳腺癌发生发展的作用机制目前尚不清楚。在多种肿瘤组织和肿瘤细胞中含IQ模序的GTP1酶活化蛋白(IQGAP1)表达上调,发挥致癌作用。因此,我们推测mi RNA-506在乳腺癌中发挥抑癌作用,且其下游靶基因为IQGAP1。本研究以mi RNA-506为切入点,为进一步探讨mi RNA-506调节乳腺癌发生发展的作用机制,为开发更有效的乳腺癌治疗靶点和方法奠定理论基础。在本研究中,我们首先采用RT-q PCR法检测mi RNA-506在恶性乳腺组织以及乳腺癌细胞系中的表达,结果显示在人乳腺组织及乳腺癌细胞系中,mi R-506表达量显著下降,且随着肿瘤分期增加,呈现逐渐减少的趋势。功能性实验结果显示,mi R-506低表达的MDA-MB-231细胞的增殖、侵袭以及粘附能力显著增加,而过表达mi R-506的HCC1937细胞的增殖、侵袭以及粘附能力显著下降,提示mi R-506在乳腺癌中发挥抑癌作用。接下来,我们检测到在人乳腺组织及乳腺癌细胞系中,IQGAP1蛋白表达显著上调,且随着肿瘤分期增加,表达逐渐增高,提示IQGAP1在乳腺癌中发挥促癌作用。荧光素酶实验证实mi R-506通过3’UTR端靶向作用于IQGAP1并下调IQGAP1表达,提示IQGAP1为mi R-506的下游靶基因。进一步的研究指出IQGAP1可以中和mi R-506所诱导的肿瘤细胞的增殖侵袭以及粘附能力。为进一步探讨mi R-506在乳腺癌中的作用机制,我们对相关的信号通路分子进行了检测,研究结果表明,mi R-506能够下调Erk1/2磷酸化,且IQGAP1可缓解mi R-506的这种作用。本研究首次证实mi R-506在乳腺癌细胞中能够作为一种肿瘤抑制因子,可直接下调IQGAP1的表达,进而抑制ERK信号通路发挥抑癌作用。本研究为将mi R-506/IQGAP1/ERK通路作为成为新的乳腺癌治疗靶点提供理论依据。
[Abstract]:Breast cancer is one of the most common malignant tumors in human beings. The incidence of breast cancer is the second highest in women. Micro RNA-506(mi R506) is closely related to the occurrence and development of many kinds of tumors, and its expression is abnormal in tumor tissues. However, the mechanism of RNA-506 regulating the development of breast cancer is unclear. The expression of GTP1 activator protein (IQGAP1), which contains IQ motif, is up-regulated in various tumor tissues and tumor cells, and plays a carcinogenic role. Therefore, we speculate that mi RNA-506 plays an inhibitory role in breast cancer, and its downstream target is IQGAP1. In this study, mi RNA-506 was used as the starting point to further explore the mechanism of mi RNA-506 regulating the occurrence and development of breast cancer, and to lay a theoretical foundation for the development of more effective therapeutic targets and methods for breast cancer. In this study, we first used RT-q PCR method to detect the expression of mi RNA-506 in malignant breast tissues and breast cancer cell lines. The results showed that the expression of mi R-506 in human breast tissues and breast cancer cell lines decreased significantly, and increased with the tumor stage. A decreasing trend. The results of functional experiments showed that the proliferation, invasion and adhesion of MDA-MB-231 cells with low expression of miR-506 were significantly increased, while the proliferation, invasion and adhesion of HCC1937 cells with overexpression of miR-506 were significantly decreased. These results suggest that mi R 506 plays an important role in the inhibition of breast cancer. Next, we detected that the expression of IQGAP1 protein in human breast tissue and breast cancer cell line was significantly up-regulated, and the expression increased gradually with the increase of tumor stage, suggesting that IQGAP1 plays a role in the promotion of breast cancer. Luciferase assay confirmed that mi R-506 targeted IQGAP1 and down-regulated IQGAP1 expression through 3'UTR terminal, suggesting that IQGAP1 is the downstream target gene of mi R-506. Further studies indicate that IQGAP1 can neutralize the proliferation, invasion and adhesion of tumor cells induced by mi R 506. In order to further study the mechanism of miR-506 in breast cancer, we detected the related signaling pathway molecules. The results showed that miR-506 could down-regulate the phosphorylation of Erk1/2, and IQGAP1 could alleviate the effect of miR-506. In this study, it was first demonstrated that mi R-506 can be used as a tumor suppressor in breast cancer cells, which can directly down-regulate the expression of IQGAP1, and then inhibit the ERK signaling pathway to play a role in tumor inhibition. This study provides a theoretical basis for using the mi R-506/IQGAP1/ERK pathway as a new therapeutic target for breast cancer.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R737.9

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