microRNA与肿瘤细胞辐射敏感性研究
发布时间：2018-08-26 16:48
【摘要】：肿瘤,尤其是恶性肿瘤,是严重危害人类健康、威胁人类生命的主要疾病之一,其发病率和死亡率仍在逐年持续地快速增长,在全球范围内已成为导致人类死亡的第一杀手。放射治疗对多种肿瘤细胞的致死效果显著且不良反应明确,因而在肿瘤治疗中应用广泛。肿瘤细胞的辐射敏感性是影响放疗效果的主要因素,如何降低肿瘤的辐射耐受性并尽可能地减轻正常组织的辐射损伤是临床放疗面临的艰巨任务,研究细胞的辐射敏感性机制对于深入了解肿瘤细胞的放疗耐受性以及开发肿瘤放疗增敏剂意义重大,虽然放射生物学已经取得了长足发展,但到目前为止细胞的辐射敏感性机制仍未完全阐明。microRNA(miRNA)是一类新颖的内源性非编码小RNA分子,通过碱基互补配对的方式引起mRNA降解或翻译的抑制在转录后水平调控基因的表达。人基因组中约60%的基因都受到miRNA的调控,因而miRNA几乎涉及参与全部的细胞进程,如细胞的增殖、分化、死亡等。近来,越来越多迹象表明miRNA与细胞辐射敏感性密切相关,miRNA可能作为新的放疗增敏靶点应用于临床。为了揭示miRNA与肿瘤辐射敏感性之间的关系,阐明miRNA影响肿瘤细胞辐射敏感性的分子机制,我们的前期研究采用miRNA芯片技术检测了电离辐射对肾癌、胃癌miRNA表达谱的影响,发现miR-185和miR-300分别在肾癌、胃癌辐照后显著下调。在本课题中,我们通过探索miR-185和miR-300对肿瘤细胞克隆存活、小鼠异种移植瘤、DNA损伤修复、细胞周期阻滞、凋亡等的影响,证明了miR-185能显著降低电离辐射条件下肾癌细胞的克隆存活和体内成瘤能力,显著提高了肾癌细胞的辐射敏感性,深入分析表明细胞辐射应激响应的关键传感因子ATR是miR-185的特异靶基因,miR-185通过调控ATR的表达显著增强电离辐射诱导的凋亡和增殖抑制;此外,我们发现miR-300能提高胃癌细胞的DNA损伤修复能力、促进电离辐射诱导的细胞周期G2期阻滞的恢复,在增强肿瘤辐射耐受性上有一定的作用。
[Abstract]:Cancer, especially malignant tumor, is one of the major diseases that seriously endanger human health and threaten human life. Its morbidity and mortality are still increasing rapidly year by year, and it has become the first killer of human death in the world. Radiotherapy is widely used in tumor therapy because of its significant lethal effect and definite adverse reactions. The radiosensitivity of tumor cells is the main factor affecting the effect of radiotherapy. How to reduce the radiation tolerance of tumor and minimize the radiation damage of normal tissue is a difficult task for clinical radiotherapy. Studying the radiosensitivity mechanism of cells is of great significance in understanding the radiation tolerance of tumor cells and developing tumor radiosensitizers, although radiobiology has made great progress. However, up to now, the radiosensitivity mechanism of cells has not been fully elucidated. MicroRNA (miRNA) is a novel class of endogenous non-coding small RNA molecules, which can induce the degradation of mRNA or inhibit the translation of mRNA at post-transcriptional level by the way of base complementary pairing. About 60% of the genes in the human genome are regulated by miRNA, so miRNA is involved in almost all cell processes, such as cell proliferation, differentiation, death, and so on. Recently, there are more and more indications that miRNA is closely related to cell radiosensitivity and may be used as a new radiosensitivity target in clinic. In order to reveal the relationship between miRNA and tumor radiosensitivity, and to elucidate the molecular mechanism of miRNA affecting the radiosensitivity of tumor cells, we used miRNA chip technique to detect the effect of ionizing radiation on the expression profile of miRNA in renal and gastric cancer. It was found that miR-185 and miR-300 were significantly down-regulated after irradiation in renal and gastric cancer respectively. In this study, we explored the effects of miR-185 and miR-300 on tumor cell clone survival, DNA damage repair, cell cycle arrest, apoptosis and so on. It was proved that miR-185 could significantly reduce the clone survival and tumorigenic ability of renal cancer cells under ionizing radiation, and significantly improve the radiosensitivity of renal cancer cells. Further analysis showed that ATR, the key sensing factor of cell response to radiation stress, was a specific target gene of miR-185, which significantly enhanced the apoptosis and proliferation inhibition induced by ionizing radiation by regulating the expression of ATR. We found that miR-300 can improve the DNA damage and repair ability of gastric cancer cells, promote the recovery of G2 phase arrest of cell cycle induced by ionizing radiation, and play a certain role in enhancing tumor radiation tolerance.
【学位授予单位】：中国科学院研究生院（近代物理研究所）
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R730.2
本文编号：2205539
[Abstract]:Cancer, especially malignant tumor, is one of the major diseases that seriously endanger human health and threaten human life. Its morbidity and mortality are still increasing rapidly year by year, and it has become the first killer of human death in the world. Radiotherapy is widely used in tumor therapy because of its significant lethal effect and definite adverse reactions. The radiosensitivity of tumor cells is the main factor affecting the effect of radiotherapy. How to reduce the radiation tolerance of tumor and minimize the radiation damage of normal tissue is a difficult task for clinical radiotherapy. Studying the radiosensitivity mechanism of cells is of great significance in understanding the radiation tolerance of tumor cells and developing tumor radiosensitizers, although radiobiology has made great progress. However, up to now, the radiosensitivity mechanism of cells has not been fully elucidated. MicroRNA (miRNA) is a novel class of endogenous non-coding small RNA molecules, which can induce the degradation of mRNA or inhibit the translation of mRNA at post-transcriptional level by the way of base complementary pairing. About 60% of the genes in the human genome are regulated by miRNA, so miRNA is involved in almost all cell processes, such as cell proliferation, differentiation, death, and so on. Recently, there are more and more indications that miRNA is closely related to cell radiosensitivity and may be used as a new radiosensitivity target in clinic. In order to reveal the relationship between miRNA and tumor radiosensitivity, and to elucidate the molecular mechanism of miRNA affecting the radiosensitivity of tumor cells, we used miRNA chip technique to detect the effect of ionizing radiation on the expression profile of miRNA in renal and gastric cancer. It was found that miR-185 and miR-300 were significantly down-regulated after irradiation in renal and gastric cancer respectively. In this study, we explored the effects of miR-185 and miR-300 on tumor cell clone survival, DNA damage repair, cell cycle arrest, apoptosis and so on. It was proved that miR-185 could significantly reduce the clone survival and tumorigenic ability of renal cancer cells under ionizing radiation, and significantly improve the radiosensitivity of renal cancer cells. Further analysis showed that ATR, the key sensing factor of cell response to radiation stress, was a specific target gene of miR-185, which significantly enhanced the apoptosis and proliferation inhibition induced by ionizing radiation by regulating the expression of ATR. We found that miR-300 can improve the DNA damage and repair ability of gastric cancer cells, promote the recovery of G2 phase arrest of cell cycle induced by ionizing radiation, and play a certain role in enhancing tumor radiation tolerance.
【学位授予单位】：中国科学院研究生院（近代物理研究所）
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R730.2
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，本文编号：2205539
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