microRNA與腫瘤細(xì)胞輻射敏感性研究
發(fā)布時間：2018-08-26 16:48
【摘要】：腫瘤,尤其是惡性腫瘤,是嚴(yán)重危害人類健康、威脅人類生命的主要疾病之一,其發(fā)病率和死亡率仍在逐年持續(xù)地快速增長,在全球范圍內(nèi)已成為導(dǎo)致人類死亡的第一殺手。放射治療對多種腫瘤細(xì)胞的致死效果顯著且不良反應(yīng)明確,因而在腫瘤治療中應(yīng)用廣泛。腫瘤細(xì)胞的輻射敏感性是影響放療效果的主要因素,如何降低腫瘤的輻射耐受性并盡可能地減輕正常組織的輻射損傷是臨床放療面臨的艱巨任務(wù),研究細(xì)胞的輻射敏感性機(jī)制對于深入了解腫瘤細(xì)胞的放療耐受性以及開發(fā)腫瘤放療增敏劑意義重大,雖然放射生物學(xué)已經(jīng)取得了長足發(fā)展,但到目前為止細(xì)胞的輻射敏感性機(jī)制仍未完全闡明。microRNA(miRNA)是一類新穎的內(nèi)源性非編碼小RNA分子,通過堿基互補(bǔ)配對的方式引起mRNA降解或翻譯的抑制在轉(zhuǎn)錄后水平調(diào)控基因的表達(dá)。人基因組中約60%的基因都受到miRNA的調(diào)控,因而miRNA幾乎涉及參與全部的細(xì)胞進(jìn)程,如細(xì)胞的增殖、分化、死亡等。近來,越來越多跡象表明miRNA與細(xì)胞輻射敏感性密切相關(guān),miRNA可能作為新的放療增敏靶點(diǎn)應(yīng)用于臨床。為了揭示miRNA與腫瘤輻射敏感性之間的關(guān)系,闡明miRNA影響腫瘤細(xì)胞輻射敏感性的分子機(jī)制,我們的前期研究采用miRNA芯片技術(shù)檢測了電離輻射對腎癌、胃癌miRNA表達(dá)譜的影響,發(fā)現(xiàn)miR-185和miR-300分別在腎癌、胃癌輻照后顯著下調(diào)。在本課題中,我們通過探索miR-185和miR-300對腫瘤細(xì)胞克隆存活、小鼠異種移植瘤、DNA損傷修復(fù)、細(xì)胞周期阻滯、凋亡等的影響,證明了miR-185能顯著降低電離輻射條件下腎癌細(xì)胞的克隆存活和體內(nèi)成瘤能力,顯著提高了腎癌細(xì)胞的輻射敏感性,深入分析表明細(xì)胞輻射應(yīng)激響應(yīng)的關(guān)鍵傳感因子ATR是miR-185的特異靶基因,miR-185通過調(diào)控ATR的表達(dá)顯著增強(qiáng)電離輻射誘導(dǎo)的凋亡和增殖抑制;此外,我們發(fā)現(xiàn)miR-300能提高胃癌細(xì)胞的DNA損傷修復(fù)能力、促進(jìn)電離輻射誘導(dǎo)的細(xì)胞周期G2期阻滯的恢復(fù),在增強(qiáng)腫瘤輻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.
【學(xué)位授予單位】：中國科學(xué)院研究生院（近代物理研究所）
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R730.2
本文編號：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.
【學(xué)位授予單位】：中國科學(xué)院研究生院（近代物理研究所）
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R730.2
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，本文編號：2205539
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