本文關(guān)鍵詞： 非小細(xì)胞肺癌 microRNA microRNA-592 SOX9　出處：《吉林大學(xué)》2016年博士論文　論文類(lèi)型：學(xué)位論文

【摘要】：肺癌特別是非小細(xì)胞肺癌(non-small cell lung cancer,NSCLC)是一種死亡率較高的惡性腫瘤。盡管在臨床學(xué)和腫瘤學(xué)的研究上取得一定的進(jìn)展,但非小細(xì)胞肺癌預(yù)后仍不容樂(lè)觀(guān),患者5年生存率低于16%。治療非小細(xì)胞肺癌的困難在于非小細(xì)胞肺癌的遺傳異質(zhì)性和表觀(guān)遺傳的改變。因此,迫切要求對(duì)NSCLC發(fā)生、發(fā)展的分子機(jī)制進(jìn)行研究,以提高對(duì)該疾病的診斷、預(yù)防和治療效果。Micro RNAs(miRNAs)是一類(lèi)長(zhǎng)度約為18-25個(gè)堿基的內(nèi)源性、非編碼單鏈小分子RNA,可與目標(biāo)m RNA分子3'端非編碼區(qū)結(jié)合,最終使其翻譯受限。越來(lái)越多的研究證實(shí)miRNAs可參與細(xì)胞增殖、細(xì)胞周期調(diào)控、細(xì)胞分化、細(xì)胞凋亡等多個(gè)生物學(xué)過(guò)程。此外,另有研究顯示,miRNAs參與包括NSCLC在內(nèi)的多種腫瘤的發(fā)生、發(fā)展過(guò)程,深入研究其相關(guān)的分子機(jī)制對(duì)NSCLC的診斷和治療有重要意義。micro RNA-592(miR-592)作為miRNAs家族的一員,已在結(jié)腸癌、肝癌、前列腺癌等多種癌癥的診斷和治療中顯示出其獨(dú)特的優(yōu)勢(shì)。研究顯示,miR-592在NSCLC細(xì)胞中的表達(dá)受到了顯著抑制,但其在NSCLC發(fā)生和發(fā)展過(guò)程中扮演的角色和相應(yīng)的分子機(jī)理尚不清楚。本實(shí)驗(yàn)研究了miR-592在NSCLC發(fā)展過(guò)程中的生物學(xué)作用及其相應(yīng)的分子機(jī)制,為miR-592應(yīng)用于NSCLC的診斷和治療中,提供數(shù)據(jù)支持。具體實(shí)驗(yàn)過(guò)程如下:實(shí)驗(yàn)?zāi)康?研究miR-592對(duì)NSCLC細(xì)胞生物功能的影響,探討其相關(guān)的分子機(jī)制。為NSCLC的診斷和治療尋找新的靶點(diǎn)。試驗(yàn)方法:本實(shí)驗(yàn)采用實(shí)時(shí)定量PCR(real time quantitative RT-PCR,RT-q PCR)比較了miR-592在肺癌組織與癌旁組織,正常細(xì)胞與肺癌細(xì)胞系中的表達(dá)差異。分析miR-592表達(dá)差異與腫瘤分期和腫瘤淋巴轉(zhuǎn)移相互關(guān)系。為了進(jìn)一步研究過(guò)miR-592對(duì)NSCLC細(xì)胞生物功能的影響,本實(shí)驗(yàn)將miR-592 mimic轉(zhuǎn)化入A549細(xì)胞。采用CCK8實(shí)驗(yàn)、克隆形成實(shí)驗(yàn)、細(xì)胞劃痕實(shí)驗(yàn)、Transwell侵襲實(shí)驗(yàn)對(duì)過(guò)表達(dá)miR-592 mimic的A549細(xì)胞增殖能力、轉(zhuǎn)移能力,侵襲能力進(jìn)行分析。為了徹底闡明miR-592抑制非小細(xì)胞肺癌的作用機(jī)理,采用target Scan和miRanda軟件對(duì)miR-592可能的靶基因進(jìn)行了預(yù)測(cè),并對(duì)靶基因的功能進(jìn)行驗(yàn)證。最后,我們?cè)谛∈篌w內(nèi)檢測(cè)了miR-592對(duì)小鼠癌癥增長(zhǎng)的影響。實(shí)驗(yàn)結(jié)果:我們采用RT-q PCR對(duì)40份肺癌組織和癌旁組織中miR-592的表達(dá)情況進(jìn)行了分析,結(jié)果顯示:miR-592在肺癌組織中的表達(dá)情況顯著低于癌旁組織。我們分析了miR-592的差異表達(dá)與臨床分期和淋巴轉(zhuǎn)移之間的關(guān)系,結(jié)果顯示:III-IV肺癌患者腫瘤組織中miR-592的表達(dá)量顯著低于I-II肺癌患者;發(fā)生淋巴轉(zhuǎn)移的肺癌患者腫瘤組織中miR-592的表達(dá)量顯著低于未發(fā)生轉(zhuǎn)移的患者。對(duì)肺癌細(xì)胞系(A549,H1299,SPCA1、H358)與正常肺細(xì)胞系(BEAS-2B)中miR-592表達(dá)水平研究顯示:miR-592在所有的肺癌細(xì)胞系的表達(dá)水平均顯著低于在正常肺細(xì)胞的中的表達(dá)水平。為了進(jìn)一步研究過(guò)表達(dá)miR-592對(duì)NSCLC細(xì)胞生物學(xué)功能的影響,本實(shí)驗(yàn)將miR-592 mimic轉(zhuǎn)化入A549細(xì)胞中。CCK8結(jié)果顯示轉(zhuǎn)染miR-592 mimic組的細(xì)胞活性與對(duì)照組(轉(zhuǎn)染miR-Ctrl)相比受到了顯著的抑制;克隆形成實(shí)驗(yàn)顯示轉(zhuǎn)染miR-592 mimic組的A549細(xì)胞株克隆形成率顯著低于轉(zhuǎn)染miR-Ctrl的對(duì)照組;細(xì)胞劃痕實(shí)驗(yàn)和Transwell侵襲實(shí)驗(yàn)結(jié)果顯示轉(zhuǎn)染miR-592 mimic組與對(duì)照相比A549細(xì)胞的轉(zhuǎn)移和侵襲能力都受到了顯著的抑制。本實(shí)驗(yàn)采用軟件對(duì)miR-592的靶基因進(jìn)行了預(yù)測(cè),結(jié)果顯示miR-592可與SOX9基因的3’區(qū)域(SOX9 3’-UTR)進(jìn)行結(jié)合。為了進(jìn)一步驗(yàn)證SOX9 3’-UTR是否是miR-592的直接靶點(diǎn),本實(shí)驗(yàn)將插入野生型SOX9(WT)和突變SOX9(Mut)的熒光素表達(dá)質(zhì)粒與miR-592或miR-Ctrl共轉(zhuǎn)入A549細(xì)胞中。結(jié)果顯示:轉(zhuǎn)入SOX9(WT)熒光素表達(dá)質(zhì)粒的熒光強(qiáng)度顯著低于對(duì)照組。為進(jìn)一步研究SOX9的功能,我們采用RT-q PCR技術(shù)分析了40腫瘤樣本與癌旁組織中SOX9的表達(dá)情況,結(jié)果顯示在肺癌腫瘤組織中SOX9的表達(dá)水平顯著高于癌旁組織,并采用斯皮爾曼等級(jí)相關(guān)分析對(duì)數(shù)據(jù)進(jìn)行分析(Spearman’s rank test),結(jié)果顯示在40份腫瘤組織樣品中SOX9的表達(dá)水平與miR-592的表達(dá)呈負(fù)相關(guān)。為了驗(yàn)證過(guò)表達(dá)miR-592對(duì)A549細(xì)胞活性、遷移和侵襲作用的抑制是通過(guò)對(duì)SOX9基因的抑制實(shí)現(xiàn)的。本實(shí)驗(yàn)將miR-592-mimic和p VAX1-SOX9(不含3′-UTR區(qū)域)、miR-592-mimic和p VAX1空載體、miR-Ctrl和p VAX1空載體共轉(zhuǎn)入A549細(xì)胞中。結(jié)果顯示:miR-592-mimic和p VAX1-SOX9(不含3′-UTR區(qū)域)緩解了miR-592對(duì)SOX9表達(dá)的抑制作用;同時(shí),過(guò)表達(dá)SOX9基因可以有效緩解miR-592對(duì)腫瘤細(xì)胞增殖、細(xì)胞轉(zhuǎn)移、細(xì)胞侵襲實(shí)驗(yàn)的抑制作用。動(dòng)物實(shí)驗(yàn)顯示與miR-Ctrl相比過(guò)表達(dá)miR-592可以有效減小腫瘤的體積,降低腫瘤的重量。同時(shí),我們還分析了腫瘤組織中過(guò)表達(dá)miR-592對(duì)SOX9基因表達(dá)的影響。結(jié)果顯示:在腫瘤組織中隨著miR-592表達(dá)的提高,SOX9基因表達(dá)受到顯著的抑制。綜上所述,miR-592是通過(guò)抑制SOX9的表達(dá)來(lái)實(shí)現(xiàn)對(duì)腫瘤生長(zhǎng)的抑制的。結(jié)論:綜上所述,當(dāng)前的研究表明miR-592表達(dá)在非小細(xì)胞肺癌組織和細(xì)胞系明顯下調(diào),低表達(dá)的miR-592與TNM分期和腫瘤轉(zhuǎn)移負(fù)相關(guān);過(guò)表達(dá)miR-592在體外抑制肺癌細(xì)胞增殖,克隆形成,遷移和侵襲,在體內(nèi)抑制腫瘤增長(zhǎng),在一定程度上通過(guò)抑制靶蛋白SOX9來(lái)實(shí)現(xiàn),這些研究建議miR-592能夠作為抑癌基因,是一個(gè)潛在的理療目標(biāo)。
[Abstract]:Lung cancer especially non-small cell lung cancer (non-small cell lung cancer, NSCLC) is a kind of malignant tumor with high mortality. Although some progress in clinical study and oncology, but non-small cell lung cancer patients is still not optimistic, 5 years survival rate is less than 16%. in the treatment of non small cell lung cancer is difficult to view the genetic changes of genetic heterogeneity and non-small cell lung cancer. Therefore, the urgent requirements for NSCLC, to study the molecular mechanism of the development, to improve the diagnosis of the disease, prevention and treatment effect of.Micro RNAs (miRNAs) is a class of endogenous length is about 18-25 nucleotides, encoding non small single stranded RNA but, with the target m RNA molecular 3'non encoding region of the translation is limited. More and more studies have confirmed that miRNAs may be involved in cell proliferation, cell cycle regulation, cell differentiation, apoptosis and other biological Process. In addition, other research shows that miRNAs is involved in a variety of tumors including NSCLC, occurrence, development, in-depth study of the related molecular mechanism of the diagnosis and treatment of NSCLC have important significance of.Micro RNA-592 (miR-592) as a member of the miRNAs family, has been in colon cancer, liver cancer, shows its unique advantages in diagnosis and for the treatment of prostate cancer and other cancers. The study showed that the expression of miR-592 in NSCLC cells was inhibited, but the incidence of NSCLC and the molecular role of the development process and the corresponding mechanism is not clear. The experimental study on the biological function of miR-592 in the development of NSCLC and the molecular mechanism of the corresponding and for the diagnosis and treatment of miR-592 in NSCLC, to provide data support. The specific process is as follows: the experimental objective: To study the effect of miR-592 on NSCLC cell biological function, explore the related Molecular mechanism. To find new targets for the diagnosis and treatment of NSCLC. Methods: the experiment using quantitative real-time PCR (real time quantitative RT-PCR, RT-q PCR) were compared in lung cancer tissues and cancer adjacent tissues miR-592, expression differences between normal cells and lung cancer cell lines. The expression of miR-592 and tumor metastasis staging difference each other the relationship between tumor and lymph node. In order to further study the effect of miR-592 on NSCLC cell biological function, this experiment will miR-592 mimic into A549 cells by CCK8 experiment, clone formation assay, cell scratch assay, Transwell invasion assay, A549 cell proliferation on the expression of miR-592 mimic metastasis ability analysis to invasion. The mechanism of inhibition of miR-592 thorough elucidation of non-small cell lung cancer, the target gene of miR-592 was predicted by target Scan and miRanda software, and the target gene The function is verified. Finally, we tested the effect of miR-592 on mice of cancer growth in mice. Results: We used the expression of RT-q PCR on miR-592 in 40 lung cancer tissues and adjacent tissues were analyzed. The results showed that: miR-592 in lung cancer tissues was significantly lower than that of adjacent tissues. Analysis of differential expression and clinical miR-592 staging and lymph node metastasis and the relationship between the results showed that the expression of miR-592 III-IV in lung cancer tissue was significantly lower than that of I-II in patients with lung cancer; expression of miR-592 lymph node metastasis in patients with lung cancer tumor tissue were significantly lower than that in non metastatic patients. In lung cancer cell lines (A549. H1299, SPCA1, H358) and normal lung cell line (BEAS-2B) miR-592 expression level in the study showed that the expression level of miR-592 in lung cancer cell lines were all significantly lower than that in normal lung fine The expression level of the cell. In order to further study the effect of miR-592 overexpression on NSCLC cell biology function, this experiment will be transformed into miR-592 mimic.CCK8 results in A549 cells transfected with miR-592 showed that the cell activity of mimic group and control group (transfected with miR-Ctrl) compared inhibited significantly; clone formation assay indicated that the expression of miR-592 in mimic group the A549 cell clone formation rate was significantly lower than the control group transfected with miR-Ctrl; cell scratch assay and Transwell invasion assay showed that transfection of miR-592 mimic group with the control force than the metastasis and invasion of A549 cells was significantly inhibited. This experiment adopts the software of miR-592 target genes were predicted, the results showed that miR-592 with SOX9 gene 3 'region (SOX9 3 -UTR) combined. In order to verify the SOX9 3 -UTR is a direct target of miR-592, this experiment will be inserted into the Wild type and mutant SOX9 (WT) SOX9 (Mut) luciferase expression plasmid and miR-592 or miR-Ctrl were transfected into A549 cells. The results showed: to SOX9 (WT) expression of fluorescein fluorescence intensity was significantly lower than the control group. To study the function of SOX9, we use RT-q PCR technology to analyze the expression of SOX9 40 tumor samples and in the adjacent tissues. Results showed that the expression level of SOX9 in lung cancer tissues was significantly higher than that in paracancerous tissues, and by using the Spielman rank correlation analysis to analyze the data ("Spearman s rank test), was negatively related to the expression results showed that the expression level of miR-592 and SOX9 in 40 tumor tissue samples. In order to verify. Over expression of miR-592 activity in A549 cells, inhibit the migration and invasion effect is achieved by inhibition of the SOX9 gene. The miR-592-mimic and P VAX1-SOX9 (not including the 3 '-UTR region), miR- 592-mimic and P VAX1 miR-Ctrl P VAX1 and empty vector and empty vector were transfected into A549 cells. The results showed that miR-592-mimic and P VAX1-SOX9 (not including the 3 '-UTR region) alleviated the inhibitory effect of miR-592 on the expression of SOX9; at the same time, the overexpression of SOX9 gene can effectively alleviate the miR-592 on the proliferation of tumor cell metastasis inhibition the role of cell invasion experiments. Animal experiments show that compared with miR-Ctrl over expression of miR-592 can effectively reduce tumor volume, reduce the tumor weight. At the same time, we also analyzed the effect of overexpression of miR-592 on the expression of SOX9 gene in tumor tissue. The results showed that in tumor tissues with the expression of miR-592 SOX9 gene expression was significantly increased. The inhibition of miR-592. In conclusion, by inhibiting the expression of SOX9 to inhibit tumor growth. In conclusion, the present study shows that the expression of miR-592 in non small cell Lung cancer tissues and cell lines was significantly lower, miR-592 and low expression of TNM staging and tumor metastasis negative correlation; overexpression of miR-592 inhibits the proliferation of lung cancer cells in vitro, colony formation, migration and invasion in vivo, inhibit tumor growth by inhibiting SOX9 protein target to achieve in a certain extent, these studies suggest that miR-592 can be used as a tumor suppressor gene is a potential therapeutic target.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R734.2

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