【摘要】：研究背景軟骨肉瘤是軟骨來源的惡性骨腫瘤,其發(fā)病率僅次于骨肉瘤而位于原發(fā)性惡性骨腫瘤的第二位。手術(shù)雖是軟骨肉瘤首選和有效的治療手段,但要求腫瘤徹底切除,否則極易復(fù)發(fā)。由于軟骨肉瘤對(duì)化療的敏感性欠佳,因此化療在臨床上的應(yīng)用受到了極大的限制。如何提高軟骨肉瘤對(duì)化學(xué)治療的敏感性,一直是軟骨肉瘤治療領(lǐng)域的一個(gè)核心問題。微小RNA (microRNA, miRNA)是由19-25個(gè)核苷酸組成的小單鏈非編碼RNA,廣泛表達(dá)于高等真核生物基因組中。每一種miRNA都具有物種特異性。到目前為止,已發(fā)現(xiàn)一百多種miRNA在細(xì)胞的增殖、分化、遷移以及細(xì)胞周期、凋亡等生物過程中發(fā)揮重要作用。隨著研究的不斷深入,miRNA在腫瘤的發(fā)生、發(fā)展、治療等各個(gè)環(huán)節(jié)所起的重要作用已為大家公認(rèn)。1miRNA通過與mRNA結(jié)合對(duì)機(jī)體進(jìn)行調(diào)控,相同miRNA在不同組織中與不同的靶基因結(jié)合發(fā)揮不同的調(diào)節(jié)作用,都顯示了miRNA的調(diào)節(jié)機(jī)制是一個(gè)復(fù)雜的網(wǎng)絡(luò)結(jié)構(gòu)。正常情況下,miRNA通過精準(zhǔn)的網(wǎng)絡(luò)調(diào)節(jié)維持機(jī)體各細(xì)胞、組織中蛋白水平維持平衡,然而當(dāng)其功能缺失或獲得,將打破原有平衡。有研究表明niRNA作為一種潛在的抑癌/促癌因子,在許多人類腫瘤組織中miRNA表達(dá)異常,因此在腫瘤的診斷、治療和預(yù)后中具有重要意義。隨著對(duì)miRNA與腫瘤發(fā)生發(fā)展相關(guān)性研究的不斷深入,越來越多的證據(jù)表明miRNA參與了調(diào)控腫瘤細(xì)胞對(duì)化療的敏感性,這對(duì)揭示腫瘤的耐藥機(jī)制有著重要意義。腫瘤化療耐藥是腫瘤患者預(yù)后差的主要原因之一。miRNA突變、異常表達(dá)或異常加工均會(huì)導(dǎo)致miRNA功能異常,并導(dǎo)致其靶蛋白表達(dá)異常。若靶蛋白與腫瘤細(xì)胞對(duì)藥物敏感性相關(guān),則相關(guān)miRNA的異常將會(huì)導(dǎo)致腫瘤細(xì)胞對(duì)藥物敏感性的改變。miRNA參與化療耐藥的機(jī)制一般可分為：與凋亡相關(guān)的miRNA介導(dǎo)的化療耐藥,與藥物轉(zhuǎn)運(yùn)相關(guān)miRNA介導(dǎo)的化療耐藥,與細(xì)胞修復(fù)相關(guān)miRNA介導(dǎo)的化療耐藥,以及與藥物作用靶點(diǎn)相關(guān)miRNA介導(dǎo)的化療耐藥等。目前,miRNA在腫瘤耐藥中的研究剛剛起步,目前研究大多是通過對(duì)比耐藥細(xì)胞株與親本敏感細(xì)胞株之間miRNA表達(dá)譜異常,尋找與藥物敏感性相關(guān)的關(guān)鍵miRNA,從而進(jìn)一步對(duì)腫瘤細(xì)胞化療耐受機(jī)制進(jìn)行深入研究和尋找新的藥物作用靶點(diǎn)。順鉑是抗實(shí)體腫瘤的一線用藥,為鉑的金屬絡(luò)合物,其作用類似于烷化劑,干擾DNA復(fù)制,為周期非特異性抗腫瘤藥物,具有抗癌譜廣、作用強(qiáng)、與多種抗腫瘤藥有協(xié)同作用且無交叉耐藥等特點(diǎn),是目前聯(lián)合化療最常使用的藥物之一。本研究分為兩個(gè)部分,以順鉑為例分別探討microRNA-100 (miR-100)與microRNA-23b (miR-23b)恢復(fù)軟骨肉瘤細(xì)胞對(duì)順鉑敏感性的機(jī)制,為miRNAs成為軟骨肉瘤的治療策略提供理論基礎(chǔ)。第一部分：miR-100恢復(fù)軟骨肉瘤細(xì)胞對(duì)順鉑敏感性的實(shí)驗(yàn)研究[研究目的]探討miR-100增加軟骨肉瘤細(xì)胞對(duì)順鉑敏感性的機(jī)制,為軟骨肉瘤基于miR-100的化療策略提供了理論基礎(chǔ)。[方法]1.采用實(shí)時(shí)定量PCR (quantitative real-time PCR, qRT-PCR)檢測(cè)miR-100在多種人軟骨肉瘤細(xì)胞系、正常軟骨細(xì)胞系以及患者軟骨肉瘤組織標(biāo)本中的表達(dá)水平。2.采用濃度梯度法對(duì)軟骨肉瘤CH-2879細(xì)胞系進(jìn)行藥物篩選,獲得對(duì)順鉑耐受的CH-2879細(xì)胞(命名為：CH-2879/DDP細(xì)胞),qRT-PCR檢測(cè)并比較CH-2879細(xì)胞及CH-2879/DDP細(xì)胞的miR-100表達(dá)水平：MTT及克隆形成實(shí)驗(yàn)檢測(cè)比較兩種細(xì)胞在順鉑作用下的增殖能力和克隆形成能力。3. miRNA數(shù)據(jù)庫(TargetScan, Pictar, and MicroRNA)預(yù)測(cè)miR-100的作用靶點(diǎn)。4.采用脂質(zhì)體2000法將pre-miR-100和anti-miR-100以及它們的陰性對(duì)照分別轉(zhuǎn)入CH-2879細(xì)胞,qRT-PCR驗(yàn)證轉(zhuǎn)染后細(xì)胞miR-100的表達(dá)水平,蛋白質(zhì)印跡法(western blot)檢測(cè)提高或抑制miR-100后mTOR的表達(dá)水平以及]mTOR下游蛋白S6K和4EBP1的磷酸化水平。5.熒光素酶報(bào)告基因法(Luciferase reporter assay)進(jìn)一步驗(yàn)證miR-100作用于mTOR的3’端非翻譯區(qū)(3'untranslated region, UTR)。6.將CDDP. BEZ235以及CDDP+BEZ235分別處理CH-2879/DDP細(xì)胞及CH-2879細(xì)胞,觀察抑制mTOR通路,軟骨肉瘤細(xì)胞對(duì)順鉑的敏感性。7.將miR-100及其對(duì)照分別轉(zhuǎn)染CH-2879細(xì)胞及CH-2879/DDP細(xì)胞,觀察miR-100高表達(dá)與軟骨肉瘤細(xì)胞對(duì)順鉑敏感性的關(guān)系。8.外源性S6K過表達(dá)質(zhì)粒轉(zhuǎn)染事先已經(jīng)轉(zhuǎn)染過miR-100的軟骨肉瘤細(xì)胞,觀察mTOR通路活性恢復(fù)后,軟骨肉瘤細(xì)胞對(duì)順鉑耐受性的變化。[結(jié)果]1.miR-100在人軟骨肉瘤細(xì)胞和患者軟骨肉瘤標(biāo)本中的表達(dá)下調(diào)。2. CH-2879/DDP細(xì)胞中miR-100表達(dá)下調(diào),提示該基因與軟骨肉瘤化療耐受有關(guān)。3. mTOR及其所在信號(hào)通路是目前腫瘤病理機(jī)制研究的熱點(diǎn),正如我們預(yù)測(cè)的一樣,mTOR是miR-100的直接靶點(diǎn)之一。miR-100的過／低表達(dá)能抑制／恢復(fù)mTOR的表達(dá)水平。4.miR-100的高表達(dá)增加軟骨肉瘤對(duì)順鉑的敏感性,進(jìn)一步印證了該基因與軟骨肉瘤化療耐受有關(guān)。5. mTOR通路活性的恢復(fù)使miR-100過表達(dá)的軟骨肉瘤細(xì)胞表現(xiàn)出對(duì)順鉑的耐受,提示miR-100的過表達(dá)增加軟骨肉瘤細(xì)胞對(duì)順鉑的敏感性是通過對(duì)mTOR通路的抑制實(shí)現(xiàn)的。[結(jié)論]與正常軟骨細(xì)胞相比,miR-100在軟骨肉瘤細(xì)胞及軟骨肉瘤患者標(biāo)本中的表達(dá)均下調(diào),提示miR-100是軟骨肉瘤的抑制基因；與原代軟骨肉瘤細(xì)胞相比,miR-100在CH-2879/DDP細(xì)胞中表達(dá)下調(diào),這不僅說明miR-100具有腫瘤抑制功能,而且與軟骨肉瘤對(duì)順鉑的化療敏感性有關(guān)。nTOR在多種惡性腫瘤中活化,可以成為治療癌癥的一個(gè)有前景的治療靶點(diǎn)。在本研究中,我們確定了mTOR是miR-100直接靶目標(biāo),并首次報(bào)道了miR-100過表達(dá)通過抑制mTOR通路增加軟骨肉瘤細(xì)胞對(duì)順鉑的敏感性,為軟骨肉瘤基于miR-100的治療策略提供了理論基礎(chǔ)。第二部分：miR-23b恢復(fù)軟骨肉瘤細(xì)胞對(duì)順鉑敏感性的實(shí)驗(yàn)研究[研究目的]探討miR-23b增加軟骨肉瘤細(xì)胞對(duì)順鉑敏感性的機(jī)制,為軟骨肉瘤基于miR-23b的化療策略提供了理論基礎(chǔ)。[方法]1.采用qRT-PCR檢測(cè)miR-23b在多種人軟骨肉瘤細(xì)胞系、正常軟骨細(xì)胞系以及患者軟骨肉瘤組織標(biāo)本中的表達(dá)水平。2.采用脂質(zhì)體2000法將pre-miRs和control-miRs轉(zhuǎn)染SW1353細(xì)胞；并在轉(zhuǎn)染后不同時(shí)間點(diǎn)檢測(cè)細(xì)胞的增殖情況。3.在常規(guī)細(xì)胞培養(yǎng)條件下,CH-2879細(xì)胞與CH-2879/DDP細(xì)胞分別接受順鉑刺激48小時(shí),利用顯微鏡觀察細(xì)胞形態(tài)的改變以及利用qRT-PCR檢測(cè)miR-23b的表達(dá)。4.根據(jù)以往報(bào)道我們預(yù)測(cè)并驗(yàn)證Src是miR-23b的直接靶目標(biāo)。5.通過采用不同濃度的順鉑分別作用于CH-2879細(xì)胞,48小時(shí)后收集細(xì)胞行western blot分析,驗(yàn)證miR-23b過表達(dá)抑制Src-Akt通路的作用。6.采用脂質(zhì)體2000法將pre-miR-negative或pre-miR-23b分別轉(zhuǎn)入CH-2879細(xì)胞,qRT-PCR驗(yàn)證轉(zhuǎn)染后細(xì)胞1miR-23b的表達(dá)水平,western blot檢測(cè)提高或抑制miR-23b后總的Src和磷酸化Src的水平。7.采用脂質(zhì)體2000法,將含有野生型(wt)和突變型(mut) Src 3'UTR轉(zhuǎn)染細(xì)胞,轉(zhuǎn)染后利用熒光素酶報(bào)告基因法進(jìn)一步驗(yàn)證miR-23b作用于Src3'UTR區(qū)。8.以contral-miR或pre-miR-23b分別轉(zhuǎn)染CH-2879細(xì)胞、SW1353細(xì)胞和CH-2879/DDP細(xì)胞,用不同濃度的順鉑處理細(xì)胞后MTT法測(cè)定細(xì)胞活性。9.將：niR-23b轉(zhuǎn)染CH-2879細(xì)胞及CH-2879/DDP細(xì)胞,觀察miR-23b過表達(dá)恢復(fù)軟骨肉瘤細(xì)胞對(duì)順鉑敏感性的作用。10.外源性Src過表達(dá)質(zhì)粒轉(zhuǎn)染事先已經(jīng)轉(zhuǎn)染過niR-23b的軟骨肉瘤細(xì)胞,觀察Src-Akt通路活性恢復(fù)后,軟骨肉瘤細(xì)胞對(duì)順鉑耐受性的變化。[結(jié)果]1. miR-23b在多種軟骨肉瘤細(xì)胞系及軟骨肉瘤患者標(biāo)本組織中的表達(dá)下調(diào)。2. CH-2879/DDP細(xì)胞中miR-23b表達(dá)下調(diào),提示該基因也與軟骨肉瘤對(duì)順鉑的化療耐受有關(guān)。3.Src激酶參與了多種腫瘤的增殖、遷移和入侵,CH-2879/DDP細(xì)胞的Src-Akt通路活性的上調(diào)4.軟骨肉瘤細(xì)胞中Src是miR-23b的直接靶目標(biāo)5. miR-23b的過度表達(dá)通過直接抑制Src-Akt通路恢復(fù)了軟骨肉瘤細(xì)胞對(duì)順鉑的敏感性。6.Src-Akt通路活性的恢復(fù)增加了miR-23b過表達(dá)軟骨肉瘤細(xì)胞對(duì)順鉑的耐藥性。[結(jié)論]同miR-100一樣,miR-23b在軟骨肉瘤細(xì)胞中的表達(dá)下調(diào),提示它是一種腫瘤抑制基因,與軟骨肉瘤對(duì)順鉑的化療敏感性有關(guān)。我們經(jīng)實(shí)驗(yàn)確認(rèn),Src是miR-23b的一個(gè)直接靶向目標(biāo),Akt是一種用于調(diào)節(jié)新陳代謝、細(xì)胞周期進(jìn)展和細(xì)胞存活率的細(xì)胞質(zhì)絲氨酸和蘇氨酸激酶,miR-23b可以通過對(duì)Src-Akt通路的負(fù)向調(diào)節(jié)提高軟骨肉瘤細(xì)胞對(duì)順鉑的敏感性,為軟骨肉瘤基于miR-23b的治療策略提供了理論依據(jù)。
[Abstract]:Background Chondrosarcoma is a malignant bone tumor of cartilage origin. The incidence of osteosarcoma is second only to osteosarcoma. Surgery is the first choice and effective treatment for chondrosarcoma, but it requires complete resection of the tumor, otherwise it is easy to recur. Clinical applications have been greatly limited. How to improve the sensitivity of chondrosarcoma to chemotherapy has always been a core issue in the field of chondrosarcoma treatment. Up to now, more than 100 kinds of microRNAs have been found to play an important role in cell proliferation, differentiation, migration, cell cycle, apoptosis and other biological processes. The same microRNAs bind to different target genes in different tissues and play different regulatory roles, indicating that the regulatory mechanism of microRNAs is a complex network structure. Studies have shown that niRNA, as a potential tumor suppressor/promoter, is abnormal in the expression of microRNAs in many human tumor tissues, so it is important in the diagnosis, treatment and prognosis of cancer. MicroRNAs are involved in the regulation of chemosensitivity of tumor cells, which is important for revealing the mechanism of tumor resistance. Chemosensitivity is one of the main causes of poor prognosis in cancer patients. Mutations in microRNAs, abnormal expression or abnormal processing can lead to abnormal function of microRNAs and abnormal expression of target proteins. The mechanisms of microRNAs involved in chemosensitivity include apoptosis-related microRNAs-mediated chemosensitivity, drug transport-related microRNAs-mediated chemosensitivity, and cell repair-related microRNAs-mediated chemosensitivity. At present, the study of microRNAs in tumor resistance has just begun. At present, most of the research is to find the key microRNAs related to drug sensitivity by comparing the abnormal expression profiles of microRNAs between drug-resistant cell lines and parental sensitive cell lines. Cisplatin is a first-line antitumor drug, a metal complex of platinum. It acts as an alkylating agent, interferes with DNA replication, and is a periodically nonspecific antitumor drug. It has a broad spectrum of anticancer drugs, has a strong effect, and has synergistic effect with a variety of antitumor drugs without cross-resistance. This study is divided into two parts. Take microRNA-100 and microRNA-23b as examples to explore the mechanism of restoring the sensitivity of chondrosarcoma cells to cisplatin, and to provide theoretical basis for microRNAs to become a therapeutic strategy for chondrosarcoma. Part I: MicroRNA-100 restores cartilage. [Objective] To explore the mechanism of increasing the sensitivity of chondrosarcoma cells to cisplatin by microarray-100, and to provide a theoretical basis for the chemotherapy strategy of chondrosarcoma based on microarray-100. [Methods] 1. Real-time quantitative PCR (qRT-PCR) was used to detect microarray-100 in multiple human chondrosarcoma cells. The expression levels of CH-2879 cells (named CH-2879/DDP cells) and CH-2879 cells and CH-2879/DDP cells were detected by qRT-PCR. The expression levels of microarray-100 in CH-2879 cells and CH-2879/DDP cells were compared. Ping: MTT assay and cloning assay were used to compare the proliferation and cloning ability of the two cells under cisplatin. 3. The Target Scan (Pictar, and MicroRNA) database predicted the target of microRNA-100. 4. Pre-microRNA-100, anti-microRNA-100 and their negative control were transferred into CH-2879 cells by liposome 2000, respectively. PCR was used to verify the expression of microRNAs-100, Western blot was used to detect the expression of mTOR after microRNAs-100, and phosphorylation of downstream mTOR proteins S6K and 4EBP1.5 Luciferase reporter assay was used to further verify the effect of microRNAs-100 on the 3'untranslated region of mTOR. The sensitivity of chondrosarcoma cells to cisplatin and inhibition of mTOR pathway were observed. 7. Mi-100 and its control were transfected into CH-2879 cells and CH-2879/DDP cells respectively. The high expression of Mi-100 and the sensitivity of chondrosarcoma cells to cisplatin were observed. Relationship. 8. Exogenous S6K overexpression plasmid was transfected into chondrosarcoma cells which had previously been transfected with Mi-100 to observe the changes of cisplatin tolerance of chondrosarcoma cells after the activity of mTOR pathway was restored. [Results] 1. The expression of Mi-100 in human chondrosarcoma cells and chondrosarcoma samples was down-regulated. 2. The expression of Mi-100 in CH-2879/DDP cells was down-regulated. It is suggested that this gene is related to chemotherapeutic tolerance of chondrosarcoma. 3. mTOR and its signaling pathway are the hotspots in the study of tumor pathology. As we predicted, mTOR is one of the direct targets of microRNA-100. Over/under-expression of microRNA-100 can inhibit/restore the expression of mTOR. 4. Over-expression of microRNA-100 can increase the cis-cis of chondrosarcoma. The sensitivity to platinum further confirmed that the gene was related to chemotherapeutic tolerance of chondrosarcoma. 5. Restoration of the activity of mTOR pathway made the over-expressed chondrosarcoma cells show tolerance to cisplatin, suggesting that the overexpression of microRNA-100 increased the sensitivity of chondrosarcoma cells to cisplatin by inhibiting the mTOR pathway. Compared with normal chondrocytes, the expression of miR-100 was down-regulated in chondrosarcoma cells and chondrosarcoma specimens, suggesting that it was an inhibitor gene of chondrosarcoma; compared with primary chondrosarcoma cells, the expression of miR-100 was down-regulated in CH-2879/DDP cells, which not only showed that the expression of microRNA-100 had tumor-suppressing function, but also showed that it had the effect of cisplatin on chondrosarcoma cells. In this study, we identified mTOR as a direct target for microarray-100, and reported for the first time that microarray-100 overexpression increases the sensitivity of chondrosarcoma cells to cisplatin by inhibiting the mTOR pathway. Part II: Experimental study on the effect of microRNAs-23b on cisplatin sensitivity of chondrosarcoma cells [Objective] To explore the mechanism of microRNAs-23b increasing the sensitivity of chondrosarcoma cells to cisplatin, and to provide a theoretical basis for the chemotherapy strategy of chondrosarcoma based on microRNAs-23b. [Methods]1. QRT-PCR was used to detect the sensitivity of chondrosarcoma cells to cisplatin. Expression of microRNAs-23b in chondrosarcoma cell lines, normal chondrocyte lines and chondrosarcoma tissue specimens from patients. 2. Pre-microRNAs and control-microRNAs were transfected into SW1353 cells by liposome 2000 method. Cell proliferation was detected at different time points after transfection. 3. CH-2879 cells and CH-2 cells were cultured under normal conditions. 879 / DDP cells were stimulated by cisplatin for 48 hours. Cell morphological changes were observed under microscope and the expression of microarray-23b was detected by qRT-PCR. 4. According to previous reports, we predicted and verified that Src was the direct target of microarray-23b. 5. Different concentrations of cisplatin were used to treat CH-2879 cells. After 48 hours, the cells were collected and Wester was performed. Pre-microRNA-negative or pre-microRNA-23b were transfected into CH-2879 cells by liposome 2000. The expression of 1microRNA-23b was verified by qRT-PCR. The total Src and phosphorylated Src levels were increased or inhibited by Western blot. Liposome 2000 was used. METHODS: Transfected cells containing wild type (wt) and mutant type (mut) Src 3'UTR were transfected and further validated by luciferase reporter gene assay. 8. Contrl-Mi or pre-Mi-23b were used to transfect CH-2879 cells, SW1353 cells and CH-2879/DDP cells respectively. MTT assay was used to detect the effect of microwave-23b on Src 3'UTR region. Activity: NiR-23b was transfected into CH-2879 cells and CH-2879/DDP cells to observe the effect of microarray-23b overexpression on restoring the sensitivity of chondrosarcoma cells to cisplatin. [Results] 1. The expression of Mi-23b was down-regulated in chondrosarcoma cell lines and samples from patients with chondrosarcoma. 2. The down-regulated expression of Mi-23b in CH-2879/DDP cells suggested that the gene was also involved in the chemotherapeutic tolerance of chondrosarcoma to cisplatin. 3. Src kinase was involved in the proliferation, migration and invasion of various tumors, and Src-Akt pathway in CH-2879/DDP cells. Upregulation of pathway activity 4. Src is the direct target of microRNAs-23b in chondrosarcoma cells 5. Overexpression of microRNAs-23b restores the sensitivity of chondrosarcoma cells to cisplatin by directly inhibiting the Src-Akt pathway. 6. Recovery of Src-Akt pathway activity increases the resistance of microRNAs-23b overexpression chondrosarcoma cells to cisplatin. The down-regulation of R-23b expression in chondrosarcoma cells suggests that it is a tumor suppressor gene and is related to the chemosensitivity of chondrosarcoma to cisplatin. We have confirmed that Src is a direct target of microRNA23b, and Akt is a cytoplasmic serine and threonine used to regulate metabolism, cell cycle progression and cell survival. Acid kinase, microRNA23b, can enhance the sensitivity of chondrosarcoma cells to cisplatin by negatively regulating the Src-Akt pathway, providing a theoretical basis for the treatment strategy of chondrosarcoma based on microRNA23b.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R738

【共引文獻(xiàn)】

相關(guān)期刊論文 前10條

1 李俊;王建中;黃新生;白廣平;童華;周雷;劉建平;;RNAi沉默miRNA-224-5p對(duì)喉鱗狀細(xì)胞癌Hep-2細(xì)胞增殖、凋亡及侵襲能力的影響[J];中國(guó)耳鼻咽喉頭頸外科;2013年09期

2 裴麗玲;李建生;任維華;;miRNAs與肝細(xì)胞癌發(fā)生研究進(jìn)展[J];實(shí)用肝臟病雜志;2014年02期

3 丁琛琛;李瓊;王閣;;miRNA-224通過HOXD10影響Hep3B細(xì)胞遷移[J];第三軍醫(yī)大學(xué)學(xué)報(bào);2014年13期

4 鄧振宇;馮宇鵬;何小科;;NF-κB信號(hào)通路參與miR-183抑制結(jié)腸癌細(xì)胞侵襲和遷移性研究[J];解剖學(xué)研究;2014年03期

5 曾靜;唐瑞雪;何融泉;陳罡;;MicroRNAs在視網(wǎng)膜母細(xì)胞瘤的研究新進(jìn)展[J];國(guó)際眼科雜志;2014年11期

6 趙曉蕾;蔡林;鄧洲銘;;microRNA與骨肉瘤的研究進(jìn)展[J];中國(guó)骨與關(guān)節(jié)雜志;2014年10期

7 王路;余伯龍;岑建華;彭新宇;劉友利;曾芳芳;劉雄;;鼻咽癌患者血漿miR-24異常表達(dá)的臨床意義[J];南方醫(yī)科大學(xué)學(xué)報(bào);2015年05期

8 劉雅瓊;;埃茲蛋白、CD44v6、E-cadherin及β-catenin在宮頸鱗狀細(xì)胞癌中的表達(dá)及與侵襲轉(zhuǎn)移的關(guān)系[J];廣東醫(yī)學(xué);2015年09期

9 喻超;江建新;黎志鵬;肖杰;潘耀振;孫誠(chéng)誼;;microRNA-100對(duì)人胰腺癌細(xì)胞增殖及皮下成瘤能力的影響[J];貴陽醫(yī)學(xué)院學(xué)報(bào);2015年08期

10 朱楠;荊玨華;;骨肉瘤相關(guān)microRNA研究概況[J];臨床骨科雜志;2013年05期

相關(guān)博士學(xué)位論文 前10條

1 范磊;MicroRNA145對(duì)骨肉瘤細(xì)胞增殖和轉(zhuǎn)移等生物學(xué)行為的影響及相關(guān)機(jī)制研究[D];華中科技大學(xué);2013年

2 金一;MicroRNA-376c靶向調(diào)控TGFA抑制骨肉瘤細(xì)胞增殖與轉(zhuǎn)移的研究[D];中南大學(xué);2013年

3 閆康;NKD1參與介導(dǎo)miR-195對(duì)骨肉瘤轉(zhuǎn)移的抑制作用[D];第四軍醫(yī)大學(xué);2013年

4 文錚;CDK5磷酸化Raf激酶抑制蛋白在帕金森病中的作用研究[D];華中科技大學(xué);2013年

5 潘偉波;骨肉瘤細(xì)胞MG63中內(nèi)源性microRNA-27a對(duì)骨肉瘤惡性行為的影響及其調(diào)控靶基因的研究[D];浙江大學(xué);2013年

6 姜茂竹;乳腺癌不同分子亞型差異表達(dá)microRNAs的綜合分析及microRNA-9-5p功能研究[D];南方醫(yī)科大學(xué);2013年

7 趙廣義;microRNA-221在骨肉瘤中作用及機(jī)制的研究[D];第四軍醫(yī)大學(xué);2013年

8 沈克;Has-miR-139調(diào)控人結(jié)腸癌細(xì)胞浸潤(rùn)轉(zhuǎn)移及多藥耐藥的分子機(jī)理研究[D];華東理工大學(xué);2014年

9 郭繼剛;microRNA在神經(jīng)母細(xì)胞瘤轉(zhuǎn)移及骨肉瘤發(fā)生過程中的研究[D];南京大學(xué);2011年

10 霍威;miRNA調(diào)控TRAIL表達(dá)對(duì)前列腺癌細(xì)胞產(chǎn)生選擇性細(xì)胞毒作用[D];吉林大學(xué);2014年

相關(guān)碩士學(xué)位論文 前10條

1 樊智彬;microRNA-224在大腸癌中的表達(dá)及其功能研究[D];河北醫(yī)科大學(xué);2013年

2 蔣慶詳;MicroRNA-429對(duì)膀胱癌細(xì)胞增殖侵襲的影響[D];南華大學(xué);2013年

3 朱英;PAK5和Ezrin基因在骨肉瘤組織中的表達(dá)及其臨床意義[D];蘇州大學(xué);2014年

4 朱楠;MicroRNA-199a-3p對(duì)人骨肉瘤細(xì)胞凋亡的影響[D];安徽醫(yī)科大學(xué);2014年

5 裴麗玲;四種miRNAs在肝細(xì)胞性肝癌中的表達(dá)及意義[D];安徽醫(yī)科大學(xué);2014年

6 陳雪;miR-34а對(duì)肺腺癌細(xì)胞輻射敏感性的影響及其作用機(jī)制的研究[D];中國(guó)疾病預(yù)防控制中心;2013年

7 何涵;miR-98促進(jìn)肝癌發(fā)生發(fā)展機(jī)制初步研究[D];南方醫(yī)科大學(xué);2014年

8 陳鵬;P65、VEGF和MMP-9在骨肉瘤組織中的表達(dá)及臨床病理意義[D];蘇州大學(xué);2013年

9 梁增輝;MiR-183在肝癌中的表達(dá)水平及其臨床意義[D];天津醫(yī)科大學(xué);2014年

10 于開文;黃芩素對(duì)A549肺腺癌細(xì)胞的抗增殖作用及機(jī)制的研究[D];延邊大學(xué);2014年

，

本文編號(hào)：2184733