本文選題：視網(wǎng)膜母細胞瘤 + 胰島素樣生長因子受體1　； 參考：《武漢大學》2015年博士論文

【摘要】：視網(wǎng)膜母細胞瘤(Retinoblastoma, RB)是最常見的嬰幼兒眼內(nèi)惡性腫瘤,全世界發(fā)病率大約1：20000,我國每年新病例約有1000人,占全世界每年新病例的20%,而存活率僅為63%,對患兒的視力和生命造成極大的威脅和危害,己成為醫(yī)患雙方共同關(guān)注的重點。視網(wǎng)膜母細胞瘤多發(fā)生于5歲以前,可單眼或雙眼發(fā)病,常因患兒瞳孔區(qū)發(fā)白(白瞳癥)或斜視就診,也有晚期出現(xiàn)視力下降、眼球突出、青光眼等才引起家長注意,此時已到晚期,治療效果較差。根據(jù)分期不同,往往采用手術(shù)治療或保存治療。目前國際上推薦采用化學減容法治療取得了良好的效果,是目前RB治療的新趨勢。但由于其不容忽視的毒副作用,眾多學者開始探索尋求新的生物治療方法,基因治療成為熱點。微小RNA (micro-RNA)是一類長度為20-24個核苷酸的非編碼單鏈小分子RNA,廣泛分布于組織和細胞中,參與調(diào)控個體發(fā)育、細胞凋亡、增殖和分化等生命活動,與多種腫瘤的發(fā)生和發(fā)展密切相關(guān),其作用靶點可為抑癌基因,可為癌基因。miRNA-145定位于染色體5q32-33,已經(jīng)在乳腺癌、結(jié)腸癌和淋巴癌等相關(guān)疾病研究中證實其幾乎在所有腫瘤組織中表達下調(diào),能夠抑制腫瘤細胞的增殖和凋亡。但其在視網(wǎng)膜母細胞瘤中的作用及相關(guān)機制研究尚未見報道。胰島素樣生長因子1受體(IGF-1R)屬于酪氨酸蛋白激酶家族,能夠促進細胞增生、轉(zhuǎn)移并抑制細胞凋亡,與腫瘤細胞侵襲、轉(zhuǎn)移、促進新生血管形成等密切相關(guān)。有研究證明,其被配體活化后可通過p-Akt的磷酸化激活PI3K/Akt通路促進脈絡(luò)膜黑色素瘤的侵襲和轉(zhuǎn)移；脈絡(luò)膜黑色素瘤組織高表達IGF-1R也與其發(fā)生轉(zhuǎn)移及預(yù)后呈正相關(guān)。我們推測其在視網(wǎng)膜母細胞瘤中也可能起到了相似作用,但尚無相關(guān)研究證實。本課題首先采用脂質(zhì)體介導的基因轉(zhuǎn)染技術(shù),觀察miRNA-145對視網(wǎng)膜母細胞瘤細胞增殖和凋亡的影響；隨后采用免疫組化方法研究了臨床視網(wǎng)膜母細胞瘤標本中IGF-1R的表達,并通過體外培養(yǎng)的視網(wǎng)膜母細胞瘤細胞細胞系-Y79細胞,對IGF-1R與細胞的增殖和凋亡的關(guān)系進行研究,初步探討了IGF-1R成為視網(wǎng)膜母細胞瘤的治療新靶點的可能性。最后對miR-145和IGF-1R對人視網(wǎng)膜母細胞瘤細胞的調(diào)控機制進行了進一步的探索,為探索治療視網(wǎng)膜母細胞瘤的新手段提供實驗依據(jù)。本課題包括以下三部分內(nèi)容：第一部分Mir-145對視網(wǎng)膜母細胞瘤Y79細胞增殖和凋亡的影響目的：探討MicroRNA 145(miR-145)對視網(wǎng)膜母細胞瘤Y79細胞的增殖和凋亡的影響。方法：將人視網(wǎng)膜母細胞瘤細胞株Y79分為四組：miR-145干預(yù)組、陰性miRNA對照組、空脂質(zhì)體組、空白對照組。脂質(zhì)體轉(zhuǎn)染法將miR-145轉(zhuǎn)入Y79細胞；熒光定量PCR檢測轉(zhuǎn)染后48h成熟miR-145的表達；CCK-8法檢測轉(zhuǎn)染48h后的細胞增殖抑制率；流式細胞術(shù)檢測細胞周期；Annexin V/PI免疫熒光雙染色和流式細胞術(shù)檢測細胞凋亡。通過單因素方差分析分析比較各組數(shù)據(jù)。結(jié)果：采用脂質(zhì)體轉(zhuǎn)染方法,成功將miR-145轉(zhuǎn)染至Y79細胞；熒光定量PCR顯示：miR-145干預(yù)組成熟miR-145表達(79.06±3.45)明顯增加,與陰性miRNA對照組(1.06±0.03)、空脂質(zhì)體組(0.93±0.02)和空白組(1.00±0.02)比較,差異有統(tǒng)計學意義(F=229.853,P0.05)；miR-145干預(yù)組的增殖抑制率(21.64%)明顯高于陰性miRNA對照組(2.57%)、空脂質(zhì)體組(3.97%)(F=34.13,P0.05)；miR-145抑制Y79細胞周期于G1期(P0.01)；Annexin V/PI免疫熒光雙染色和流式細胞術(shù)顯示miR-145干預(yù)組Annexin V陽性和Annexin V/PI雙陽性細胞明顯增多,陽性率明顯高于其他三組,差異有統(tǒng)計學意義(F=35.434,P0.05)。結(jié)論：miR-145可以抑制視網(wǎng)膜母細胞瘤細胞Y79的增殖,誘導細胞凋亡。第二部分IGF-1R在視網(wǎng)膜母細胞瘤中的表達和作用目的：研究IGF-1R對人視網(wǎng)膜母細胞瘤細胞的增殖和凋亡的影響。方法：免疫組化法檢測IGF-1R在人視網(wǎng)膜母細胞瘤組織中的表達。培養(yǎng)人視網(wǎng)膜母細胞瘤細胞Y79后并分為三組：IGF-1R siRNA干預(yù)組、陰性siRNA對照組、空白對照組。以脂質(zhì)體為載體把小干擾RNA (IGF-1R siRNA)導入Y79細胞；Real-Time PCR分析RNA干擾后IGF-1R mRNA的水平；Western blot檢測IGF-1R蛋白表達水平；CCK-8法檢測轉(zhuǎn)染24h后的細胞增殖抑制率；Annexin V/PI免疫熒光雙染色和流式細胞術(shù)檢測細胞凋亡。通過單因素方差分析分析比較各組數(shù)據(jù)。結(jié)果：免疫組化法證實IGF-1R在人視網(wǎng)膜母細胞瘤細胞中有表達；小干擾RNA (IGF-1R siRNA)靶向阻止IGF-1R基因在Y79細胞中的表達；Real-Time PCR提示：siRNA組(0.426)的IGF-1R mRNA的基因表達明顯下降,與陰性對照組(0.983)和空白對照組(1.000)相比,差異有統(tǒng)計學意義(P0.01); Western blot檢測顯示siRNA組的IGF-1R蛋白表達水平分別為陰性siRNA對照組的22.4%,空白對照組的24.0%；CCK-8檢測細胞提示siRNA組的A值(0.30)低于CSI組(0.40)和NC(0.42),差異有顯著差異(P0.05)。Annexin V/PI雙染色結(jié)合流式檢測細胞凋亡結(jié)果顯示：siRNA組Annexin V率為28.9%,明顯高于陰性對照組(6.4%)和空白對照組(6.6%),差異具有統(tǒng)計學意義(P0.01)。結(jié)論：IGF-1R在人視網(wǎng)膜母細胞瘤細胞中表達,且通過特異性降低IGF-1R蛋白表達,能夠抑制Y79細胞的增殖。第三部分 miR-145通過抑制IGF-1R的表達來調(diào)控視網(wǎng)膜母細胞瘤細胞的增殖和凋亡目的：研究miR-145調(diào)控視網(wǎng)膜母細胞瘤細胞的增殖和凋亡的機制。方法：培養(yǎng)人視網(wǎng)膜母細胞瘤細胞株Y79后,將實驗分為三組：實驗分為三組：miR-145mimics干預(yù)組、陰性miRNA對照組、空白對照組。Real-Time PCR分析IGF-1R的mRNA的水平；Western blot檢測IGF-1R蛋白的表達水平。構(gòu)建pMIR-REPORT-IGF-1R 3'-UTR熒光素酶質(zhì)粒。熒光素酶活性檢測法檢測miR-145與IGF-1R3'-UTR之間的相互作用。各組數(shù)據(jù)的比較采用單因素方差分析。結(jié)果：Real-Time PCR結(jié)果提示miR-145mimics干預(yù)組的IGF-1R mRNA的量明顯下降(0.498),與陰性miRNA對照組為(0.951)和空白對照組(1)相比,差異有顯著意義(P0.05)。Western blot檢測顯示miR-145組的IGF-1R蛋白表達水平明下降,與陰性miRNA對照組為(0.951)和空白對照組(1)相比,差異具有統(tǒng)計學意義(P0.01)。熒光素酶活性檢測顯示miR-145干預(yù)組的螢火蟲熒光素酶的活性明顯降低(P0.01),提示miR-145與IGF-1R的發(fā)生相互作用。結(jié)論：miR-145可以通過降低IGF-1R的表達來抑制人網(wǎng)膜母細胞瘤細胞Y79的增殖。
[Abstract]:Retinoblastoma (RB) is the most common intraocular malignant tumor in infants and infants. The incidence of the disease is about 1:20000 in the world. There are about 1000 new cases in China each year, accounting for 20% of the new cases in the world, and the survival rate is only 63%. It has made a great threat and harm to the children's vision and life. It has become a common relationship between the doctors and patients. The focal point of note. Retinoblastoma occurs more than 5 years old, can monocular or binocular disease, often because of children's pupil white (white pupil) or strabismus treatment, also have late appearance of vision decline, eye protrusion, glaucoma, and so on to the parents attention, this time to the late, treatment effect is poor. According to different stages, often use surgical treatment or Conservation therapy is a new trend in RB therapy at present. However, because of its toxic and side effects that can not be ignored, many scholars have begun to explore new biotherapy methods. Gene therapy has become a hot spot. Small RNA (micro-RNA) is a class of 20-24 nucleotides. RNA, a small single strand of small molecule, is widely distributed in tissues and cells. It participates in the regulation of individual development, apoptosis, proliferation and differentiation. It is closely related to the occurrence and development of various tumors. The target can be the tumor suppressor gene and the oncogene.MiRNA-145 is located in chromosome 5q32-33. It has been found in breast, colon and lymphatic cancer. In the study of related diseases, it is confirmed that it is almost down-regulated in all tumor tissues and can inhibit the proliferation and apoptosis of tumor cells. However, the study of its role in retinoblastoma and its related mechanism have not yet been reported. The insulin like growth factor 1 receptor (IGF-1R) belongs to the tyrosine protein kinase family, which can promote cell proliferation and transfer. Migration and inhibition of apoptosis are closely related to the invasion, metastasis and angiogenesis of tumor cells. Studies have shown that the ligand activation can activate the PI3K/Akt pathway through the phosphorylation of p-Akt to promote the invasion and metastasis of choroidal melanoma, and the high expression of IGF-1R in the choroidal melanoma tissue is also associated with its metastasis and prognosis. We speculate that it may also play a similar role in retinoblastoma, but there is no related research yet. Firstly, the effect of miRNA-145 on the proliferation and apoptosis of retinoblastoma cells was observed by liposome mediated gene transfection, and then the clinical retina was studied by immunohistochemical method. The expression of IGF-1R in the tumor of the mother cell tumor and the relationship between the proliferation and apoptosis of IGF-1R and cell by -Y79 cells cultured in vitro, the possibility of IGF-1R as a new target for the treatment of retinoblastoma is preliminarily discussed. The latter is the latter to the retinoblastoma of human retinoblastoma and the human retinoblastoma of the human retinoblastoma. The mechanism of cell regulation has been further explored to provide experimental basis for the exploration of the novice segment of retinoblastoma. This topic includes the following three parts: the first part: the effect of Mir-145 on the proliferation and apoptosis of Y79 cells in retinoblastoma: To explore the Y79 fine of MicroRNA 145 (miR-145) for retinoblastoma Effect of cell proliferation and apoptosis. Methods: the human retinoblastoma cell line Y79 was divided into four groups: miR-145 intervention group, negative miRNA control group, empty liposome group, blank control group. MiR-145 was transferred into Y79 cells by liposome transfection; fluorescence quantitative PCR was used to detect the expression of 48h mature miR-145 after transfection; CCK-8 method was used to detect the transfection of 48h. Cell proliferation inhibition rate; flow cytometry to detect cell cycle; Annexin V/PI immunofluorescence double staining and flow cytometry to detect cell apoptosis. The data were compared and analyzed by single factor analysis of variance. Results: the transfection method of liposome was used to transfect miR-145 to Y79 cells successfully; fluorescence quantitative PCR showed miR-145 intervention composition The expression of mature miR-145 (79.06 + 3.45) was significantly increased, compared with negative miRNA control group (1.06 + 0.03), empty liposome group (0.93 + 0.02) and blank group (1 + 0.02), the difference was statistically significant (F=229.853, P0.05), and the proliferation inhibition rate (21.64%) in miR-145 intervention group was significantly higher than that of negative miRNA control group (2.57%), and air liposome group (3.97%) (F=34.13, P0.05). MiR-145 inhibited Y79 cell cycle in G1 phase (P0.01), Annexin V/PI immunofluorescence double staining and flow cytometry showed that Annexin V positive and Annexin V/PI double positive cells increased significantly in miR-145 intervention group, and the positive rate was significantly higher than those of the other three groups, the difference was statistically significant (F= 35.434). The proliferation and apoptosis of cell Y79, inducing apoptosis. Second part IGF-1R expression in retinoblastoma and its purpose: To study the effect of IGF-1R on the proliferation and apoptosis of human retinoblastoma cells. Methods: immunohistochemical method was used to detect the expression of IGF-1R in human retinoblastoma tissue. The tumor cell Y79 was divided into three groups: the IGF-1R siRNA intervention group, the negative siRNA control group and the blank control group. The small interference RNA (IGF-1R siRNA) was introduced into Y79 cells with liposome as the carrier; Real-Time PCR was used to analyze the level of IGF-1R protein after RNA interference; The rate of colonization, Annexin V/PI immunofluorescence double staining and flow cytometry were used to detect cell apoptosis. The data were compared and analyzed by single factor analysis of variance. Results: immunohistochemistry showed that IGF-1R was expressed in human retinoblastoma cells; small interference RNA (IGF-1R siRNA) targeting the expression of IGF-1R gene in Y79 cells; Real-Time PCR indicated that the gene expression of IGF-1R mRNA in group siRNA (0.426) decreased significantly, compared with negative control group (0.983) and blank control group (1), the difference was statistically significant (P0.01); Western blot detection showed that the expression level of IGF-1R protein in siRNA group was divided into 22.4% of negative siRNA control group and 24% in blank control group; Detection cells suggested that the A value of siRNA group (0.30) was lower than that of group CSI (0.40) and NC (0.42). The difference was significant (P0.05).Annexin V/PI double staining combined flow cytometry showed that the Annexin V rate of siRNA group was 28.9%, which was significantly higher than that of negative control group (6.4%) and blank control group (6.6%). The difference was statistically significant (P0.01). Conclusion: IGF- 1R is expressed in human retinoblastoma cells and can inhibit the proliferation of Y79 cells by specific reduction of the expression of IGF-1R protein. Third part miR-145 regulates the proliferation and apoptosis of retinoblastoma cells by inhibiting the expression of IGF-1R: the study of miR-145 regulating the proliferation and apoptosis of retinoblastoma cells of retinoblastoma Methods: after training the human retinoblastoma cell line Y79, the experiment was divided into three groups: the experiment was divided into three groups: the miR-145mimics intervention group, the negative miRNA control group, the blank control group.Real-Time PCR analysis of IGF-1R mRNA level; Western blot detected the expression level of IGF-1R protein. Construction pMIR-REPORT-IGF-1R 3'-UTR luciferase The interaction between miR-145 and IGF-1R3'-UTR was detected by the assay of luciferase activity. The data of each group were compared by single factor variance analysis. Results: the results of Real-Time PCR showed that the amount of IGF-1R mRNA in the miR-145mimics intervention group decreased significantly (0.498), compared with the negative miRNA control group (0.951) and the blank control group (1). The significant (P0.05).Western blot detection showed that the expression level of IGF-1R protein in the miR-145 group decreased obviously, compared with the negative miRNA control group (0.951) and the blank control group (1), the difference was statistically significant (P0.01). The luciferase activity in miR-145 intervention group was significantly decreased (P0.01), suggesting miR-145 (P0.01), suggesting miR-145. Conclusion: miR-145 can inhibit the proliferation of human omentoma cell line Y79 by decreasing the expression of IGF-1R. IGF-1R
【學位授予單位】：武漢大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R739.7

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