【摘要】：[背景]肝細(xì)胞肝癌(hepatocellular carcinoma, HCC)是我國(guó)最常見(jiàn)的惡性腫瘤之一,發(fā)病率位居各大惡性腫瘤的第四位,且近年來(lái)呈逐年上升的趨勢(shì)；因其惡性程度高、進(jìn)展十分迅速、預(yù)后極差,死亡率已位居各大惡性腫瘤的第二位。有必要積極探索與HCC相關(guān)的基因,為HCC發(fā)病機(jī)制研究以及臨床診療提供新思路和新靶標(biāo)。長(zhǎng)鏈非編碼RNA (long non-coding RNAs, IncRNAs)是近年來(lái)發(fā)現(xiàn)的與腫瘤發(fā)生、發(fā)展密切相關(guān)的一類缺乏蛋白編碼能力的RNA分子。新近研究表明,lncRNAs可作為競(jìng)爭(zhēng)性內(nèi)源RNA (competing endogenous RNA, ceRNA),通過(guò)其微小RNA反應(yīng)元件(]mniRNA response elements, MREs)競(jìng)爭(zhēng)結(jié)合miRNAs,抑制miRNAs的功能與活性,從而在轉(zhuǎn)錄后水平調(diào)節(jié)miRNAs靶基因mRNAs表達(dá)。UCA1 (Urothelial carcinoma associated 1)是首先在膀胱癌中發(fā)現(xiàn)的一種新的IncRNA分子,文獻(xiàn)報(bào)道其在膀胱癌、結(jié)直腸癌、乳腺癌等腫瘤中高表達(dá)并與腫瘤惡性進(jìn)展密切相關(guān)。但UCA1在HCC中的表達(dá)模式、功能角色及潛在作用機(jī)制尚未見(jiàn)文獻(xiàn)報(bào)道。[目的]探討UCA1在HCC中的表達(dá)模式及臨床意義；分析RNA干擾UCA1對(duì)HCC細(xì)胞增殖、克隆形成、細(xì)胞周期、侵襲與遷移以及裸鼠移植瘤生長(zhǎng)的影響；并深入探討基于ceRNA模式的UCA1--miRNA--mRNA--pathway調(diào)控網(wǎng)絡(luò)在HCC發(fā)生發(fā)展中的作用機(jī)制。[方法](1)1ncRNA芯片篩選HCC癌組織中的IncRNA分子；(2)實(shí)時(shí)熒光定量PCR (Quantitative Real-time PCR, qRT-PCR)驗(yàn)證篩選的UCAl;(3)Fisher精確概率法、Kaplan-Meier生存曲線以及Cox回歸模型分析UCA1表達(dá)與HCC患者臨床病理參數(shù)及預(yù)后的相關(guān)性；(4)構(gòu)建UCA1短發(fā)夾RNA干擾載體,轉(zhuǎn)染高表達(dá)UCA1的HCC細(xì)胞株,檢測(cè)干擾效率；(5)CCK-8法檢測(cè)細(xì)胞增殖、流式細(xì)胞術(shù)檢測(cè)細(xì)胞周期、平板法檢測(cè)細(xì)胞克隆形成、Transwell小室法檢測(cè)細(xì)胞侵襲與遷移以及裸鼠皮下成瘤實(shí)驗(yàn)對(duì)UCA1在HCC中的生物學(xué)功能進(jìn)行分析；(6)生物信息學(xué)預(yù)測(cè)可與UCA1發(fā)生作用的miRNA,以及相應(yīng)miR NA的靶基因；(7)qRT-PCR及免疫組化分析臨床HCC標(biāo)本中UCA1、miRNA以及靶基因三者表達(dá)之間的相關(guān)性；(8)雙熒光素酶試驗(yàn)及RNA結(jié)合蛋白免疫沉淀(RNA Binding Protein Immunoprecipitation, RIP)試驗(yàn)驗(yàn)證UCA1可與miRNA作用于RNA誘導(dǎo)沉默復(fù)合物(RNA-induced silencing complex, RISC); (9)分析UCA1是否可抑制miRNA的生物學(xué)功能；(10)雙熒光素酶試驗(yàn)驗(yàn)證miRNA與靶基因之間的關(guān)系；(11) qRT-PCR與Western blot分析UCA1、miRNA對(duì)其靶基因mRNA及蛋白表達(dá)的影響；(12)Western blot分析與靶基因相關(guān)的信號(hào)通路蛋白及其磷酸化蛋白表達(dá)變化。[結(jié)果](1)通過(guò)IncRNA基因芯片檢測(cè)并且qRT-PCR證實(shí),UCA1在HCC癌組織中表達(dá)明顯高于癌旁組織,P0.001。(2)UCA1與HCC患者TNM分期、是否有遠(yuǎn)距離轉(zhuǎn)移密切相關(guān),P0.001；生存曲線顯示高表達(dá)UCAl的HCC患者總生存時(shí)間明顯縮短,P0.001；單因素及多因素回歸分析顯示UCA1可用于判斷HCC患者的不良預(yù)后。(3)構(gòu)建兩個(gè)針對(duì)UCA1的RNA干擾載體,分別轉(zhuǎn)染高表達(dá)UCA1的HCC細(xì)胞株(SMMC-7721和HepG2細(xì)胞),干擾效率分別為siUCA1#1：81%和78%；siUCAl#2:54%和47%; siUCA1#1+siUCAl#2:66%和60%,選用siUCA1#1干擾載體(即siUCA1)進(jìn)行后繼UCA1功能學(xué)研究。(4)siUCA1轉(zhuǎn)染SMMC-7721和HepG2細(xì)胞后,可體外抑制細(xì)胞增殖、克隆形成能力以及侵襲與遷移,并且誘導(dǎo)HCC細(xì)胞周期G0/G1期阻滯；同時(shí),siUCA1轉(zhuǎn)染HCC細(xì)胞,可體內(nèi)抑制裸鼠移植瘤的生長(zhǎng)。(5)生物信息學(xué)預(yù)測(cè)UCA1序列中存在可與miR-216b、miR-665、miR-326、miR-212-5p、miR-338-3p、 miR-567及 miR-136-3p互補(bǔ)結(jié)合的MREs；在siUCA1轉(zhuǎn)染的HCC細(xì)胞中,僅miR-216b表達(dá)明顯升高(2倍)；而其余6個(gè)miRNAs的表達(dá)無(wú)明顯變化或有輕微變化(1.5倍)。(6)構(gòu)建UCA1的熒光素酶報(bào)告載體,與miR-216b共轉(zhuǎn)染HCC細(xì)胞,雙熒光素酶試驗(yàn)證實(shí)二者可通過(guò)MRE互補(bǔ)結(jié)合；RIP試驗(yàn)進(jìn)一步證實(shí)UCA1與miR-216b相互作用于RISC (7) r niR-216b在HCC癌組織中表達(dá)與癌旁相比明顯降低,P0.01,且HCC癌組織中UCA1與miR-216b的表達(dá)呈顯著負(fù)相關(guān),r=-0.6224, P0.0001。 (8) miR-216b可抑制HCC細(xì)胞的增殖與克隆形成、侵襲與轉(zhuǎn)移、裸鼠移植瘤的生長(zhǎng)以及誘導(dǎo)細(xì)胞周期G0/G1期阻滯；而UCA1可在體、內(nèi)外逆轉(zhuǎn)miR-216b對(duì)HCC細(xì)胞生長(zhǎng)與轉(zhuǎn)移的抑制效應(yīng)。(9)生物信息學(xué)預(yù)測(cè)成纖維生長(zhǎng)因子受體1 (fibroblast growth factor receptor 1, FGFR1)是miR-216b的靶基因之一。雙熒光素酶試證實(shí)FGFR1是miR-216b的靶基因,]miR-216b或siUCA1均可下調(diào)HCC細(xì)胞中FGFR1 mRNA及蛋白的表達(dá)；UCA1過(guò)表達(dá)可上調(diào)FGFR1 mRNA及蛋白的表達(dá)；而當(dāng)miR-216b與UCA1同時(shí)共轉(zhuǎn)染時(shí)可恢復(fù)FGFR1 mRNA及蛋白的表達(dá)。(10)在HCC組織標(biāo)本中,FGFR1蛋白與mRNA的表達(dá)與UCA1的表達(dá)呈顯著正相關(guān),r=0.7114與0.6116,P0.0001；而與miR-216b的表達(dá)呈顯著負(fù)相關(guān),r=-0.5040與-0.7094,P0.0001。(11)Western blot分析顯示,UCA1不是通過(guò)FGFR1-JNK及FGFR1-p38 MAPK信號(hào)通路,而是通過(guò)FGFR1-ERK1/2信號(hào)通路來(lái)促進(jìn)HCC惡性進(jìn)展。[結(jié)論]UCA1在HCC中高表達(dá),且與TNM分期、轉(zhuǎn)移及患者預(yù)后相關(guān)。UCA1可作為一個(gè)癌基因促進(jìn)HCC細(xì)胞增殖、侵襲與遷移以及裸鼠移植瘤的形成。機(jī)制研究發(fā)現(xiàn)UCA1可作為ceRNA競(jìng)爭(zhēng)結(jié)合miR-216 b,可逆轉(zhuǎn)miR-216b對(duì)HCC細(xì)胞的生長(zhǎng)及轉(zhuǎn)移的抑制作用,并解除miR-216b對(duì)其靶基因FGFR1的抑制,FGFR1表達(dá)增高,且通過(guò)ERK信號(hào)(UCA1-miR-216b-FGFR1-ERK pathway)促進(jìn)HCC發(fā)生發(fā)展。本研究為HCC發(fā)病機(jī)制的探索提供了新的思路,也為靶向IncRNAs的HCC診斷與治療提供了新的發(fā)展方向以及新的靶標(biāo)。
[Abstract]:[BACKGROUND] HEPATOCELLULAR CARCINOMA (HCC) is one of the most common malignant tumors in China. The incidence of HCC is the fourth of the major malignant tumors, and has been increasing year by year in recent years, because of its high degree of malignancy, rapid progress and poor prognosis. The mortality rate has been the second in the major malignancies. It is necessary to actively explore the gene related to HCC, and provide a new thought and a new target for the pathogenesis of HCC and the clinical diagnosis and treatment. Long-chain non-coding RNAs (IncRNAs) is a kind of RNA molecule which is closely related to tumorigenesis and development in recent years. Recent studies have shown that lncRNAs can be used as competitive endogenous RNA (cRNA) to compete with miRNAs through its microRNA response elements (MREs) to inhibit the function and activity of miRNAs, so as to regulate the expression of miRNAs target gene mRNAs at the post-transcriptional level. UCA1 (Urodynamic carcinoma associated 1) is a new kind of IncRNA molecule, which is first found in bladder cancer. It is reported that it is highly expressed in bladder cancer, colorectal cancer, breast cancer and other tumors and is closely related to the malignant progression of the tumor. However, the expression pattern, function and potential mechanism of UCA1 in HCC have not been reported in the literature. [Objective] To study the expression pattern and clinical significance of UCA1 in HCC, and to analyze the effect of RNA interference on proliferation, clone formation, cell cycle, invasion and migration of HCC cells and the growth of transplanted tumor in nude mice. The role of UCA1--miRNA--patway control network in the development of HCC was discussed. [Methods] (1)1 ncRNA chip was used to screen the IncRNA molecule in the tissue of HCC. (2) Real-time fluorescence quantitative PCR (qRT-PCR) was used to verify the screening UCAl; (3) Fisher's exact probability method, the Kaplan-Meier survival curve and the Cox regression model were used to analyze the relationship between the expression of UCA1 and the clinicopathological parameters and prognosis of HCC patients. (4) constructing a UCA short hairpin RNA interference vector, transfecting the HCC cell strain with high expression of UCA1, detecting the interference efficiency, (5) detecting cell proliferation by the CCK-8 method, detecting the cell cycle by flow cytometry, and detecting the cell clone formation by the plate method, The biological function of UCA1 in HCC was analyzed by Transwell's cell method, and the biological function of UCA1 in HCC was analyzed by transwell chamber method. (6) Bioinformatics was used to predict the miRNAs that could interact with UCA1 and the target genes of the corresponding miR-NA; (7) qRT-PCR and immunohistochemistry were used to analyze the UCA1 in the clinical HCC specimens. The correlation between the expression of the miRNA and the target gene; (8) the double-luciferase assay and the RNA Binding Protein Immunopreservation (RIP) test verify that the UCA1 and the miRNA act on the RNA-induced silencing complex (RISC); (9) analyzing whether the UCA1 can inhibit the biological function of the miRNA; (10) the double-luciferase test verifies the relation between the miRNA and the target gene; (11) qRT-PCR and Western blot analysis the influence of the UCA1 and the miRNA on the mRNA and the protein expression of the target gene; (12) Western blot was used to analyze the expression of signal pathway protein and its phosphorylated protein in the target gene. [Results] (1) The expression of UCA1 in the tissues of HCC was significantly higher than that in the adjacent tissues (P 0.01). (2) The TNM staging of UCA1 and HCC was closely related to the long-distance metastasis, and the survival time of the HCC patients with high expression of UCAl was significantly shortened in the survival curve, P 0.001; single factor and multi-factor regression analysis showed that UCA1 could be used to judge the poor prognosis of HCC patients. (3) Two cell lines (SMMC-7721 and HepG2 cells) with high expression of UCA1 were constructed, and the interference efficiency was siUCAl # 1:81% and 78% respectively; siUCAl # 2:54% and 47%; siUCAl # 1 + siUCAl # 2:66% and 60%, respectively. A follow-up UCA1 functional study was performed using the siUCA1 # 1 interference vector (i.e., siUCA1). (4) After the SMMC-7721 and HepG2 cells were transfected with siUCA1, the cell proliferation, the formation of the clone and the invasion and migration can be inhibited in vitro, and the cell cycle G0/ G1 arrest of HCC was induced. (5) Bioinformatics predicts that there are MREs that can be complementary to miR-216b, miR-665, miR-326, miR-212-5p, miR-338-3p, miR-567 and miR-136-3p in the UCA1 sequence; in the HCC cells transfected with siUCA1, only miR-216b expression is significantly increased (2-fold); while the expression of the remaining 6 miRNAs has no significant change or slight change (1.5 times). (6) The luciferase reporter vector of UCA1 was constructed, and the HCC cells were co-transfected with miR-216b. The two-luciferase assay confirmed that both of them could be combined by MRE. The RIP test further confirmed that the expression of UCA1 and miR-216b in RISC (7) r niR-216b was significantly lower than that in the adjacent tissues (P0.01). The expression of UCA1 and miR-216b in HCC was negatively correlated with the expression of miR-216b, r =-0.6224, P.0001. (8) miR-216b can inhibit the proliferation and clone formation, invasion and metastasis of HCC cells, the growth of transplanted tumor in nude mice and the induction of cell cycle G0/ G1 phase, and UCA1 can reverse the inhibitory effect of miR-216b on the growth and metastasis of HCC cells. (9) Bioinformatics predicts that the fibroblast growth factor receptor 1 (FGFR1) is one of the target genes of miR-216b. Double-luciferase assay confirmed that FGFR1 is a target gene of miR-216b, and both miR-216b or siUCA1 can downregulate the expression of FGFR1 mRNA and protein in the HCC cell; the overexpression of UCA1 can upregulate the expression of FGFR1 mRNA and protein; and when miR-216b is co-transfected with UCA1, the expression of FGFR1 mRNA and protein can be recovered. (10) In the specimens of HCC, the expression of FGFR1 protein and mRNA was positively correlated with the expression of UCA1, r = 0.7114 and 0.6116, P.0001; while the expression of FGFR1 and miR-216b was negatively correlated with the expression of miR-216b, r =-0.5040 and-0.7094, P.0001. (11) Western blot analysis showed that UCA1 was not a MAPK signal pathway through FGFR1-JNK and FGFR1-p38, but instead of the FGFR1-ERK1/2 signaling pathway, the malignant progression of HCC was promoted. [Conclusion] UCA1 is highly expressed in HCC and is related to TNM staging, metastasis and prognosis of patients. UCA1 can be used as an oncogene to promote the proliferation, invasion and migration of HCC cells and the formation of transplanted tumor in nude mice. The mechanism study found that UCA1 could be used as ceRNA to bind to miR-216b, which could reverse the inhibition of miR-216b on the growth and metastasis of HCC cells, and release the inhibition of miR-216b on the target gene FGFR1, and the expression of FGFR1 was increased, and the development of HCC was promoted by the ERK signal (UCA1-miR-216b-FGFR1-ERK patway). This study provides a new way for the exploration of the pathogenesis of HCC, and also provides a new development direction and a new target for the diagnosis and treatment of HCC.
【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R735.7

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7 聶翠蓉;RNA：縱是配角也精彩[N];科技日?qǐng)?bào);2009年

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9 馮衛(wèi)東　王小龍;英在地球早期環(huán)境模擬條件下合成類RNA[N];科技日?qǐng)?bào);2009年

10 記者 常麗君;新技術(shù)讓研究進(jìn)入單細(xì)胞內(nèi)RNA的世界[N];科技日?qǐng)?bào);2011年

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