【摘要】：口腔鱗狀細(xì)胞癌(Oral squamous cell carcinoma,OSCC)是口腔惡性腫瘤中最常見(jiàn)的一類(lèi),且較易早期發(fā)生淋巴結(jié)轉(zhuǎn)移;發(fā)病率每年仍在不斷增長(zhǎng)。癌癥雖然成因復(fù)雜,不能一概而論,但是多年來(lái),學(xué)者們一直致力于從遺傳,環(huán)境,基因等多個(gè)層面研究惡性腫瘤形成機(jī)制,以期可以從根源上預(yù)防惡性腫瘤的發(fā)生,并找到更好的診斷、治療惡性腫瘤的方法。本文著重于研究口腔鱗癌淋巴結(jié)轉(zhuǎn)移的分子通路,細(xì)胞信號(hào)通路并對(duì)關(guān)鍵環(huán)節(jié)加以阻斷,試圖尋找診治口腔鱗狀細(xì)胞癌的新靶點(diǎn)。細(xì)胞癌變和轉(zhuǎn)移是一個(gè)多因素、多基因、多環(huán)節(jié)參與的復(fù)雜過(guò)程,其中有著復(fù)雜的基因調(diào)控因素。近幾年研究發(fā)現(xiàn)長(zhǎng)鏈非編碼RNA(long non-coding RNA,lnc RNAs)在細(xì)胞發(fā)育和代謝以及腫瘤的發(fā)生發(fā)展過(guò)程中發(fā)揮著重要的作用。某些腫瘤根本不存在蛋白質(zhì)編碼基因的變異,而只有l(wèi)nc RNAs的表達(dá)異常,幾個(gè)lnc RNAs就可以使轉(zhuǎn)錄過(guò)程發(fā)生改變。肺腺癌轉(zhuǎn)移相關(guān)轉(zhuǎn)錄本1(metastasis-associated lung adenocarcinoma transcript1,MALAT-1)是第一個(gè)被發(fā)現(xiàn)與腫瘤轉(zhuǎn)移能力可能相關(guān)的lnc RNAs。MALAT-1在RNA聚合酶Ⅱ作用下合成,其表達(dá)產(chǎn)物定位于核散斑中,而參與m RNA前體加工的絲氨酸/精氨酸富集蛋白家族(serine/arginine richedprotein,SR protein,SR蛋白家族)也定位于核散斑中,基于兩者的共定位關(guān)系,有學(xué)者通過(guò)一系列研究發(fā)現(xiàn)MALAT-1與SR蛋白磷酸化直接相關(guān)。MALAT-1在核散斑的定位是調(diào)控SR蛋白家族成員表達(dá),定位和活化的結(jié)構(gòu)基礎(chǔ),有研究證實(shí),MALAT-1與miRNA-320s關(guān)系密切,MALAT-1可調(diào)控下游hsa-miR-320a(hsa-miRNA-320s家族的成員之一)的表達(dá)。Y盒結(jié)合蛋白(Y-box binding protein 1,YB-1)由編碼蛋白質(zhì)基因YB-1編碼,是一種多功能冷休克蛋白,具有結(jié)合核酸的功能,被認(rèn)為是一種腫瘤蛋白,涉及腫瘤細(xì)胞增殖與凋亡過(guò)程的許多方面;有研究發(fā)現(xiàn)YB-1可以結(jié)合至hsa-miRNA-320s之后參與調(diào)節(jié)miRNA的表達(dá)和調(diào)控。晚近宏基因組學(xué)生物信息分析數(shù)據(jù)顯示,趨化因子受體CCR7的靶基因之一可能是hsa-miR-320a,目前尚無(wú)該方面實(shí)證研究文獻(xiàn)支持。腫瘤細(xì)胞遷移具有靶向組織特異性。向特定組織遷移的分子調(diào)控過(guò)程類(lèi)似于炎癥反應(yīng)中免疫細(xì)胞的浸潤(rùn)與遷移,趨化因子及其受體在腫瘤的發(fā)生、浸潤(rùn)與轉(zhuǎn)移及預(yù)后均有密切關(guān)系。趨化因子及其受體在腫瘤細(xì)胞選擇性轉(zhuǎn)移向特定組織器官產(chǎn)生作用已得到眾多文獻(xiàn)研究支持,研究表明趨化因子及其受體調(diào)控腫瘤細(xì)胞淋巴結(jié)轉(zhuǎn)移過(guò)程,類(lèi)似趨化因子在炎癥過(guò)程中調(diào)節(jié)免疫細(xì)胞的遷移。本課題組前期研究及有文獻(xiàn)研究均表明趨化因子受體CCR7在口腔鱗癌淋巴結(jié)轉(zhuǎn)移中具有重要作用。綜上所述,提出以下假設(shè):MALAT-1通過(guò)活化SR蛋白或YB-1蛋白,調(diào)控趨化因子受體m RNA前體miRNA-320s的加工,影響趨化因子受體CCR7在口腔鱗癌中的表達(dá),從而可能對(duì)口腔鱗癌淋巴結(jié)轉(zhuǎn)移行為造成影響。課題研究分三個(gè)部分:1、實(shí)時(shí)熒光定量檢測(cè)口腔鱗癌組織標(biāo)本,定性觀察MALAT-1、miRNA-320s、SRSF1、YB-1、CCR7等分子表達(dá)情況;2、人舌癌細(xì)胞株SCC-9、SCC-25,在細(xì)胞水平,通過(guò)免疫共沉淀、免疫印跡法檢驗(yàn)相關(guān)RNA(MALAT-1,miRNA-320s)與SRSF1蛋白或YB-1的相關(guān)性;3、通過(guò)基因調(diào)控技術(shù)轉(zhuǎn)染miRNA inhibitor沉默miRNA-320s后進(jìn)行免疫共沉淀、免疫印跡及實(shí)時(shí)熒光定量檢測(cè)趨化因子受體CCR7的表達(dá),并分析可能存在的相互關(guān)系。創(chuàng)新:本課題的創(chuàng)新之處在于首次發(fā)現(xiàn)了在口腔鱗癌細(xì)胞株中看到長(zhǎng)鏈非編碼RNA MALAT-1與趨化因子受體CCR7間的相互作用。在口腔鱗癌組織標(biāo)本中看到了MALAT-1與CCR7呈正相關(guān)關(guān)系;在人舌癌細(xì)胞株中看到了MALAT-1、SRSF1、miRNA-320d間可以相互結(jié)合,且miRNA-320d可以影響CCR7的表達(dá)。以上MALAT-1影響CCR7表達(dá)的可能分子通路尚未見(jiàn)文獻(xiàn)報(bào)道�！狙芯糠椒ā康谝徊糠�:實(shí)時(shí)熒光定量檢測(cè)定性觀察MALAT-1、miRNA-320s、SRSF1、YB-1、CCR7等分子在口腔鱗癌組織及癌旁組織中的表達(dá)1.切取、保存口腔鱗癌及癌旁組織標(biāo)本術(shù)中切取少量T3/T4期口腔癌組織及癌旁組織6組置于凍存管,由病理科鑒定為口腔鱗癌組織,以有無(wú)淋巴結(jié)轉(zhuǎn)移分為兩組,-80℃冰箱保存?zhèn)溆谩?.實(shí)時(shí)熒光定量PCR檢測(cè)口腔鱗癌及癌旁組織中MALAT1,SRSF1,miRNA-320s,YB-1及CCR7的表達(dá)差異。2.1 TRIZOL法抽提總RNA。2.2 RNA逆轉(zhuǎn)錄為c DNA。2.3 Real-time q PCR檢測(cè)目標(biāo)分子表達(dá)量。3.統(tǒng)計(jì)分析利用SPSS19.0及Graphpad prism 7.0對(duì)得到的實(shí)時(shí)熒光定量數(shù)據(jù)進(jìn)行統(tǒng)計(jì)分析,對(duì)計(jì)量資料兩組間采用配對(duì)t檢驗(yàn),以P≤0.05為標(biāo)準(zhǔn)視為差異具有統(tǒng)計(jì)學(xué)意義。第二部分:舌癌細(xì)胞株的相關(guān)RNA(MALAT-1,miRNA-320s)與SRSF1蛋白或YB-1的相關(guān)性研究1.細(xì)胞培養(yǎng)人舌鱗癌細(xì)胞株(SCC9、SCC25),在含有10%胎牛血清的DMEM高糖完全培養(yǎng)基中傳代培養(yǎng),37℃,5%CO_2,95%飽和濕度,傳至第六代細(xì)胞供本實(shí)驗(yàn)使用。2.RNA與蛋白質(zhì)結(jié)合免疫共沉淀2.1實(shí)驗(yàn)分組(1)對(duì)照組:加入RIP試劑盒內(nèi)提供的陰性對(duì)照兔抗;(2)實(shí)驗(yàn)組1:加入抗SF2抗體的RIP復(fù)合物;(3)實(shí)驗(yàn)組2:加入抗YB-1抗體的RIP復(fù)合物;2.2實(shí)驗(yàn)方法使用Sigma公司的免疫共沉淀試劑盒進(jìn)行RNA結(jié)合蛋白免疫共沉淀,檢測(cè)有無(wú)RNA-抗體-蛋白質(zhì)復(fù)合物的存在。3.免疫印跡實(shí)驗(yàn)檢測(cè)細(xì)胞裂解產(chǎn)物的表達(dá)及RIP復(fù)合物的表達(dá)。將細(xì)胞裂解產(chǎn)物用免疫印跡實(shí)驗(yàn)檢測(cè)裂解效率即目的分子的顯色條帶,并檢測(cè)免疫共沉淀實(shí)驗(yàn)的復(fù)合物表達(dá)情況。4.實(shí)時(shí)熒光定量PCR4.1免疫共沉淀實(shí)驗(yàn)中的RNA-抗體-蛋白質(zhì)復(fù)合物濃度、純度檢驗(yàn)。4.2 RNA逆轉(zhuǎn)錄為c DNA。4.3 Real-time q PCR。5.統(tǒng)計(jì)分析:Graphpad prism 7.0對(duì)得到的實(shí)時(shí)熒光定量數(shù)據(jù)進(jìn)行統(tǒng)計(jì)分析,對(duì)計(jì)量資料兩組間采用配對(duì)t檢驗(yàn),以P≤0.05為標(biāo)準(zhǔn)視為差異具有統(tǒng)計(jì)學(xué)意義。第三部分:基因調(diào)控技術(shù)沉默miRNA-320d,觀察CCR7的表達(dá)根據(jù)第二部分實(shí)驗(yàn)結(jié)果:hsa-miRNA-320d(hsa-miRNA-320s家族成員之一,篩選了a、b、d、e)與MALAT-1具有相關(guān)關(guān)系。1.細(xì)胞miRNA-320d inhibitor轉(zhuǎn)染1.1分組(1)對(duì)照組:miRNA Inhibitor Negative Control#1(4464058);(2)實(shí)驗(yàn)組:miRNA-320d inhibitor(4464066);1.2方法使用Lipofectamine公司的RNAi MAX轉(zhuǎn)染試劑盒進(jìn)行細(xì)胞miRNA inhibitor轉(zhuǎn)染,沉默細(xì)胞內(nèi)miRNA-320d。2.免疫印跡實(shí)驗(yàn)檢測(cè)轉(zhuǎn)染后細(xì)胞裂解產(chǎn)物的表達(dá)及RIP復(fù)合物的表達(dá)。將細(xì)胞裂解產(chǎn)物用免疫印跡實(shí)驗(yàn)檢測(cè)裂解效率即目的分子的表達(dá)情況,并檢測(cè)免疫共沉淀實(shí)驗(yàn)的復(fù)合物表達(dá)情況。3.實(shí)時(shí)熒光定量PCR3.1轉(zhuǎn)染后的RIP復(fù)合物純度、濃度檢測(cè);3.2 RNA逆轉(zhuǎn)錄為c DNA;3.3 Real-time q PCR。4.統(tǒng)計(jì)分析:Graphpad prism 7.0對(duì)得到的實(shí)時(shí)熒光定量數(shù)據(jù)進(jìn)行統(tǒng)計(jì)分析,對(duì)計(jì)量資料兩組間采用配對(duì)t檢驗(yàn),以P≤0.05為標(biāo)準(zhǔn)視為差異具有統(tǒng)計(jì)學(xué)意義。【結(jié)果】第一部分:實(shí)時(shí)熒光定量檢測(cè)定性觀察MALAT-1、miRNA-320s、SRSF1、YB-1、CCR7等分子在口腔鱗癌組織及癌旁組織中的表達(dá)1.MALAT-1、SRSF1、YB-1、CCR7在淋巴結(jié)轉(zhuǎn)移組的口腔鱗癌組織中的表達(dá)高于無(wú)淋巴結(jié)轉(zhuǎn)移組且高于癌旁組織。(P0.01)2.miRNA-320d在淋巴結(jié)轉(zhuǎn)移組的口腔鱗癌組織中的表達(dá)低于無(wú)淋巴結(jié)轉(zhuǎn)移組。(P≤0.05)第二部分:舌癌細(xì)胞株的相關(guān)RNA(MALAT-1,miRNA-320s)與SRSF1蛋白或YB-1的相關(guān)性研究1.MALAT-1可以與SRSF1相互結(jié)合。(見(jiàn)WB條帶及實(shí)時(shí)熒光定量統(tǒng)計(jì)分析)2.miRNA-320d(miRNA-320s家族系列中的一員)與SRSF1可以相互結(jié)合(見(jiàn)WB條帶及實(shí)時(shí)熒光定量統(tǒng)計(jì)分析)3.MALAT-1、miRNA-320d與YB-1未見(jiàn)結(jié)合。(見(jiàn)WB條帶)結(jié)果表明:MALAT-1,miRNA-320d通過(guò)SRSF1有相互結(jié)合。第三部分:基因調(diào)控技術(shù)沉默miRNA-320d,觀察CCR7的表達(dá)轉(zhuǎn)染沉默miRNA-320d后抑制了基因的表達(dá),同時(shí)觀察到CCR7表達(dá)量升高,證明miRNA-320d與CCR7之間存在相互作用�！窘Y(jié)論】1.通過(guò)實(shí)時(shí)熒光定量檢測(cè)定性觀察發(fā)現(xiàn)淋巴結(jié)轉(zhuǎn)移組lnc RNA MALAT-1、SRSF1、CCR7相對(duì)于無(wú)淋巴結(jié)轉(zhuǎn)移組均有不同程度高表達(dá);2.通過(guò)免疫共沉淀、免疫印跡法檢驗(yàn)發(fā)現(xiàn)相關(guān)RNA(MALAT-1,miRNA-320d)通過(guò)SRSF1蛋白可以互相結(jié)合;3.實(shí)時(shí)熒光法定量RNA-蛋白質(zhì)復(fù)合物中MALAT-1,miRNA-320s的含量,MALAT-1,miRNA-320d通過(guò)SRSF1有相互結(jié)合;4.基因調(diào)控技術(shù)沉默miRNA-320s,免疫共沉淀、免疫印跡及實(shí)時(shí)熒光定量實(shí)驗(yàn)發(fā)現(xiàn)趨化因子受體CCR7的表達(dá)增強(qiáng),可以推論MALAT-1、SRSF1、miRNA-320d、CCR7間存在相互作用關(guān)系,從分子層面揭示MALAT-1對(duì)趨化因子受體CCR7的影響,為以MALAT-1為分子靶向的口腔鱗癌淋巴結(jié)轉(zhuǎn)移相關(guān)基礎(chǔ)與應(yīng)用的進(jìn)一步研究提供一定理論基礎(chǔ)。
[Abstract]:Oral squamous cell carcinoma (OSCC) is the most common type of oral malignancies, and is prone to early lymph node metastasis; the incidence is still growing every year. This paper focuses on the molecular pathway of lymph node metastasis in oral squamous cell carcinoma, the cell signaling pathway and the blockade of the key links, trying to find a new target for the diagnosis and treatment of oral squamous cell carcinoma. Carcinogenesis and metastasis is a complex process involving many factors, genes and links, among which there are complex gene regulatory factors. In recent years, studies have found that long non-coding RNA (lnc RNAs) plays an important role in cell development and metabolism, as well as in the occurrence and development of tumors. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) was the first to be found to be associated with tumor metastasis. Synthesized under the action of II, the expressed products are localized in nuclear speckles, and the serine/arginine rich protein family (SR protein, SR protein family) involved in the processing of M RNA precursors is also localized in nuclear speckles. Based on the co-localization relationship between the two proteins, a series of studies have found that MALAT-1 and SR protein phosphorylation. The localization of MALAT-1 in nuclear speckles is the structural basis for regulating the expression, localization and activation of SR protein family members. Studies have confirmed that MALAT-1 is closely related to microRNAs-320s. MALAT-1 can regulate the expression of downstream hsa-microRNAs-320a (a member of the hsa-microRNAs-320s family). Y-box binding protein 1 (YB-1) is a coding protein. YB-1 is a multifunctional cold shock protein that binds nucleic acids and is considered to be a tumor protein involved in many aspects of the proliferation and apoptosis of tumor cells. The data show that one of the target genes of chemokine receptor CCR7 may be hsa-microRNA-320a, and there is no empirical literature to support this aspect.Tumor cell migration has tissue-specific targeting.The molecular regulation of migration to specific tissues is similar to the infiltration and migration of immune cells in inflammatory reaction, and chemokines and chemokine receptors in tumors. Chemokines and chemokine receptors have been supported by many literatures. Chemokines and chemokine receptors have been shown to regulate lymph node metastasis of tumor cells, and chemokines like chemokines regulate immunity during inflammation. In summary, the following hypothesis is proposed: MALAT-1 regulates chemokine receptor m RNA precursor microRNA-320s processing by activating SR protein or YB-1 protein, affecting chemokine receptor CCR7. The research is divided into three parts: 1. Real-time fluorescence quantitative detection of oral squamous cell carcinoma tissue samples, qualitative observation of MALAT-1, microRNA-320s, SRSF1, YB-1, CCR7 and other molecular expression; 2, human tongue cancer cell lines SCC-9, SCC-25, at the cellular level, through immunization. Co-precipitation, Western blot assay was used to detect the correlation between RNA (MALAT-1, microRNAs-320s) and SRSF1 protein or YB-1; 3. MiNA inhibitor silenced microRNAs-320s was transfected by gene regulation technology, then co-precipitated by immunoblotting and real-time fluorescence quantitative detection of chemokine receptor CCR7 expression, and to analyze the possible correlation. The innovation of this study is that the interaction between long-stranded non-coding RNA MALAT-1 and chemokine receptor CCR7 was found in oral squamous cell carcinoma cell lines for the first time. The possible molecular pathways of MALAT-1 affecting CCR7 expression have not been reported in literature. [Methods] Part 1: Qualitative observation of the expression of MALAT-1, microRNA320s, SRSF1, YB-1, CCR7 in oral squamous cell carcinoma and adjacent tissues by real-time fluorescence quantitative detection. Six groups of oral squamous cell carcinoma (OSCC) tissues and adjacent tissues (T3/T4 stage) were harvested and placed in cryopreserved tubes. The specimens were divided into two groups with or without lymph node metastasis. 2. The expressions of MALAT1, SRSF1, microRNA-320s, YB-1 and CCR7 in OSCC and adjacent tissues were detected by real-time quantitative PCR. Difference.2.1 Total RNA.2.2 RNA was retrieved by TRIZOL and the expression of target molecule was detected by C DNA.2.3 Real-time Q PCR. Part 2: Correlation between the expression of related RNA (MALAT-1, microRNA-320s) and SRSF1 protein or YB-1 in tongue cancer cell lines 1. Human tongue squamous cell carcinoma cell lines (SCC9, SCC25) were subcultured in DMEM high glucose complete medium containing 10% fetal bovine serum at 37 C, 5% CO_2, 95% saturated humidity and passed to the sixth generation cells for use in this experiment. Protein-binding immunoprecipitation 2.1 experimental group (1) control group: adding negative control rabbit anti-RIP kit; (2) experimental group 1: adding anti-SF2 antibody RIP complex; (3) experimental group 2: adding anti-YB-1 antibody RIP complex; 2.2 experimental method using Sigma company's immunoprecipitation kit for RNA-binding protein immunoprecipitation 3. Immunoblotting assay was used to detect the expression of cell lysate products and RIP complex. Immunoblotting assay was used to detect the color bands of the target molecule whose lysis efficiency was the target molecule. Immunocoprecipitation assay was used to detect the complex expression. 4. Real-time fluorescence quantitative analysis. The concentration and purity of RNA-antibody-protein complex in PCR 4.1 immunoprecipitation assay were tested. Part 3: Gene regulation technique silenced microRNAs-320d. CCR7 expression was observed according to the second part of the experiment: hsa-microRNAs-320d (hsa-microRNAs-320s family members, screened a, b, d, e) and MALAT-1 has a correlation. 1. Cell microRNAs-320d inhibitor transfection 1.1 grouping (1) control group: MiRNA Inhibitor Negative Control #1 (control group: MiRNA Inhibitor Negative Control #1) 4464058; (2) Experimental group: MiRNA-320d inhibitor (4464066); 1. Real-time fluorescence quantitative PCR 3.1 transfected RIP complex purity, concentration detection; 3.2 RNA reverse transcription into C DNA; 3.3 Real-time Q PCR.4. Statistical analysis: Graphpad prism 7.0 on the obtained real-time fluorescence quantitative data Statistical analysis showed that there was significant difference between the two groups by paired t test and P < 0.05 as the standard. [Results] Part 1: Qualitative observation of MALAT-1, microRNA-320s, SRSF1, YB-1, CCR7 in oral squamous cell carcinoma and adjacent tissues by real-time fluorescence quantitative detection. The expression of microRNA-320d in the lymph node metastasis group was lower than that in the non-lymph node metastasis group. (P < 0.05) Part 2: Correlation between the expression of related RNA (MALAT-1, microNA-320s) and SRSF1 protein or YB-1 in tongue cancer cell lines. Study 1. MALAT-1 can bind to SRSF1. (See WB banding and real-time fluorescence quantitative analysis) 2. MiNA-320d (a member of the family of microNA-320s) can bind to SRSF1 (see WB banding and real-time fluorescence quantitative analysis) 3. MALAT-1, microNA-320d and YB-1 do not bind to each other. (See WB banding) The results showed that MALAT-1, microNA-320d through S-1. RSF1 was combined with each other. Part 3: Gene regulation technique silenced microRNAs-320d, observed CCR7 expression transfected silenced microRNAs-320d inhibited gene expression, and observed CCR7 expression increased, indicating that there was interaction between microRNAs-320d and CCR7. [Conclusion] 1. Qualitative observation of lymph node metastasis by real-time fluorescence quantitative detection. Histological LNC RNA MALAT-1, SRSF1, CCR7 were highly expressed in different degrees compared with the non-lymph node metastasis group. 2. Through immunoprecipitation, Western blotting test showed that the related RNA (MALAT-1, microRNA320d) could bind to each other through SRSF1 protein. 3. Real-time fluorescence assay was used to quantify the contents of MALAT-1, microRNA320s, MALAT-1 and microRNA320d in RNA-protein complexes. Through SRSF1 binding to each other; 4. Gene regulation technology silencing of microRNAs-320s, immunoprecipitation, Western blot and real-time fluorescence quantitative assay found that the expression of chemokine receptor CCR7 increased, we can infer that there is interaction between MALAT-1, SRSF1, microRNAs-320d, CCR7, reveal the effect of MALAT-1 on chemokine receptor CCR7 from the molecular level. MALAT-1 as a molecular targeted lymph node metastasis of oral squamous cell carcinoma related to the basis and application of further research to provide a theoretical basis.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R739.8

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