【摘要】：隨著環(huán)境污染及食品安全問題日趨嚴重,吸煙、飲酒等不良生活習慣逐漸向年輕化發(fā)展,致使腫瘤發(fā)病率逐年增高。目前腫瘤已經(jīng)成為威脅人類健康的重大疾病。我國不管發(fā)病率還是死亡率均居世界前列,給國民健康造成了極大的危害。腫瘤及其相關并發(fā)癥的研究越來越被研究者們所重視。雖然近些年在腫瘤診斷方法及治療手段上已取得長足的進步。但對于肺癌、肝癌、胰腺癌等惡性腫瘤的治療效果、預后和遠期生存率仍然較差。其主要原因歸結為對腫瘤發(fā)生發(fā)展機制的認識不夠深入。脊柱為腫瘤骨轉(zhuǎn)移最為常見的部位,高達70%的癌癥患者會發(fā)生脊柱轉(zhuǎn)移。脊柱轉(zhuǎn)移瘤可導致脊髓壓迫及病理性骨折,使患者癱瘓,完全失去自理能力。嚴重影響患者的生活質(zhì)量,從而加速病情的進展。至今國內(nèi)外學者對腫瘤脊柱轉(zhuǎn)移的機制尚不清楚,致使缺乏有效的治療方法。因此脊柱轉(zhuǎn)移瘤的治療仍然是困擾醫(yī)學界的一大難題。手術雖然能有效促進恢復,但并發(fā)癥多,創(chuàng)傷較大且短時間內(nèi)容易復發(fā),使部分患者在術后一月內(nèi)死亡。因此,探尋介導腫瘤脊柱轉(zhuǎn)移的關鍵靶分子,是提高脊柱轉(zhuǎn)移瘤病人臨床療效,改善患者預后及生存質(zhì)量的新方向。部分腫瘤具有較強的嗜骨性,晚期容易發(fā)生骨轉(zhuǎn)移,例如肝癌、肺癌、乳腺癌等。脊柱為肝癌骨轉(zhuǎn)移最為常見的部位,發(fā)生脊柱轉(zhuǎn)移患者存活率不到3%。肝細胞癌(hepatocellular carcinoma,HCC)是一種全球范圍內(nèi)常見的惡性腫瘤,占原發(fā)性肝癌的90%以上�；颊叱３０橛懈蝺�(nèi)及肝外轉(zhuǎn)移。HCC早期臨床癥狀及體征多不典型,很難及早發(fā)現(xiàn)。明確診斷時大多病程已進入中、晚期,失去手術機會。因其惡性程度高、早期發(fā)現(xiàn)難、進展速度快、治療復雜、術后復發(fā)及轉(zhuǎn)移率較高等特點,使HCC患者療效不佳,預后較差。以往對HCC研究主要以microRNA及編碼蛋白的RNA為主,長鏈非編碼RNA研究相對較少。目前國內(nèi)外對HCC的分子機制研究還不夠深入,因此我們需進一步對HCC在發(fā)生、發(fā)展及轉(zhuǎn)移過程中的分子生物學機制進行探索。尋找可預測HCC發(fā)生的分子標志物,為HCC診療開辟新途徑。人類基因組是由龐大且復雜的核苷酸序列排列而成。目前已知可編碼蛋白的基因僅占人類基因組序列的2%,其余98%不具備編碼蛋白能力的序列被認為是基因組中無用的“噪聲”。這類從基因組轉(zhuǎn)錄而來,且不編碼蛋白的RNA分子稱為非編碼RNA(non-coding RNA,ncRNA)。早期,研究者僅僅對編碼RNA進行關注,但近年來人們的目光逐漸被非編碼RNA所吸引。隨著研究的不斷深入,發(fā)現(xiàn)長鏈非編碼RNA(long non-coding RNA,lncRNA)與人類多種疾病如阿爾茨海默癥、腫瘤、亨廷頓氏病的發(fā)生、發(fā)展存在著重要的關系。LncRNA轉(zhuǎn)錄本長度大于200nt,且不具備蛋白編碼的能力。最新研究表明,lncRNA在生命活動過程中扮演著重要角色,可通過調(diào)控mRNA和蛋白表達水平影響生物學行為。目前越來越多的腫瘤相關lncRNA得以發(fā)現(xiàn),其通過多種方式調(diào)控著腫瘤的生長、轉(zhuǎn)移、侵潤與凋亡,成為全新腫瘤標志物及藥物靶標,顯著推進了腫瘤研究的進展。Ji等通過測序技術發(fā)現(xiàn)了肺腺癌轉(zhuǎn)移相關轉(zhuǎn)錄本(metastasis-associated lung adenocarcinoma transcript 1,MALAT 1),對225例Ⅲ期非小細胞肺癌(non-small cell lung cancer,NSCLC)患者進行篩查。發(fā)現(xiàn)70例轉(zhuǎn)移患者的樣本中MALAT1過表達,且具有病程及組織特異性。提示MALAT 1可作為Ⅰ期NSCLC患者潛在標志物。該基因在其他腫瘤中也陸續(xù)被發(fā)現(xiàn),但在NSCLC患者中的表達最為顯著。MALAT 1可通過激活腫瘤轉(zhuǎn)移相關基因來促進腫瘤轉(zhuǎn)移,還可參與mRNA前體的可變剪切和絲氨酸/精氨酸剪接因子的磷酸化修飾,來影響基因的功能及表達。隨著對腫瘤基因組學及轉(zhuǎn)錄組學研究的不斷深入,研究者發(fā)現(xiàn)不但同種腫瘤中可存在不同的lncRNA,而且同一lncRNA也可在不同腫瘤中差異表達。HULC最早發(fā)現(xiàn)在肝癌細胞中過表達,可作為原發(fā)性肝癌較為敏感的分子標志物,其在前列腺癌、胃癌中也出現(xiàn)異常表達情況。H19作為一個原癌基因,在多種消化系統(tǒng)腫瘤中表達量升高。綜上所述,lncRNA在腫瘤學研究中發(fā)揮著至關重要的作用。目前,脊柱轉(zhuǎn)移瘤患者多采取微創(chuàng)治療方案,脊柱后路開放式手術相對較少。因此組織樣本較為珍貴,收集相對困難,且骨組織RNA較難提取。致使國內(nèi)外對于lncRNA在脊柱轉(zhuǎn)移瘤中的研究尚處空白。LncRNA在HCC中的研究仍然較少,并且絕大多數(shù)lncRNA調(diào)控機制尚不明確。由此提示我們,是否可以通過高通量測序技術進行篩選及驗證,找到全新的關鍵lncRNA作為腫瘤診斷及治療靶標,為脊柱轉(zhuǎn)移瘤和HCC臨床診療提供新策略�；诖宋覀冮_展了以下三部分研究,現(xiàn)總結如下。第一章:脊柱轉(zhuǎn)移瘤轉(zhuǎn)錄組lncRNA表達譜分析目的:建立脊柱轉(zhuǎn)移瘤差異表達lncRNA及mRNA表達譜,并對其長度及外顯子數(shù)量進行預測。明確差異表達mRNA可富集的分子功能、生物學過程和疾病通路相關信息。方法:對脊柱轉(zhuǎn)移瘤患者配對組織(腫瘤組織及癌旁組織)中RNA進行提取,利用高通量測序技術構建脊柱轉(zhuǎn)移瘤中差異表達lncRNA及mRNA表達譜。隨后通過pathway分析及GO分析對差異表達mRNA的分子功能、參與生物學過程及疾病通路進行富集。最后對差異表達lncRNA長度及外顯子數(shù)目進行預測,并通過對比與編碼基因間位置關系,將差異表達lncRNA分類。結果:通過高通量測序技術,在脊柱轉(zhuǎn)移瘤組織中找到171條差異表達lncRNA和2929條差異表達mRNA,其中有66條全新未被報道的lncRNA。對差異表達mRNA進行pathway分析和GO分析。結果顯示,脊柱轉(zhuǎn)移瘤中差異表達的mRNA可富集到31種疾病,79種通路及1535種分子功能,其中包括腫瘤相關疾病及腫瘤相關通路。進一步明確了脊柱轉(zhuǎn)移瘤中異常表達mRNA參與的分子功能、生物學過程和對疾病通路的調(diào)節(jié)。171條差異表達lncRNA中,大部分外顯子數(shù)目小于5個,長度小于10000nt,均少于mRNA。其中Antisense共有50條,已知的19條,未知的31條;Sence共有53條,已知的51條,未知的2條;Bidirectionsl共有6條,已知的4條,未知的2條;Intergenic共有40條,已知的20條,未知的20條;Intronic共有22條,已知的8條,未知的14條。結論:成功構建了脊柱轉(zhuǎn)移瘤lncRNA、mRNA表達譜。在171條差異表達lncRNA中發(fā)現(xiàn)66條全新未被報道的lncRNA。明確了2929條差異表達mRNA參與的分子功能、生物學過程和對疾病通路的調(diào)節(jié)。為腫瘤學研究及后續(xù)實驗提供了寶貴的數(shù)據(jù)資源。第二章:lnc000489在脊柱轉(zhuǎn)移瘤患者血漿中的表達及臨床特征相關性分析目的:通過在血漿中驗證,找出脊柱轉(zhuǎn)移瘤患者血漿中高表達的lncRNA。了解其分子功能、生物學過程和疾病通路相關信息。明確其在脊柱轉(zhuǎn)移瘤中的診斷價值。方法:從前期構建的脊柱轉(zhuǎn)移瘤lncRNA表達譜中挑選20條全新的lncRNA。將脊柱轉(zhuǎn)移瘤患者血漿設為實驗組,健康志愿者血漿設為對照組。通過qRT-PCR實驗檢測候選lncRNA在血漿中表達量,統(tǒng)計分析后找出在脊柱轉(zhuǎn)移瘤中具有顯著差異的lncRNA。利用ROC曲線計算靈敏度和特異性。隨后對差異表達lncRNA進行共表達分析,并對共表達mRNA進行pathway和GO分析。最后統(tǒng)計分析差異表達lncRNA與臨床特征間的相關性。結果:脊柱轉(zhuǎn)移瘤患者血漿中l(wèi)nc00489表達量相對于健康志愿者顯著升高(P0.05),ROC曲線分析顯示lnc00489對脊柱轉(zhuǎn)移瘤具有一定的診斷價值。與lnc00489存在共表達關系的mRNA共有51條,可富集到實體腫瘤、卵巢癌、口腔癌、前列腺癌等多種腫瘤相關疾病和Wnt、Hh、Hedgehog signaling pathway、Basal cell carcinoma等腫瘤相關通路,進一步說明了lnc00489可能與腫瘤的發(fā)生、發(fā)展及轉(zhuǎn)移存在相關性。Lnc00489表達量與臨床特征進行相關性分析,顯示lnc00489與轉(zhuǎn)移椎體個數(shù)及是否伴有內(nèi)臟轉(zhuǎn)移顯著相關。轉(zhuǎn)移椎體數(shù)量越多病情相對嚴重。腫瘤主要的轉(zhuǎn)移途徑為血運轉(zhuǎn)移,內(nèi)臟及椎體血供相對豐富。綜上所述lnc00489可能在腫瘤脊柱轉(zhuǎn)移的過程中發(fā)揮著重要作用,其有望成為潛在的血漿標志物,為脊柱轉(zhuǎn)移瘤的診斷及治療提供了新思路。結論:Lnc00489表達量在脊柱轉(zhuǎn)移瘤患者血漿中顯著升高,對脊柱轉(zhuǎn)移瘤具有一定的診斷價值。與lnc00489共表達的mRNA可富集到多種腫瘤相關疾病和通路。血漿中l(wèi)nc00489表達量與轉(zhuǎn)移椎體數(shù)量和是否伴有內(nèi)臟轉(zhuǎn)移具有相關性,其有望成為診斷脊柱轉(zhuǎn)移瘤全新的血漿分子標志物。第三章:lnc34822在HCC患者血漿中表達及臨床特征相關性研究目的:從構建的lncRNA數(shù)據(jù)庫中找到一條在HCC中差異表達的lncRNA,明確其在HCC中的診斷價值。方法:利用前期建立的lncRNA數(shù)據(jù)庫,結合相關文獻調(diào)研篩選出10條高表達lncRNA。通過在HCC患者組織及血漿中驗證,明確是否存在高表達的lncRNA。ROC曲線分析計算診斷靈敏度和特異性。利用qRT-PCR實驗檢測候選lncRNA在組織、血漿及細胞系(Hep3B、HepG-2、SMMC-7721、Huh7.5、LO2)中表達量。統(tǒng)計分析差異表達lncRNA在血漿中的穩(wěn)定性,與外周血細胞間關系,不同細胞系中表達情況,在HCC患者術前、術后及復發(fā)時表達量的變化情況和與臨床特征間的相關性。結果:有報道稱,同種lncRNA可在不同腫瘤中進行調(diào)控,同種腫瘤也可受到多種不同lncRNA的影響。結合文獻調(diào)研從構建的脊柱轉(zhuǎn)移瘤lncRNA表達譜中篩選出10條高表達lncRNA。經(jīng)過在HCC患者組織及血漿中驗證后,發(fā)現(xiàn)lnc34822在HCC中表達量顯著上調(diào)(P0.01),并且可以在血漿中穩(wěn)定表達。Lnc34822在肝癌細胞系中表達量明顯高于正常肝細胞系,且與外周血細胞沒有相關性。ROC曲線分析顯示,lnc34822對HCC具有一定的診斷價值。Lnc34822在HCC患者術后血漿中表達量明顯降低,而復發(fā)時又迅速升高,由此推斷l(xiāng)nc34822有望成為一個動態(tài)監(jiān)測HCC患者病情進展的血漿標志物。通過與臨床信息相關性分析發(fā)現(xiàn)lnc34822血漿中表達量與AFP及肝上腫瘤個數(shù)呈正相關。肝癌患者血液中AFP含量顯著升高,目前已成為臨床上廣泛應用的腫瘤標志物。肝上腫瘤數(shù)量越多病情越嚴重。進一步說明了lnc34822有望成為HCC潛在的血漿診斷標志物。結論:Lnc34822在HCC患者血漿中穩(wěn)定高表達,且與外周血細胞沒有相關性,對HCC具有一定的診斷價值。血漿中l(wèi)nc34822表達量可動態(tài)監(jiān)測HCC患者病情進展,其有望成為診斷HCC全新的血漿分子標志物。通過以上研究,我們成功構建了全新lncRNA數(shù)據(jù)庫,為腫瘤學研究提供了寶貴的數(shù)據(jù)資源。并從中找到與脊柱轉(zhuǎn)移瘤和HCC發(fā)生、發(fā)展相關的lncRNA,為脊柱轉(zhuǎn)移瘤和HCC臨床診斷及治療提供了新思路。
[Abstract]:With the environmental pollution and food safety becoming more and more serious, bad habits such as smoking and drinking are gradually becoming younger and younger. The incidence of cancer is increasing year by year. Although great progress has been made in the diagnosis and treatment of cancer in recent years, the prognosis and long-term survival rate of lung cancer, liver cancer, pancreatic cancer and other malignant tumors are still poor. Spine is the most common site of bone metastasis. Up to 70% of cancer patients have spinal metastasis. Spinal metastasis can cause spinal cord compression and pathological fracture, paralysis, complete loss of self-care ability. It seriously affects the quality of life of patients, thus accelerating the progress of the disease. The mechanism of spinal metastasis is still unclear, resulting in the lack of effective treatment. Therefore, the treatment of spinal metastasis is still a major problem in the medical community. Although surgery can effectively promote recovery, it has many complications, large trauma and short-term recurrence, so that some patients died within one month after surgery. The key target molecule of spinal metastasis is to improve the clinical efficacy, prognosis and quality of life of patients with spinal metastases. Less than 3%. Hepatocellular carcinoma (HCC) is a common malignant tumor worldwide, accounting for more than 90% of primary liver cancer. Patients often have intrahepatic and extrahepatic metastases. The early clinical symptoms and signs of HCC are often atypical and difficult to detect. Most of the definite diagnosis of HCC has entered the middle, late stage, lost the opportunity for surgery. Because of its high degree of malignancy, difficulty in early detection, rapid progress, complex treatment, high rate of recurrence and metastasis, HCC patients have poor prognosis and poor curative effect. Therefore, we need to further explore the molecular biology mechanism of HCC in the process of occurrence, development and metastasis. To find molecular markers that can predict the occurrence of HCC will open up a new way for the diagnosis and treatment of HCC. Two percent of the sequences, and 98 percent of the other sequences that do not encode proteins, are considered useless "noise" in the genome. RNA molecules transcribed from the genome and that do not encode proteins are called non-coding RNA (ncRNA). In the early days, researchers focused only on coding RNA, but in recent years, people's attention has gradually been focused on non-coding RN. As the research progresses, it has been found that long non-coding RNA (lncRNA) plays an important role in the development of human diseases such as Alzheimer's disease, tumor and Huntington's disease. Nowadays, more and more tumor-associated lncRNAs have been found to regulate the growth, metastasis, invasion and apoptosis of tumors in various ways. They have become new tumor markers and drug targets, and have greatly promoted the progress of tumor research. Ji et al. identified metastasis-associated lung adenocarcinoma transcript 1 (MALAT 1) by sequencing and screened 225 patients with stage III non-small cell lung cancer (NSCLC). These results suggest that MALAT-1 may be a potential marker for stage I NSCLC patients. The gene has been found in other tumors, but it is most significantly expressed in NSCLC patients. MALAT-1 can promote tumor metastasis by activating Tumor Metastasis-related genes, and can also participate in the alterable splicing of mRNA precursors and phosphorylation repair of serine/arginine splicing factors. With the development of tumor genomics and transcriptome, researchers have found that not only different lncRNA can be found in the same tumor, but also the same lncRNA can be differentially expressed in different tumors. HULC was first found to be overexpressed in hepatocellular carcinoma cells, which can be regarded as a more sensitive primary hepatocellular carcinoma. H19, as a proto-oncogene, is highly expressed in a variety of digestive system tumors. In summary, lncRNA plays a vital role in oncology research. At present, spinal metastases are treated with minimally invasive treatment and posterior spinal opening. Therefore, tissue samples are relatively rare, collection is relatively difficult, and it is difficult to extract RNA from bone tissues. As a result, the study of lncRNA in spinal metastases is still blank at home and abroad. Sequencing techniques were screened and validated to identify novel key lncRNA targets for the diagnosis and treatment of spinal metastases and HCC, providing new strategies for clinical diagnosis and treatment. Methods: RNA was extracted from paired tissues (tumor tissues and adjacent tissues) of patients with spinal metastases, and high-throughput sequencing was used to construct spinal rotation. Differentially expressed lncRNA and mRNA expression profiles in tumor metastasis were then analyzed by pathway analysis and GO analysis to enrich the molecular functions of differentially expressed mRNA and participate in biological processes and disease pathways. Results: 171 differentially expressed lncRNA and 2929 differentially expressed mRNAs were found in spinal metastases by high-throughput sequencing, of which 66 were completely new and unreported. Pathway analysis and GO analysis of differentially expressed mRNAs were performed. The results showed that differentially expressed mRNAs in spinal metastases were enriched in 31 diseases and 79 common diseases. Pathway and 1 535 molecular functions, including tumor-related diseases and tumor-related pathways, further clarify the molecular functions, biological processes and regulation of the abnormal expression of mRNA in spinal metastases. There are 50 ntisense, 19 known, 31 unknown; 53 Sence, 51 known, 2 unknown; 6 Bidirectionsl, 4 known, 2 unknown; 40 Intergenic, 20 known, 20 unknown; 22 Intronics, 8 known, 14 unknown. Conclusion: We have successfully constructed lncRNA, mRNA of spinal metastases. Expression profiles. Among 171 differentially expressed lncRNAs, 66 novel unreported lncRNAs were found. The molecular functions, biological processes and regulation of disease pathways of 2929 differentially expressed mRNAs were identified. This provides valuable data for oncology research and follow-up experiments. Chapter 2: The expression of lnc000489 in the plasma of patients with spinal metastases. Objective: To identify the high expression of lncRNA in the plasma of patients with spinal metastases by validating its clinical features. The expression of candidate lncRNA in plasma was detected by qRT-PCR assay. After statistical analysis, significant differences in lncRNA expression in spinal metastases were found. The sensitivity and specificity were calculated by ROC curve. Then, the differential expression of lncR was detected. Results: The expression of lnc00489 in the plasma of patients with spinal metastases was significantly higher than that of healthy volunteers (P 0.05). ROC curve analysis showed that lnc00489 had certain diagnostic value for spinal metastases. There are 51 mRNAs co-expressed with lnc00489, which can be enriched in many tumor-related diseases such as solid tumors, ovarian cancer, oral cancer, prostate cancer and other tumor-related pathways such as Wnt, Hh, Hedgehog signaling pathway, Basal cell carcinoma. This further indicates that lnc00489 may be associated with the occurrence, development and metastasis of tumors. Correlation analysis between Lnc00489 expression and clinical features showed that lnc00489 was significantly associated with the number of metastatic vertebrae and visceral metastasis. Lnc00489 may be a potential plasma marker for the diagnosis and treatment of spinal metastases. Conclusion: The expression of Lnc00489 is significantly elevated in the plasma of patients with spinal metastases and has diagnostic value for spinal metastases. Tumor-related diseases and pathways. The expression of lnc00489 in plasma is correlated with the number of metastatic vertebrae and visceral metastasis. It is expected to be a new plasma molecular marker for the diagnosis of spinal metastases. Chapter 3: Expression of lnc34822 in plasma of HCC patients and its correlation with clinical features. Objective: To find the correlation between the expression of lncRNA in the constructed lncRNA database. Methods: Ten highly expressed lncRNA were screened from the previously established lncRNA database and the related literature. The sensitivity and specificity of diagnosis were determined by validating the presence of highly expressed lncRNA in tissues and plasma of HCC patients. The expression of candidate lncRNA in tissues, plasma and cell lines (Hep3B, HepG-2, SMMC-7721, Huh7.5, LO2) was detected by qRT-PCR. The stability of the differentially expressed lncRNA in plasma, the relationship between the differentially expressed lncRNA and peripheral blood cells, the expression in different cell lines, the changes of the expression in HCC patients before, after and after HCC, and the recurrence of the expression of lncRNA were statistically analyzed. Results: It has been reported that homologous lncRNA can be regulated in different tumors, and homologous tumors can also be affected by a variety of different lncRNA. Ten highly expressed lncRNA were screened from the constructed lncRNA expression profiles of spinal metastases based on literature investigation. After being verified in HCC patients'tissues and plasma, lnc34822 was found. The expression of Lnc34822 in HCC cell line was significantly higher than that in normal liver cell line, and there was no correlation between Lnc34822 and peripheral blood cells. It is concluded that lnc34822 may be a plasma marker for monitoring the progression of HCC.
【學位授予單位】：中國人民解放軍軍事醫(yī)學科學院
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R735.7

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