长链非编码RNA在脑胶质瘤中差异表达的相关研究
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摘要
神经胶质瘤是脑神经神经系统是最为常见的恶性肿瘤，致死率高、复发率高、死亡率高，目前对于胶质瘤的治疗方法包括手术治疗、化学药物治疗、放射治疗、新生物治疗等，然而预后的改善仍然较为有有限。胶质瘤治疗困难的主要原因包括：肿瘤细胞通常过度的增殖和广泛的组织浸润、发病位置难以进行手术切除、病理类型不易确定等。因此寻找有效的神经胶质瘤分子诊断标记和分子靶点，阻断肿瘤细胞的恶性增殖，提升治疗效率一直是研究的热点。长链非编码RNA是人类转录组中一大类重要的调控分子，是指那些长度大于200nt的非编码RNA，其序列上缺乏明显的有开放读码框，不能编码蛋白，可以在转录前、转录后和表观遗传学多个水平参与对靶基因的调控而发挥重要的生物学功能。已有研究证明lncRNA几乎涉及了生物体所有生理和病理过程，lncRNA的异常表达与临床上许多肿瘤及非肿瘤疾病关系密切，因此被寄望成为为肿瘤治疗的重要分子靶点，然而目前我们对于lncRNA在胶质瘤发生发展过程中的重要作用，仍知之甚少。
本论文开展lncRNA的异常表达与脑胶质瘤的关联研究，具体选取了3种在其他实体肿瘤中被发现有重要功能的3种lncRNA，结肠癌差异表达（CRNDE）、尿路上皮癌抗原（UCA1）、肺腺癌转移相关转录因子1(MALAT1)，利用荧光定量PCR检测，3种lncRNA在胶质瘤组织和癌旁组织中的表达差异，并将lncRNA的表达量变化情况与胶质瘤的病理分级和复发情况相关联，开展临床治疗。同时我们还在尝试在胶质瘤细胞中外源性过表达lncRNAUCA1，观察其对于肿瘤细胞增殖能力的影响，并探讨可能的作用机制。
Malignant glioma is a common and severe primary brain tumor with a high recurrencerate and an extremely high mortality rate within2years of diagnosis, even when surgical,radiological, and chemotherapeutic interventions are applied. There are a lot of reasons forfutile therapy on gliomas including: rapid the proliferation, soakage and metastasis of tumorcells, short course, difficult diagnosis of the disease in the early stage, complex lesion location,etc How to find the markers for the and molecular glioma diagnosis and neural targeteffectively for blocking the proliferation and metastasis of tumor cells, improving the therapyefficiency remain to be elucidate.
LncRNA is most commonly defned as a non-protein-coding RNA molecule longer than200nucleotides. Evidence suggests that many lncRNAs involved in disease-associatedprocesses such as cancer initiation and progression. lncRNAs are becoming recognized as ahallmark feature of many types of diseases. Importantly, cancer-associated lncRNAs mayserve as diagnostic or predictive biomarkers of cancer and also provide a new therapeuticstrategy of selectively silencing cancer-associated lncRNAs. However, there are stillsignificant gaps in our current understanding of lncRNAfunction in glioma.
To study of human long noncoding RNAs on glioma cell proliferation and explore itsmolecular mechanisms. Three cancer-associated lncRNAs including urothelial cancerassociated1(UCA1), metastasis-associated lung adenocarcinoma transcript1(MALAT1)，colorectal neoplasia differentially expressed (CRNDE), were validate screened in40groupsof glioma and its adjacent tissue. Their relationship with the pathological type were alsosummarized. Constructed expression vector of UCA1, and exogenously expressed lncRNAUCA1in glioma cell U251. Using colony formation assay, CCK-8cell viability analysis,flow cytometry cell cycle, we tend to explore the influence of lncRNA UCA1on the gliomacell biological function and the possible mechanism.
Using qRT-PCR to validate screened three lncRNAs in40groups of glioma and itsadjacent tissues, we found that the expression of MALAT1increase in75%HCC tissues, the percentage of lncRNA CRNDE and UCA1is65%and60%.Expression of three lncRNAswere significantly different in low-grade gliomas (WHO I-II level) and high-grade gliomas(WHO III-IV grade). The eukaryotic expression plasmid of lncRNA UCA1was successfullyconstructed. The Clone forming ability of glioma cell U251was increased by exogenouslyexpressed lncRNA UCA1; CCK-8detection showed that, lncRNA UCA1may accelerate theproliferation of U251; cell cycle analysis showed that, glioma cell with sexogenousexpression of UCA1, in G0/G1phase cells decreased, S phase increased relatively, but G2/Mhad no obvious change, it suggests that UCA1may promote tumor proliferation by affectingthe cell cycle. Our study demonstrates that the expression level was significantly increased3lncRNA CRNDE, MALTA1, UCA1in glioma tissues, and is associated with themalignantdegree of tumor, might be involved in the biological process of glioma cells; lncRNA UCA1can promote the proliferation of glioma cells by affecting the cell cycle.The research mayprovide a new idea on molecular diagnostic markers and potential therapeutic targets forglioma.
本论文开展lncRNA的异常表达与脑胶质瘤的关联研究，具体选取了3种在其他实体肿瘤中被发现有重要功能的3种lncRNA，结肠癌差异表达（CRNDE）、尿路上皮癌抗原（UCA1）、肺腺癌转移相关转录因子1(MALAT1)，利用荧光定量PCR检测，3种lncRNA在胶质瘤组织和癌旁组织中的表达差异，并将lncRNA的表达量变化情况与胶质瘤的病理分级和复发情况相关联，开展临床治疗。同时我们还在尝试在胶质瘤细胞中外源性过表达lncRNAUCA1，观察其对于肿瘤细胞增殖能力的影响，并探讨可能的作用机制。
Malignant glioma is a common and severe primary brain tumor with a high recurrencerate and an extremely high mortality rate within2years of diagnosis, even when surgical,radiological, and chemotherapeutic interventions are applied. There are a lot of reasons forfutile therapy on gliomas including: rapid the proliferation, soakage and metastasis of tumorcells, short course, difficult diagnosis of the disease in the early stage, complex lesion location,etc How to find the markers for the and molecular glioma diagnosis and neural targeteffectively for blocking the proliferation and metastasis of tumor cells, improving the therapyefficiency remain to be elucidate.
LncRNA is most commonly defned as a non-protein-coding RNA molecule longer than200nucleotides. Evidence suggests that many lncRNAs involved in disease-associatedprocesses such as cancer initiation and progression. lncRNAs are becoming recognized as ahallmark feature of many types of diseases. Importantly, cancer-associated lncRNAs mayserve as diagnostic or predictive biomarkers of cancer and also provide a new therapeuticstrategy of selectively silencing cancer-associated lncRNAs. However, there are stillsignificant gaps in our current understanding of lncRNAfunction in glioma.
To study of human long noncoding RNAs on glioma cell proliferation and explore itsmolecular mechanisms. Three cancer-associated lncRNAs including urothelial cancerassociated1(UCA1), metastasis-associated lung adenocarcinoma transcript1(MALAT1)，colorectal neoplasia differentially expressed (CRNDE), were validate screened in40groupsof glioma and its adjacent tissue. Their relationship with the pathological type were alsosummarized. Constructed expression vector of UCA1, and exogenously expressed lncRNAUCA1in glioma cell U251. Using colony formation assay, CCK-8cell viability analysis,flow cytometry cell cycle, we tend to explore the influence of lncRNA UCA1on the gliomacell biological function and the possible mechanism.
Using qRT-PCR to validate screened three lncRNAs in40groups of glioma and itsadjacent tissues, we found that the expression of MALAT1increase in75%HCC tissues, the percentage of lncRNA CRNDE and UCA1is65%and60%.Expression of three lncRNAswere significantly different in low-grade gliomas (WHO I-II level) and high-grade gliomas(WHO III-IV grade). The eukaryotic expression plasmid of lncRNA UCA1was successfullyconstructed. The Clone forming ability of glioma cell U251was increased by exogenouslyexpressed lncRNA UCA1; CCK-8detection showed that, lncRNA UCA1may accelerate theproliferation of U251; cell cycle analysis showed that, glioma cell with sexogenousexpression of UCA1, in G0/G1phase cells decreased, S phase increased relatively, but G2/Mhad no obvious change, it suggests that UCA1may promote tumor proliferation by affectingthe cell cycle. Our study demonstrates that the expression level was significantly increased3lncRNA CRNDE, MALTA1, UCA1in glioma tissues, and is associated with themalignantdegree of tumor, might be involved in the biological process of glioma cells; lncRNA UCA1can promote the proliferation of glioma cells by affecting the cell cycle.The research mayprovide a new idea on molecular diagnostic markers and potential therapeutic targets forglioma.
引文
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