癌症相关MicroRNA检测及成像研究
摘要
MicroRNA（miRNA）目前是一个十分活跃的研究领域，它对于深入探讨生命现象的本质、解释细胞行为和疾病发生机制、以及疾病诊断、基因治疗药物的开发都具有重大意义。MicroRNA研究连续被《Science》杂志评为年度十大科技之一、年度重大突破。MicroRNA通过基因沉默机制，调控细胞的增殖、发育、分化及凋亡等关键的生命过程，但有关microRNA的生物功能研究尚在探索阶段。同时细胞内microRNA的表达水平与人类重大疾病，尤其是癌症，密切相关。对microRNA与人类重大疾病的关系及机理的研究，可以继RNA干扰（RNAi）之后，形成新的基因治疗药物；由于microRNA是细胞内源性小分子RNA，它可能比外源性引入的小RNA更直接有效。在microRNA生物功能研究中，其分析方法具有至关重要的作用。目前应用的microRNA分析方法主要有Northern Blot、RT-PCR及Microarray，由于这些方法操作过程的复杂性或灵敏度方面的限制，远远不能满足microRNA生物功能研究的需要。
对于microRNA操作简便的高灵敏度分析、细胞内microRNA的实时荧光成像分析进行系统深入的研究，以期为micoRNA生物功能的研究提供实用可靠的分析检测技术平台，对进一步探索microRNA的生物学功能至关重要。论文主要应用滚环扩增、环化扩增、杂交链反应等扩增方法结合氧化石墨烯材料研究开发了microRNA检测和活细胞内成像的新方法，主要内容如下：
1、发展了一种基于挂锁探针的指数滚环扩增，能够高灵敏地、高特异地检测microRNA。这个反应由目标microRNA引发，在反应过程中累计产生DNA产物。不像PCR等一般的核酸扩增反应，此方法很简单，不要求额外的引物加入，额外引物通常会造成引物二聚体或非特异性扩增。随着设计的指数扩增反应，能够灵敏地检测到低至0.24zmol的荧光信号。另外，合理设计的Padlock Probe探针和T4RNA ligase2的特异性连接，使该方法能够区分单个核苷酸的不同，具有很好的特异性。使用这种方法，成功的检测到了人类肺癌细胞总RNA样品中的let-7a，这个结果也说明，本文设计的基于挂锁探针的指数滚环扩增（P-ERCA）对于生物研究的应用和癌症早期诊断具有重要的潜在意义。
2、发展了一种精确的、灵敏的基于石墨烯保护的目标靶分子microRNA的环状指数扩增检测microRNA的方法。在这个反应中，目标靶分子microRNA被石墨烯表面非共价吸附所保护，防止了microRNA被酶解。通过重复的杂交、延伸、酶切和Trigger的释放，完成环状指数扩增。不像大多数报道的反应中，microRNA释放作为下一轮循环的引物，我们设计的方法中，释放的DNA Trigger作为下一轮扩增的引物更加稳定，能够更好的在反应中持续进行。而且，SYBR Green I染料的多分子嵌入结合双链DNA，增强了荧光信号。基于石墨烯保护的目标靶分子microRNA的环状指数扩增反应展现了很好的特异性，能够区分单核苷酸的不同，能够灵敏的定量检测microRNA到10.8fM。同时进行了人类肺细胞microRNA的定量检测，说明这个方法能够在生物医学研究和临床早期诊断中作为可靠的、灵敏的microRNA定量方法。
3、发展了一种基于石墨烯的活细胞内microRNA成像，这种方法结合石墨烯和杂交链反应，能够灵敏的检测到细胞内的microRNA，并在活细胞内进行成像。石墨烯作为载体，能够运送设计的发夹探针H1和H2进入细胞内，进入细胞后，石墨烯又能作为探针H1、H2和microRNA引发的杂交链反应的平台，富集产生的双链DNA产物，产生相对集中的高荧光强度。这种方法能够很好地作为活细胞内microRNA成像的工具，用于细胞内microRNA的直接观察，为癌症的早期诊断和观察提供一个新的成像工具。
4、发展了一种基于石墨烯的活细胞内microRNA同时成像的方法，这种方法结合石墨烯和杂交链反应，能够同时灵敏的检测到细胞内的两种microRNA，并在活细胞内进行microRNA的同时成像。石墨烯作为载体，运送设计的发夹探针进入细胞内，进入细胞后，石墨烯又作为microRNA引发的杂交链反应的平台，富集产生的双链DNA产物，产生相对集中的高荧光强度。由于杂交链反应的特异性，这种方法能够很好地用于活细胞内两种或两种以上microRNA同时成像，进行细胞内不同表达含量的microRNA的同时观察，为癌症的早期诊断和直接观察提供一个新的工具。
MicroRNA (miRNA) is a very active area currently, it is great significance to elucidate theessence phenomenon of life and explain the mechanism of cell behavior and disease, as well asdisease diagnosis, gene therapy drug. Study on microRNA was named the year 's top ten sciencenews of Science consecutively. Through gene silencing mechanisms, microRNA regulate criticallife processes, such as, cell proliferation, development, differentiation and apoptosis, but studieson the biological function of microRNA still in the exploratory stage. While the expression levelof intracellular microRNA are closely related to major human diseases, especially cancer. Afterfollowing the RNA interference (RNAi), studies on the mechanism of microRNA and humanrelations major diseases will formate an new gene therapy. Since the microRNA is endogenous,it is possible more direct and effective introduce than exogenous. So, the analysis method has acrucial role in biological research of microRNA. MicroRNA analysis methods currently usedmainly Northern Blot, RT-PCR and Microarray. Due to the complexity or sensitivity limits in theoperation process, these methods can not meet the needs of the biological function of microRNAresearch.
In order to provide practical and reliable analytical detection technology platform forresearch micoRNA biological functions, to further explore the biological function of microRNA,it is important for microRNA analysis, easy to operate, high-sensitivity analysis, real-timefluorescence imaging of intracellular microRNA. This paper developed some new methods forintracellular microRNA detection and imaging, applications detection technology research, suchas the rolling circle amplification, cyclization amplification, hybridization chain reaction andgraphene.The main contents are as follows:
1. A high specific and ultrasensitive isothermal detection of label-free microRNA is achievedbased on P-ERCA reaction. This reaction is initiated by the target microRNA and catalyzed byDNA products generated and accumulated during the reaction. Unlike conventional nucleic-acidamplification reactions such as polymerase chain reaction (PCR), this reaction does not requireexogenous primers, which often cause primer dimerization or non-specific amplification. This experiment is a simple. With the exponential amplification, fluorescence signals can besensitively detected with a remarkable sensitivity of0.24zmol. Moreover, using the reasonabledesigned padlock probe and T4RNA ligase2in the specific ligation, high specificity wasachieved, even single–nucleotide difference can be discriminated. In addition, the proposedstrategy has successfully achieved the detection of let-7a in total RNA sample extracted fromhuman lung cells. The results indicate that the proposed P-ERCA strategy holds a great potentialfor further application in biomedical research and early clinical diagnostics.
2. An accurate and sensitive circular exponential amplification assay for microRNAs isdeveloped based on GO-protected target. In this assay, the target microRNA can be protectedfrom enzymatic digestion effectively after non-covalent adsorption on GO surface. Throughrepeated hybridization, extension, enzymatic cleavage and release of triggers, circularexponential amplification for microRNA was achieved. Unlike the microRNA was released andused as new triggers to initiate next cycle in most reported reaction, in this assay, the releasedDNA triggers are more stable and preferred for the sustained reaction. Moreover,multi-molecules binding of the intercalating dye SG to double-stranded DNA induced significantenhancement of fluorescence signal. The circular exponential amplification based ongraphene-protected target microRNA exhibited excellent specificity to discriminatesingle-nucleotide difference and allowed quantification of microRNAs with a sensitivity of10.8fM. The microRNAs analysis in human lung cells was also performed, indicating that thisstrategy will become a reliable and sensitive microRNAs quantification method in biomedicalresearch and early clinical diagnostics.
3. Based on graphene and hybridization chain reaction, the method is developed for imagingof living cells, microRNA is sensitive detected by this method in living cells. Graphene as acarrier, hairpin probes H1and H2can be deliveryed into the cell, but also graphene as a paltformfor hybridization chain reaction. It is results that double-stranded DNA and relative highfluorescence intensity concentration producted. This method can be used to observe microRNAimaging of living cell directly. Meanwhile, it is provide a new tool for the early diagnosis andimaging of cancer.
4. A method for imaging of microRNA is developed based on graphene and hybridizationchain reaction simultaneously in living cells. Graphene as a carrier, a hairpin probe can betransported into the cell, but also graphene as platform for hybridization chain reaction.Hybridization chain reaction produced enriched double stranded DNA product, resulting inrelatively high fluorescent. Since the specific of hybridization chain reaction, this method can beused two or more microRNA simultaneous imaging tool in living cell, and for direct observationin different expression levels of microRNA in the cell. It is provide a new tool for the earlydiagnosis of cancer.
对于microRNA操作简便的高灵敏度分析、细胞内microRNA的实时荧光成像分析进行系统深入的研究，以期为micoRNA生物功能的研究提供实用可靠的分析检测技术平台，对进一步探索microRNA的生物学功能至关重要。论文主要应用滚环扩增、环化扩增、杂交链反应等扩增方法结合氧化石墨烯材料研究开发了microRNA检测和活细胞内成像的新方法，主要内容如下：
1、发展了一种基于挂锁探针的指数滚环扩增，能够高灵敏地、高特异地检测microRNA。这个反应由目标microRNA引发，在反应过程中累计产生DNA产物。不像PCR等一般的核酸扩增反应，此方法很简单，不要求额外的引物加入，额外引物通常会造成引物二聚体或非特异性扩增。随着设计的指数扩增反应，能够灵敏地检测到低至0.24zmol的荧光信号。另外，合理设计的Padlock Probe探针和T4RNA ligase2的特异性连接，使该方法能够区分单个核苷酸的不同，具有很好的特异性。使用这种方法，成功的检测到了人类肺癌细胞总RNA样品中的let-7a，这个结果也说明，本文设计的基于挂锁探针的指数滚环扩增（P-ERCA）对于生物研究的应用和癌症早期诊断具有重要的潜在意义。
2、发展了一种精确的、灵敏的基于石墨烯保护的目标靶分子microRNA的环状指数扩增检测microRNA的方法。在这个反应中，目标靶分子microRNA被石墨烯表面非共价吸附所保护，防止了microRNA被酶解。通过重复的杂交、延伸、酶切和Trigger的释放，完成环状指数扩增。不像大多数报道的反应中，microRNA释放作为下一轮循环的引物，我们设计的方法中，释放的DNA Trigger作为下一轮扩增的引物更加稳定，能够更好的在反应中持续进行。而且，SYBR Green I染料的多分子嵌入结合双链DNA，增强了荧光信号。基于石墨烯保护的目标靶分子microRNA的环状指数扩增反应展现了很好的特异性，能够区分单核苷酸的不同，能够灵敏的定量检测microRNA到10.8fM。同时进行了人类肺细胞microRNA的定量检测，说明这个方法能够在生物医学研究和临床早期诊断中作为可靠的、灵敏的microRNA定量方法。
3、发展了一种基于石墨烯的活细胞内microRNA成像，这种方法结合石墨烯和杂交链反应，能够灵敏的检测到细胞内的microRNA，并在活细胞内进行成像。石墨烯作为载体，能够运送设计的发夹探针H1和H2进入细胞内，进入细胞后，石墨烯又能作为探针H1、H2和microRNA引发的杂交链反应的平台，富集产生的双链DNA产物，产生相对集中的高荧光强度。这种方法能够很好地作为活细胞内microRNA成像的工具，用于细胞内microRNA的直接观察，为癌症的早期诊断和观察提供一个新的成像工具。
4、发展了一种基于石墨烯的活细胞内microRNA同时成像的方法，这种方法结合石墨烯和杂交链反应，能够同时灵敏的检测到细胞内的两种microRNA，并在活细胞内进行microRNA的同时成像。石墨烯作为载体，运送设计的发夹探针进入细胞内，进入细胞后，石墨烯又作为microRNA引发的杂交链反应的平台，富集产生的双链DNA产物，产生相对集中的高荧光强度。由于杂交链反应的特异性，这种方法能够很好地用于活细胞内两种或两种以上microRNA同时成像，进行细胞内不同表达含量的microRNA的同时观察，为癌症的早期诊断和直接观察提供一个新的工具。
MicroRNA (miRNA) is a very active area currently, it is great significance to elucidate theessence phenomenon of life and explain the mechanism of cell behavior and disease, as well asdisease diagnosis, gene therapy drug. Study on microRNA was named the year 's top ten sciencenews of Science consecutively. Through gene silencing mechanisms, microRNA regulate criticallife processes, such as, cell proliferation, development, differentiation and apoptosis, but studieson the biological function of microRNA still in the exploratory stage. While the expression levelof intracellular microRNA are closely related to major human diseases, especially cancer. Afterfollowing the RNA interference (RNAi), studies on the mechanism of microRNA and humanrelations major diseases will formate an new gene therapy. Since the microRNA is endogenous,it is possible more direct and effective introduce than exogenous. So, the analysis method has acrucial role in biological research of microRNA. MicroRNA analysis methods currently usedmainly Northern Blot, RT-PCR and Microarray. Due to the complexity or sensitivity limits in theoperation process, these methods can not meet the needs of the biological function of microRNAresearch.
In order to provide practical and reliable analytical detection technology platform forresearch micoRNA biological functions, to further explore the biological function of microRNA,it is important for microRNA analysis, easy to operate, high-sensitivity analysis, real-timefluorescence imaging of intracellular microRNA. This paper developed some new methods forintracellular microRNA detection and imaging, applications detection technology research, suchas the rolling circle amplification, cyclization amplification, hybridization chain reaction andgraphene.The main contents are as follows:
1. A high specific and ultrasensitive isothermal detection of label-free microRNA is achievedbased on P-ERCA reaction. This reaction is initiated by the target microRNA and catalyzed byDNA products generated and accumulated during the reaction. Unlike conventional nucleic-acidamplification reactions such as polymerase chain reaction (PCR), this reaction does not requireexogenous primers, which often cause primer dimerization or non-specific amplification. This experiment is a simple. With the exponential amplification, fluorescence signals can besensitively detected with a remarkable sensitivity of0.24zmol. Moreover, using the reasonabledesigned padlock probe and T4RNA ligase2in the specific ligation, high specificity wasachieved, even single–nucleotide difference can be discriminated. In addition, the proposedstrategy has successfully achieved the detection of let-7a in total RNA sample extracted fromhuman lung cells. The results indicate that the proposed P-ERCA strategy holds a great potentialfor further application in biomedical research and early clinical diagnostics.
2. An accurate and sensitive circular exponential amplification assay for microRNAs isdeveloped based on GO-protected target. In this assay, the target microRNA can be protectedfrom enzymatic digestion effectively after non-covalent adsorption on GO surface. Throughrepeated hybridization, extension, enzymatic cleavage and release of triggers, circularexponential amplification for microRNA was achieved. Unlike the microRNA was released andused as new triggers to initiate next cycle in most reported reaction, in this assay, the releasedDNA triggers are more stable and preferred for the sustained reaction. Moreover,multi-molecules binding of the intercalating dye SG to double-stranded DNA induced significantenhancement of fluorescence signal. The circular exponential amplification based ongraphene-protected target microRNA exhibited excellent specificity to discriminatesingle-nucleotide difference and allowed quantification of microRNAs with a sensitivity of10.8fM. The microRNAs analysis in human lung cells was also performed, indicating that thisstrategy will become a reliable and sensitive microRNAs quantification method in biomedicalresearch and early clinical diagnostics.
3. Based on graphene and hybridization chain reaction, the method is developed for imagingof living cells, microRNA is sensitive detected by this method in living cells. Graphene as acarrier, hairpin probes H1and H2can be deliveryed into the cell, but also graphene as a paltformfor hybridization chain reaction. It is results that double-stranded DNA and relative highfluorescence intensity concentration producted. This method can be used to observe microRNAimaging of living cell directly. Meanwhile, it is provide a new tool for the early diagnosis andimaging of cancer.
4. A method for imaging of microRNA is developed based on graphene and hybridizationchain reaction simultaneously in living cells. Graphene as a carrier, a hairpin probe can betransported into the cell, but also graphene as platform for hybridization chain reaction.Hybridization chain reaction produced enriched double stranded DNA product, resulting inrelatively high fluorescent. Since the specific of hybridization chain reaction, this method can beused two or more microRNA simultaneous imaging tool in living cell, and for direct observationin different expression levels of microRNA in the cell. It is provide a new tool for the earlydiagnosis of cancer.
引文
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