结直肠癌中miRNAs表达谱的研究
摘要
结直肠癌(colorectal cancer, CRC)是一种常见的消化道恶性肿瘤。其发病与高脂肪和缺少膳食纤维的不良饮食结构有关。随着我国人民群众生活水平的大幅提高和生活方式的西化,CRC的发病率逐年提高。近年,CRC在我国发病率已经上升到第5位,死亡率也居第5位。根据世界其他国家CRC发生发展的变化规律,结合我国各地区近年来癌症发病率动态,CRC将成为本世纪我国发病率上升速度最快的恶性肿瘤之一。
microRNA属于内源性非蛋白质编码小RN A (small non-protein-coding RN A)。 miRNA最早是在分析线虫遗传学信息时发现,并命名为1in-14。在细胞的生长、组织分化、各种疾病的发生、甚至在肿瘤的发生发展中miRNA都发挥着极为重要的作用。
研究证实miRNA异常表达在多数肿瘤发生发展过程中均以癌基因或抑癌基因的角色起到重要的调控作用。从各种miRNA数据库的资料中可以看出每个miRNA可调控几十甚至数百个靶基因,而同一个基因的表达也可以同时受多个miRNA干扰。这使得为数众多的miRNA与其靶基因之间形成复杂的网络系统。众多的研究表明miRNA-31在不同的肿瘤内有着不同的表达,在某些组织其表达显著升高如：大肠癌,头颈部鳞癌,肝细胞癌,口腔鳞癌,肺癌；但在其他一些组织却出现了表达下调如：膀胱癌,前列腺癌,胃癌,乳腺癌,浆液性卵巢癌等。miR-31的表达高低与肿瘤的侵袭及浸润也有相关性,如在乳腺癌miR-31的高表达导致侵袭性降低,而在结直肠癌其表达升高与侵袭性呈正相关。Ezrin蛋白是细胞膜与细胞骨架之间的连接蛋白,与肿瘤的侵袭性密切相关,是ERM蛋白(Ezrin、Radixm Moesin)家族的一员,以往又称为eytovillin、P81或villin-2。
miRNA的研究尚处于起步阶段,miRNA的表达与结肠癌的发生发展以及浸润和转移之间到底存在着什么样的具体关系,目前还不是十分明了。本研究拟采用miRNA芯片及RT-PCR,免疫组织化学等研究方法,旨在通过对比研究结直肠癌及其癌旁正常组织中micro RNAs (miRNAs)的差异表达,初步探讨结直肠癌组织中miRNA的差异表达谱及其在结直肠癌临床生物学特点判定中的检测意义。
本文收集手术切除的11例新鲜的结直肠癌和其癌旁正常组织标本,立即低温保存并提取RNA。应用AFFX miRNA表达谱芯片实验初步筛查癌及癌旁正常组织中]miRNAs的差异表达,并采用实时定量PCR技术验证芯片检测结果。结果表明结直肠癌和癌旁正常组织中miRNAs表达有明显羊异,与癌旁正常组织相比,结直肠癌中有25个miRNAs表达显著不同(P<0.001),包括15个上调和10个下调的miRNAs。高表达的miRNAs分别是：hsa-miR-31, hsa-miR-767-5p, hsa-miR-105, hsa-miR-196b, hsa-miR-224, hsa-miR-483-5, hsa-miR-1246, hsa-miR-196b, hsa-miR-663b, hsa-miR-584, hsa-miR-141, hsa-miR-18a, hsa-miR-19a, hsa-miR-452, hsa-miR-622。低表达的miRNAs分别是：hsa-miR-215, hsa-miR-4298, hsa-miR-139-5p, hsa-miR-490-5p, hsa-miR-3201, hsa-miR-363, hsa-miR-187, hsa-miR-133a, hsa-miR-1825, hsa-miR-30a。进一步的qRT-PCR结果显示：与癌旁正常组织相比,癌组织中miR-31, miR-105, miR-196b, miR-224, miR-483-5p和：miR-767-5p的mRNA表达水平明显上调(P<0.05),而miR-139-5p, miR-215, miR-490-5p和miR-4298等mRNA水平明显下调(P<0.05),与芯片结果一致。
在此基础上,选取结直肠癌中显著高表达的miR-31, miR-105和miR-196b作为进一步深入研究的对象,并进一步扩大了病例数,以53例新鲜的结直肠癌及其15例癌旁正常组织作为研究对象,应用qRT-PCR技术对比分析其异常表达与临床生物学特点之间的相关性。同时,通过Targets Scan检索,分析miR-31的密切相关基因—Ezrin,并应用免疫组化及RT-PCR方法确定其在CRC组织中的过表达意义。结合临床病理资料发现：miR-31与结直肠癌的病理分型(P<0.01)和临床分期(P<0.05)显著相关,但与淋巴转移及远处转移不相关(P>0.05); miR-105与病理分型,临床分期,淋巴结转移及远处转移均呈正相关(P<0.05)；而miR-196b只与病理分型有关(P<0.05),但与淋巴结转移和远处转移及临床分期均无关(P>0.05)。另外,实验发现Ezrin蛋白和其mRNA均在CRC组织中存在高表达,且与结直肠癌淋巴结转移关系密切。
结论结直肠癌中存在着明显的miRNAs差异表达,miRNAs特异表达可能成为结直肠癌的潜在的诊断和治疗的分子靶点。miR-31, miR-105和miR-196b高表达预示结直肠癌的不良预后。miR-31的相关基因Ezrin基因mRNA和蛋白水平的高表达可以预示结直肠癌的不良预后,即淋巴结转移。
Colorectal cancer (CRC) remains a common malignant tumor of digestive tract in the worldwide. Several dietary and other lifestyle factors have been implicated in the development of colorectal cancer. As our country's economy developed at high-speed, people's living level improved greatly and lifestyle has been Western, the incidence of CRC has improved significantly year by year. In recent years, the incidence and death rate of CRC has risen to No.5and No.5in our country. According to the changes of initiation and development of CRC in other countries and the dynamic of incidence rate of cancer in all regions of China in recent years, we can see that CRC will be one of the fastest rising malignancy cancers in China of this century.
MicroRNAs (miRNAs) are small nucleotide RNA species that are expressed from specialized genes. The first miRNA was characterized in the nematode by Lee et al, and was termed as lin-14. It has been reported that miRNAs plays an extremely important role in cell growth, cell death, apoptosis, and metastasis during the carcinogenesis and tumor progression.
MiRNAs have been found to have links with multiple types of cancer. It acts as oncogene or cancer suppressor gene and plays an important part in regulation function. In recent years, a number of informative profiling studies have determined the levels of miRNAs in various types of cancer cell lines and tumors. Multiple functional studies on tumor suppressive or oncogenic miRNAs were identified from profiling, screens or due to their cancer-associated genomic loci. Numerous miRNAs and target genes formed a complex network. Many studies showed that miRNA-31has different expression levels in cancers. Previous studies found that miR-31over-expressed in colon cancer, head and neck cancer, hepatocellular cancer, oral cavity squamous cell cancer and lung cancer; low-expressed in bladder cancer, prostate cancer, gastric cancer, breast cancer, serous ovarian cancer and so on. Many evidence demonstrated the involvement of miR-31in tumor metastasis. For example.the high expression of miR-31could prevent the metastasis of breast cancer, but promote the invasion of CRC. This discrepancy could have resulted from the different role of miR-31in these cancers. Ezrin (also known as P81or villin-2) is a member of the ERM protein (Ezrin, Radixm, Moesin family). It is connexin between cell membrane and cytoskeleton and involved in the motility of cancer cells.
The research of miRNA is still in the initial stage. But we still don't know the relationship between the expression of miRNA and the development, invasion and metastasis of CRC. In this study, we focused on the expression of miRNAs in CRC and the adjacent tissues by miRNA gene microarray, determined some cellular functions and molecular pathways targeted by these differentially expressed miRNAs, and discussed differential expression profile and the judgement of clinical biology characteristics in the CRC tissue.
11CRC and adjacent tissue treated with surgery were collected and frozen immediately. For microarray analysis, the AFFX microRNA biochip was used. Total RNA was isolated from samples and more than thousand miRNAs were analyzed. The interested miRNAs were conformed by a real-time PCR analysis. This approach enabled the identification of miRNAs whose expression is significantly altered in CRC compared with the normal tissues from the same patient. In result,25miRANs were found to be differentially expressed in tumors compared with the adjacent tissues (P<0.001), including15over-expressed miRNAs (has-miR-31,has-miR-767-5. has-miR-105, has-miR-196b-star, has-miR-224, has-miR-483-5p, has-miR-1246, has-miR-196b, has-miR-663b, has-miR-584, has-miR-141, has-miR-18a-star, has-miR-19a, has-miR-452, has-miR-622) and10low-expressed miRNAs (miR-215, miR-4298, mi-R-139-5p, has-miR-490-5p. miR-3201, miR-363. miR-187. miR-133a. miR-1825. miR-30). The further result of qRT-PCR(Real-Time quantitative fluorescence PCR) showed that the expression of miR-31. miR-105. miR-196b. miR-224, miR-483-5p and miR-767-5p in tumor has up-regulated compared with carcinoma side normal tissue(P<0.05). While miR-139-5p, miR-215. miR-490-5p and miR-4298are obviously down-regulated which consist with chip result(P<0.05).
On that basis, including miR-31. miR-105and miR-196b. strongly up-regulated in CRC were selected to the further Real time PCR study with more samples of CRC. The samples are from53of CRC and15of adjacent tissue. And this study used qRT-PCR to comparatively analyse its differential expression and the judgement of clinical biology characteristics. Meanwhile, we analysed gene Ezrin-closely related to miR-31via Targets Scan search method. And we determined its expression in CRC tissue by immunohistochemistry and RT-PCR analysis. We found miR-31was correlated with histological type (P <0.01) and the clinical stage (P<0.05). And no statistically difference was found between miR-31expression and lymph node metastasis on differentiation (P>0.05); miR-105was positive correlated with histological type, clinical stage and lymph node metastasis (P<0.05); while miR-196-5p was only correlated with the histological type of CRC. Additionally, the over-expression of Ezrin protein and mRNA were indicated by western blotting and RT-PCR in CRC, respectively. Analysis of IHC result demonstrated Ezrin was correlated with the metastasis of CRC.
Conclusion:Colorectal cancer exists obvious differences of miRNAs expression, miRNAs specifically expressed may become colorectal cancer potential diagnosis and treatment of molecular targets. miR-31, miR-105and miR-196-b high expression indicates poor outcome of colorectal cancer. miR-31related gene Ezrin gene mRNA and protein levels high expression predicts colorectal cancer adverse outcomes, namely the lymph node metastasis.
microRNA属于内源性非蛋白质编码小RN A (small non-protein-coding RN A)。 miRNA最早是在分析线虫遗传学信息时发现,并命名为1in-14。在细胞的生长、组织分化、各种疾病的发生、甚至在肿瘤的发生发展中miRNA都发挥着极为重要的作用。
研究证实miRNA异常表达在多数肿瘤发生发展过程中均以癌基因或抑癌基因的角色起到重要的调控作用。从各种miRNA数据库的资料中可以看出每个miRNA可调控几十甚至数百个靶基因,而同一个基因的表达也可以同时受多个miRNA干扰。这使得为数众多的miRNA与其靶基因之间形成复杂的网络系统。众多的研究表明miRNA-31在不同的肿瘤内有着不同的表达,在某些组织其表达显著升高如：大肠癌,头颈部鳞癌,肝细胞癌,口腔鳞癌,肺癌；但在其他一些组织却出现了表达下调如：膀胱癌,前列腺癌,胃癌,乳腺癌,浆液性卵巢癌等。miR-31的表达高低与肿瘤的侵袭及浸润也有相关性,如在乳腺癌miR-31的高表达导致侵袭性降低,而在结直肠癌其表达升高与侵袭性呈正相关。Ezrin蛋白是细胞膜与细胞骨架之间的连接蛋白,与肿瘤的侵袭性密切相关,是ERM蛋白(Ezrin、Radixm Moesin)家族的一员,以往又称为eytovillin、P81或villin-2。
miRNA的研究尚处于起步阶段,miRNA的表达与结肠癌的发生发展以及浸润和转移之间到底存在着什么样的具体关系,目前还不是十分明了。本研究拟采用miRNA芯片及RT-PCR,免疫组织化学等研究方法,旨在通过对比研究结直肠癌及其癌旁正常组织中micro RNAs (miRNAs)的差异表达,初步探讨结直肠癌组织中miRNA的差异表达谱及其在结直肠癌临床生物学特点判定中的检测意义。
本文收集手术切除的11例新鲜的结直肠癌和其癌旁正常组织标本,立即低温保存并提取RNA。应用AFFX miRNA表达谱芯片实验初步筛查癌及癌旁正常组织中]miRNAs的差异表达,并采用实时定量PCR技术验证芯片检测结果。结果表明结直肠癌和癌旁正常组织中miRNAs表达有明显羊异,与癌旁正常组织相比,结直肠癌中有25个miRNAs表达显著不同(P<0.001),包括15个上调和10个下调的miRNAs。高表达的miRNAs分别是：hsa-miR-31, hsa-miR-767-5p, hsa-miR-105, hsa-miR-196b, hsa-miR-224, hsa-miR-483-5, hsa-miR-1246, hsa-miR-196b, hsa-miR-663b, hsa-miR-584, hsa-miR-141, hsa-miR-18a, hsa-miR-19a, hsa-miR-452, hsa-miR-622。低表达的miRNAs分别是：hsa-miR-215, hsa-miR-4298, hsa-miR-139-5p, hsa-miR-490-5p, hsa-miR-3201, hsa-miR-363, hsa-miR-187, hsa-miR-133a, hsa-miR-1825, hsa-miR-30a。进一步的qRT-PCR结果显示：与癌旁正常组织相比,癌组织中miR-31, miR-105, miR-196b, miR-224, miR-483-5p和：miR-767-5p的mRNA表达水平明显上调(P<0.05),而miR-139-5p, miR-215, miR-490-5p和miR-4298等mRNA水平明显下调(P<0.05),与芯片结果一致。
在此基础上,选取结直肠癌中显著高表达的miR-31, miR-105和miR-196b作为进一步深入研究的对象,并进一步扩大了病例数,以53例新鲜的结直肠癌及其15例癌旁正常组织作为研究对象,应用qRT-PCR技术对比分析其异常表达与临床生物学特点之间的相关性。同时,通过Targets Scan检索,分析miR-31的密切相关基因—Ezrin,并应用免疫组化及RT-PCR方法确定其在CRC组织中的过表达意义。结合临床病理资料发现：miR-31与结直肠癌的病理分型(P<0.01)和临床分期(P<0.05)显著相关,但与淋巴转移及远处转移不相关(P>0.05); miR-105与病理分型,临床分期,淋巴结转移及远处转移均呈正相关(P<0.05)；而miR-196b只与病理分型有关(P<0.05),但与淋巴结转移和远处转移及临床分期均无关(P>0.05)。另外,实验发现Ezrin蛋白和其mRNA均在CRC组织中存在高表达,且与结直肠癌淋巴结转移关系密切。
结论结直肠癌中存在着明显的miRNAs差异表达,miRNAs特异表达可能成为结直肠癌的潜在的诊断和治疗的分子靶点。miR-31, miR-105和miR-196b高表达预示结直肠癌的不良预后。miR-31的相关基因Ezrin基因mRNA和蛋白水平的高表达可以预示结直肠癌的不良预后,即淋巴结转移。
Colorectal cancer (CRC) remains a common malignant tumor of digestive tract in the worldwide. Several dietary and other lifestyle factors have been implicated in the development of colorectal cancer. As our country's economy developed at high-speed, people's living level improved greatly and lifestyle has been Western, the incidence of CRC has improved significantly year by year. In recent years, the incidence and death rate of CRC has risen to No.5and No.5in our country. According to the changes of initiation and development of CRC in other countries and the dynamic of incidence rate of cancer in all regions of China in recent years, we can see that CRC will be one of the fastest rising malignancy cancers in China of this century.
MicroRNAs (miRNAs) are small nucleotide RNA species that are expressed from specialized genes. The first miRNA was characterized in the nematode by Lee et al, and was termed as lin-14. It has been reported that miRNAs plays an extremely important role in cell growth, cell death, apoptosis, and metastasis during the carcinogenesis and tumor progression.
MiRNAs have been found to have links with multiple types of cancer. It acts as oncogene or cancer suppressor gene and plays an important part in regulation function. In recent years, a number of informative profiling studies have determined the levels of miRNAs in various types of cancer cell lines and tumors. Multiple functional studies on tumor suppressive or oncogenic miRNAs were identified from profiling, screens or due to their cancer-associated genomic loci. Numerous miRNAs and target genes formed a complex network. Many studies showed that miRNA-31has different expression levels in cancers. Previous studies found that miR-31over-expressed in colon cancer, head and neck cancer, hepatocellular cancer, oral cavity squamous cell cancer and lung cancer; low-expressed in bladder cancer, prostate cancer, gastric cancer, breast cancer, serous ovarian cancer and so on. Many evidence demonstrated the involvement of miR-31in tumor metastasis. For example.the high expression of miR-31could prevent the metastasis of breast cancer, but promote the invasion of CRC. This discrepancy could have resulted from the different role of miR-31in these cancers. Ezrin (also known as P81or villin-2) is a member of the ERM protein (Ezrin, Radixm, Moesin family). It is connexin between cell membrane and cytoskeleton and involved in the motility of cancer cells.
The research of miRNA is still in the initial stage. But we still don't know the relationship between the expression of miRNA and the development, invasion and metastasis of CRC. In this study, we focused on the expression of miRNAs in CRC and the adjacent tissues by miRNA gene microarray, determined some cellular functions and molecular pathways targeted by these differentially expressed miRNAs, and discussed differential expression profile and the judgement of clinical biology characteristics in the CRC tissue.
11CRC and adjacent tissue treated with surgery were collected and frozen immediately. For microarray analysis, the AFFX microRNA biochip was used. Total RNA was isolated from samples and more than thousand miRNAs were analyzed. The interested miRNAs were conformed by a real-time PCR analysis. This approach enabled the identification of miRNAs whose expression is significantly altered in CRC compared with the normal tissues from the same patient. In result,25miRANs were found to be differentially expressed in tumors compared with the adjacent tissues (P<0.001), including15over-expressed miRNAs (has-miR-31,has-miR-767-5. has-miR-105, has-miR-196b-star, has-miR-224, has-miR-483-5p, has-miR-1246, has-miR-196b, has-miR-663b, has-miR-584, has-miR-141, has-miR-18a-star, has-miR-19a, has-miR-452, has-miR-622) and10low-expressed miRNAs (miR-215, miR-4298, mi-R-139-5p, has-miR-490-5p. miR-3201, miR-363. miR-187. miR-133a. miR-1825. miR-30). The further result of qRT-PCR(Real-Time quantitative fluorescence PCR) showed that the expression of miR-31. miR-105. miR-196b. miR-224, miR-483-5p and miR-767-5p in tumor has up-regulated compared with carcinoma side normal tissue(P<0.05). While miR-139-5p, miR-215. miR-490-5p and miR-4298are obviously down-regulated which consist with chip result(P<0.05).
On that basis, including miR-31. miR-105and miR-196b. strongly up-regulated in CRC were selected to the further Real time PCR study with more samples of CRC. The samples are from53of CRC and15of adjacent tissue. And this study used qRT-PCR to comparatively analyse its differential expression and the judgement of clinical biology characteristics. Meanwhile, we analysed gene Ezrin-closely related to miR-31via Targets Scan search method. And we determined its expression in CRC tissue by immunohistochemistry and RT-PCR analysis. We found miR-31was correlated with histological type (P <0.01) and the clinical stage (P<0.05). And no statistically difference was found between miR-31expression and lymph node metastasis on differentiation (P>0.05); miR-105was positive correlated with histological type, clinical stage and lymph node metastasis (P<0.05); while miR-196-5p was only correlated with the histological type of CRC. Additionally, the over-expression of Ezrin protein and mRNA were indicated by western blotting and RT-PCR in CRC, respectively. Analysis of IHC result demonstrated Ezrin was correlated with the metastasis of CRC.
Conclusion:Colorectal cancer exists obvious differences of miRNAs expression, miRNAs specifically expressed may become colorectal cancer potential diagnosis and treatment of molecular targets. miR-31, miR-105and miR-196-b high expression indicates poor outcome of colorectal cancer. miR-31related gene Ezrin gene mRNA and protein levels high expression predicts colorectal cancer adverse outcomes, namely the lymph node metastasis.
引文
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