前列腺癌患者血清中相关miRNA的检测
摘要
前列腺癌(Pca)为最常见的恶性肿瘤之一,也是迄今为止男性癌症中的第二大杀手,特别是在70以上人群中,居泌尿系统肿瘤的第三位,严重危害着男性的身体健康和生活质量。至今其发病原因尚不明确,但显然与家族遗传性有一定关系,并且在欧洲的发病率高于亚洲,提示与生活方式特别是饮食关系密切。但随着生活方式的西化和饮食结构的改变,亚洲国家的前列腺癌的发病率也在迅猛的增长。同时我国已逐步进入老龄化社会,老龄人口达2亿,前列腺癌的患者人群必将逐年增加。PSA检测和直肠指检时常用的前列腺癌早期筛查方法,但存在着诸多的盲区。建立一个或一系列稳定性好、特异性高的前列腺癌诊断指标,以达到病程监测的目的是很多研究者们研究的目标。
miRNA是动植物细胞内自然产生的一类非编码小RNA。近年来发现,miRNA可在多数肿瘤中特异性地表达,如结肠癌、胰腺癌、慢性淋巴细胞白血病、肺癌、神经母细胞瘤、食管癌、前列腺癌等。而且,miRNA可释放于血液中,具有很好稳定性和特异性,可作为潜在的新型肿瘤标志物。因此,血液中与前列腺癌相关的miRNA,可能对于其早期诊断和病程监测具有重要的意义。
在本研究中,我们首先根据文献选择了miR-141、miR-16、miR-103、miR-574、miR-34b、miR-485等6种前列腺癌相关miRNA,以荧光定量PCR方法检测它们在前列腺癌、前列腺增生患者和正常人血清中的含量,分析其与前列腺癌的相关性。结果显示,miRNA-103和miRNA-34b在前列腺癌患者、前列腺增生患者和PSA增高人群血清中的含量普遍较正常人增高,其中miR-34b升高最为显著,但在前列腺癌和前列腺增生患者中没有显著差异,只与PSA升高相关。说明miRNA-34b是一个与PSA相当的前列腺癌检测指标。
继而,我们用miRNA基因芯片检测了前列腺增生和Gleason6、7、8、9期的前列腺癌患者及正常人的血清。结果显示,前列腺癌血清miRNA表达谱明显与肿瘤恶性程度相关,其中156个miRNA表达差异;miR-16和miR-141在前列腺增生患者与前列腺癌各期患者血清中均有降低;miR-34在前列腺增生患者与前列腺癌各期患者血清中表达增强;miR-200c、miR-583和miR-29a等特异性升高于Gleason8期前列腺癌患者。定量PCR检测进一步显示,miR-7a和miR-7f在前列腺癌和前列腺增生患者血清中普遍降低,并且其在前列腺癌患者血清中的表达水平低于正常人和前列腺增生患者。
最后,我们合成了let-7fmiRNA,以建立检测血清let-7f的荧光定量PCR方法,为进一步应用其进行临床调查和检测奠定了基础。
Prostate cancer (Pca) is the most common malignant tumor, is so far the men's second biggest killer cancer, especially in people over 70, ranking third in the urinary system cancer, serious harm to the health of men And quality of life. Its causes are still unclear, but apparently associated with the familial history, i.e hereditary. And there is higher incidence in Europe than in Asia. That means it particularly associated with diet and lifestyle tips closely. However, with the westernization of lifestyle and dietary changes in the structure of Asian countries, the incidence of prostate cancer growth is also rapid. Meanwhile, China has gradually entered the aging society. There has been the aging population of 2 million. Prostate cancer patient population will increase year by year. PSA testing and digital rectal examination are the commonly used methods of early screening for prostate cancer, but there are many blind spots. So one objective of the study researchers is to establish one or a series of diagnostic marker of prostate cancer has good stability andhigh specificity, in order to achieve the purpose of monitoring the course of prostate cancer progress.
miRNA is a class of non-coding small RNA naturally occurring in plant and animal cells. Discovered in recent years, miRNA can be specifically expressed in the majority of tumors, such as colon cancer, pancreatic cancer, chronic lymphocytic leukemia, lung cancer, neuroblastoma, esophageal cancer, prostate cancer, etc. Moreover, miRNA can be released into the blood, with good stability and specificity as potential new tumor markers. Therefore, the serum miRNA associated with prostate cancer may of great significance for its early diagnosis and disease monitoring.
In this study, according to the literature we first selected 6 kinds of miRNAs including miR-141, miR-16, miR-103, miR-574, miR-34b, miR-485, as potential markers of prostate cancer. Then we used the fluorescent quantitative PCR to quantify them in prostate cancer, benign prostatic hyperplasia patients and normal human serumt, analyzing its correlation with prostate epecific antigen (PSA). The results showed that, miRNA-103 and miRNA-34b elevated in prostate cancer, benign prostatic hyperplasia patients and anyother patients with high serum PSA levels. In which miR-34b increased apparently, but no significant differences between prostate cancer and benign prostatic hyperplasia patients. That suggest that miRNA-34b is an equivalent marker for prostate cancer similar as PSA.
Then, we used miRNA microarray screened miRNA expression in serum of benign prostate hyperplasia patients and prostate cancer patients with Gleason6, 7,8,9 comparing to normal serum.The results showed that serum miRNA expression profiles of prostate cancer were significantly associated with tumor malignancy. Of which 156 miRNAs expression difference; miR-16 and miR-141 decreased in both of patients with benign prostatic hyperplasia and prostate cancer; miR-34 increased in benign prostatic hyperplasia and prostate cancer patients; miR-200c, miR-583 and miR-29a specifically up-regulated in Gleason8 of prostate cancer patients. The RT-PCR show that both the miR-7a and miR-7f were down-regulated in prostate cancer patients, also a little bit lower than in benign prostatic hyperplasia patients.
Finally, we synthesized a Let-7f miRNA to establish fluorescence quantitative PCR method to measure serum Let-7f. It will lay foundation to further investigate let-7f level in the clinical samples.
miRNA是动植物细胞内自然产生的一类非编码小RNA。近年来发现,miRNA可在多数肿瘤中特异性地表达,如结肠癌、胰腺癌、慢性淋巴细胞白血病、肺癌、神经母细胞瘤、食管癌、前列腺癌等。而且,miRNA可释放于血液中,具有很好稳定性和特异性,可作为潜在的新型肿瘤标志物。因此,血液中与前列腺癌相关的miRNA,可能对于其早期诊断和病程监测具有重要的意义。
在本研究中,我们首先根据文献选择了miR-141、miR-16、miR-103、miR-574、miR-34b、miR-485等6种前列腺癌相关miRNA,以荧光定量PCR方法检测它们在前列腺癌、前列腺增生患者和正常人血清中的含量,分析其与前列腺癌的相关性。结果显示,miRNA-103和miRNA-34b在前列腺癌患者、前列腺增生患者和PSA增高人群血清中的含量普遍较正常人增高,其中miR-34b升高最为显著,但在前列腺癌和前列腺增生患者中没有显著差异,只与PSA升高相关。说明miRNA-34b是一个与PSA相当的前列腺癌检测指标。
继而,我们用miRNA基因芯片检测了前列腺增生和Gleason6、7、8、9期的前列腺癌患者及正常人的血清。结果显示,前列腺癌血清miRNA表达谱明显与肿瘤恶性程度相关,其中156个miRNA表达差异;miR-16和miR-141在前列腺增生患者与前列腺癌各期患者血清中均有降低;miR-34在前列腺增生患者与前列腺癌各期患者血清中表达增强;miR-200c、miR-583和miR-29a等特异性升高于Gleason8期前列腺癌患者。定量PCR检测进一步显示,miR-7a和miR-7f在前列腺癌和前列腺增生患者血清中普遍降低,并且其在前列腺癌患者血清中的表达水平低于正常人和前列腺增生患者。
最后,我们合成了let-7fmiRNA,以建立检测血清let-7f的荧光定量PCR方法,为进一步应用其进行临床调查和检测奠定了基础。
Prostate cancer (Pca) is the most common malignant tumor, is so far the men's second biggest killer cancer, especially in people over 70, ranking third in the urinary system cancer, serious harm to the health of men And quality of life. Its causes are still unclear, but apparently associated with the familial history, i.e hereditary. And there is higher incidence in Europe than in Asia. That means it particularly associated with diet and lifestyle tips closely. However, with the westernization of lifestyle and dietary changes in the structure of Asian countries, the incidence of prostate cancer growth is also rapid. Meanwhile, China has gradually entered the aging society. There has been the aging population of 2 million. Prostate cancer patient population will increase year by year. PSA testing and digital rectal examination are the commonly used methods of early screening for prostate cancer, but there are many blind spots. So one objective of the study researchers is to establish one or a series of diagnostic marker of prostate cancer has good stability andhigh specificity, in order to achieve the purpose of monitoring the course of prostate cancer progress.
miRNA is a class of non-coding small RNA naturally occurring in plant and animal cells. Discovered in recent years, miRNA can be specifically expressed in the majority of tumors, such as colon cancer, pancreatic cancer, chronic lymphocytic leukemia, lung cancer, neuroblastoma, esophageal cancer, prostate cancer, etc. Moreover, miRNA can be released into the blood, with good stability and specificity as potential new tumor markers. Therefore, the serum miRNA associated with prostate cancer may of great significance for its early diagnosis and disease monitoring.
In this study, according to the literature we first selected 6 kinds of miRNAs including miR-141, miR-16, miR-103, miR-574, miR-34b, miR-485, as potential markers of prostate cancer. Then we used the fluorescent quantitative PCR to quantify them in prostate cancer, benign prostatic hyperplasia patients and normal human serumt, analyzing its correlation with prostate epecific antigen (PSA). The results showed that, miRNA-103 and miRNA-34b elevated in prostate cancer, benign prostatic hyperplasia patients and anyother patients with high serum PSA levels. In which miR-34b increased apparently, but no significant differences between prostate cancer and benign prostatic hyperplasia patients. That suggest that miRNA-34b is an equivalent marker for prostate cancer similar as PSA.
Then, we used miRNA microarray screened miRNA expression in serum of benign prostate hyperplasia patients and prostate cancer patients with Gleason6, 7,8,9 comparing to normal serum.The results showed that serum miRNA expression profiles of prostate cancer were significantly associated with tumor malignancy. Of which 156 miRNAs expression difference; miR-16 and miR-141 decreased in both of patients with benign prostatic hyperplasia and prostate cancer; miR-34 increased in benign prostatic hyperplasia and prostate cancer patients; miR-200c, miR-583 and miR-29a specifically up-regulated in Gleason8 of prostate cancer patients. The RT-PCR show that both the miR-7a and miR-7f were down-regulated in prostate cancer patients, also a little bit lower than in benign prostatic hyperplasia patients.
Finally, we synthesized a Let-7f miRNA to establish fluorescence quantitative PCR method to measure serum Let-7f. It will lay foundation to further investigate let-7f level in the clinical samples.
引文
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