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c-MYC调节的miRNA-92b在结直肠癌发生发展中的功能及机制探究
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中国科学院上海生命科学研究院生物化学与细胞生物学研究所,中国科学院上海生命科学研究院生物化学与细胞生物学研究所,浙江理工大学生命科学学院新元医学与生物技术研究所,中国科学院上海生命科学研究院生物化学与细胞生物学研究所,中国科学院上海生命科学研究院生物化学与细胞生物学研究所,中国科学院上海生命科学研究院生物化学与细胞生物学研究所,浙江大学医学院附属第二医院肿瘤研究所，教育部恶性肿瘤预警与干预重点实验室，浙江省医学分子生物学重点实验室,中国科学院上海生命科学研究院生物化学与细胞生物学研究所

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四川省科技厅技术创新工程专项(2013ZZ0004)，中国科学院上海生化细胞所&四川辉阳生命工程股份有限公司合作项目(Y363S21763)，国家重点基础研究发展计划(973)(2011CB510104)和浙江理工大学基金(1204807-Y)资助项目


c-MYC-Regulated miRNA-92b Inhibits Expression of The E3 Ligase FBXW7 in Colorectal Cancer
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State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University,State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine,State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

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This work was supported by grants from the Sichuan Science and Technology Project (2013ZZ0004), the Shanghai Institutes for Biological Science, Chinese Academy of Sciences & the Sichuan Huiyang Life Science and Technology Corp. Research Program (Y363S21763), National Basic Research Program of China (2011CB510104) and a Zhejiang Sci-Tech University Grant (1204807-Y)

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    摘要:

    microRNAs(miRNAs)在参与癌症发生、发展过程中起着十分重要的作用．目前，miR-92b在结直肠癌中的作用及相关机制还未见报道．本研究探讨了miR-92b在结直肠癌发生发展中的功能及潜在机制．采用RT-qPCR方法发现，miR-92b在人结直肠癌临床样本中与癌旁组织相比显著高表达．通过结肠癌细胞株SW620稳转细胞及裸鼠皮下成瘤模型，发现过表达miR-92b可以显著促进细胞增殖及体内肿瘤生长．同时还发现miR-92b可以分泌形式存在于胞外及外周血中，提示miR-92b是一个具有分泌特性的microRNA． 在分子机理方面，c-MYC可通过调节miR-92b的启动子活性从而促进后者转录，并且c-MYC在结直肠癌组织样本中也存在高表达．进一步，通过在线预测、报告质粒活性检测及蛋白质印迹技术证实FBXW7是一个新的miR-92b靶基因．由于FBXW7已报道为c-MYC泛素降解过程中的关键泛素化连接酶之一，本研究结果提示结直肠癌中c-MYC、miR-92b及FBXW7三者间可能存在分子调节环路．综上所述，本研究为miR-92b在结直肠癌中的功能及机制提供了新的视角，并为miR-92b在结直肠癌早期诊断中的应用提供了新的参考．

    Abstract:

    Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. Many microRNAs (miRNAs) have been reported to be abnormally expressed in CRC. Recent studies have identified miR-92b as a potential oncogene in several types of cancer. However, the role of miR-92b in CRC has not been clarified. This study aimed to elucidate the role of miR-92b in CRC progression. Relative quantitative PCR revealed that miR-92b expression was significantly increased in human CRC tissues compared to the adjacent tissues. Overexpression of miR-92b in the colorectal cancer cell line SW620 substantially increased cell viability in vitro and xenograft tumor growth in vivo. Also, miR-92b was identified as a secreted miRNA, which can be detected in both cultured medium and the peripheral blood of xenograft mice. Furthermore, we demonstrated that c-MYC, which was also elevated in CRC tissues, promoted the transcription of miR-92b by regulating its promoter activity. Luciferase assay and Western blot analysis revealed that FBXW7 was a novel target of miR-92b and can be negatively regulated by c-MYC. As FBXW7 is a major E3 ligase of c-MYC, our data suggested a potential positive regulatory feedback loop among c-MYC, miR-92b and FBXW7 in CRC. Collectively, we partly provided evidence on how miR-92b is regulated and the potential implications of miR-92b in CRC diagnosis.

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尹晓飞,吴帅,杨远勤,方先龙,徐海能,刘新垣,郑树,章康健. c-MYC调节的miRNA-92b在结直肠癌发生发展中的功能及机制探究[J].生物化学与生物物理进展,2016,43(7):673-683

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  • 收稿日期:2016-04-14
  • 最后修改日期:2016-06-08
  • 接受日期:2016-06-16
  • 在线发布日期: 2016-07-19
  • 出版日期: 2016-07-20
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