title: microRNA-1827 represses MDM2 to positively regulate tumor suppressor p53 and suppress tumorigenesis.
abstract: The tumor suppressor p53 plays a central role in tumor prevention. The E3 ubiquitin ligase MDM2 is the most critical negative regulator of p53, which binds to p53 and degrades p53 through ubiquitation. MDM2 itself is a transcriptional target of p53, and therefore, MDM2 forms a negative feedback loop with p53 to tightly regulate p53 levels and function. microRNAs (miRNAs) play a key role in regulation of gene expression. miRNA dysregulation plays an important role in tumorigenesis. In this study, we found that miRNA miR-1827 is a novel miRNA that targets MDM2 through binding to the 3'-UTR of MDM2 mRNA. miR-1827 negatively regulates MDM2, which in turn increases p53 protein levels to increase transcriptional activity of p53 and enhance p53-mediated stress responses, including apoptosis and senescence. Overexpression of miR-1827 suppresses the growth of xenograft colorectal tumors, whereas the miR-1827 inhibitor promotes tumor growth in mice in a largely p53-dependent manner. miR-1827 is frequently down-regulated in human colorectal cancer. Decreased miR-1827 expression is associated with high MDM2 expression and poor prognosis in colorectal cancer. In summary, our results reveal that miR-1827 is a novel miRNA that regulates p53 through targeting MDM2, and highlight an important role and the underlying mechanism of miR-1827 in tumor suppression.
authors: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ 08903, USA.
authors: Cen
authors: C
authors: Zhang
authors: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ 08903, USA.
authors: Juan
authors: J
authors: Liu
authors: Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors: Chunwen
authors: C
authors: Tan
authors: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ 08903, USA.
authors: Xuetian
authors: X
authors: Yue
authors: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ 08903, USA.
authors: Yuhan
authors: Y
authors: Zhao
authors: Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors: Jiaping
authors: J
authors: Peng
authors: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ 08903, USA.
authors: Xiaolong
authors: X
authors: Wang
authors: Center for Systems Biology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ 08903, USA.
authors: Saurabh V
authors: SV
authors: Laddha
authors: Center for Systems Biology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ 08903, USA.
authors: Chang S
authors: CS
authors: Chan
authors: Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors: Shu
authors: S
authors: Zheng
authors: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ 08903, USA.|Department of Pharmacology, Rutgers, State University of New Jersey, Piscataway, NJ 08854, USA.
authors: Wenwei
authors: W
authors: Hu
authors: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ 08903, USA.|Department of Pharmacology, Rutgers, State University of New Jersey, Piscataway, NJ 08854, USA.
authors: Zhaohui
authors: Z
authors: Feng
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; C561495:MIRN1827 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2; microRNA; negative feedback loop; p53; tumor suppressor