title: Tumor suppressor functions of miR-133a in colorectal cancer.
abstract: Dysregulated microRNA (miRNA) expression was profiled through a miRNA array comparison between human colorectal cancer tumors and their adjacent normal tissues. Specifically, using laser capture micro-dissection, miR-133a was shown to be significantly downregulated in primary colorectal cancer specimens compared with matched adjacent normal tissue. Ectopic expression of miR-133a significantly suppressed colorectal cancer cell growth in vitro and in vivo. Cell-cycle analysis revealed that miR-133a induced a G0/G1-phase arrest, concomitant with the upregulation of the key G1-phase regulator p21(Cip1). We further revealed that miR-133a markedly increased p53 protein and induced p21(Cip1) transcription. Studies in silico revealed that the 3'UTR of the ring finger and FYVE-like domain containing E3-ubiquitin protein ligase (RFFL), which regulates p53 protein, contains an evolutionarily conserved miR-133a binding site. miR-133a repressed RFFL-3'UTR reporter activity and reduced RFFL protein levels, indicating that miR-133a directly bound to RFFL mRNA and inhibited RFFL translation. Moreover, miR-133a sensitized colon cancer cells to doxorubicin and oxaliplatin by enhancing apoptosis and inhibiting cell proliferation. These data add weight to the significance of miR-133a in the development of CRC.
  
  
  CONCLUSIONS
  miR-133a serves as a potential tumor suppressor upstream of p53 in colorectal cancer and may sensitize cells to therapeutics.
authors.affiliation: Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong. junyu@cuhk.edu.hk.
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Dong
authors.forename: Junhong
authors.initials: J
authors.lastname: Zhao
authors.forename: Chung-Wah
authors.initials: CW
authors.lastname: Wu
authors.forename: Lijing
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Kang
authors.forename: Wing-Wah
authors.initials: WW
authors.lastname: Leung
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Francis K L
authors.initials: FK
authors.lastname: Chan
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
authors.forename: Simon S M
authors.initials: SS
authors.lastname: Ng
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; C548234:MIRN133 microRNA, human; D035683:MicroRNAs; D009944:Organoplatinum Compounds; D016159:Tumor Suppressor Protein p53; D000077150:Oxaliplatin; D004317:Doxorubicin