title: LIF negatively regulates tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancers.
abstract: Leukaemia inhibitory factor (LIF) has been recently identified as a p53 target gene, which mediates the role of p53 in maternal implantation under normal physiological conditions. Here we report that LIF is a negative regulator of p53; LIF downregulates p53 protein levels and function in human colorectal cancer (CRC) cells. The downregulation of p53 by LIF is mediated by the activation of Stat3, which transcriptionally induces inhibitor of DNA-binding 1 (ID1). ID1 upregulates MDM2, a key negative regulator of p53, and promotes p53 protein degradation. LIF is overexpressed in a large percentage of CRCs. LIF overexpression promotes cellular resistance towards chemotherapeutic agents in cultured CRC cells and colorectal xenograft tumours in a largely p53-dependent manner. Overexpression of LIF is associated with a poor prognosis in CRC patients. Taken together, LIF is a novel negative regulator of p53, overexpression of LIF is an important mechanism for the attenuation of p53, which promotes chemoresistance in CRCs.
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, New Jersey 08903, USA.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Yu
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, New Jersey 08903, USA.
authors.forename: Xuetian
authors.initials: X
authors.lastname: Yue
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, New Jersey 08903, USA.
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: 1] Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, New Jersey 08903, USA [2] Department of Breast Surgery, Qilu Hospital, Shandong University, Ji'nan 250012, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.affiliation: 1] Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, New Jersey 08903, USA [2] First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wu
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, New Jersey 08903, USA.
authors.forename: Cen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, New Jersey 08903, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, New Jersey 08903, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lin
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Zijun Y
authors.initials: ZY
authors.lastname: Xu-Monette
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Ken H
authors.initials: KH
authors.lastname: Young
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, New Jersey 08903, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, New Jersey 08903, USA.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, New Jersey 08903, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, New Jersey 08903, USA.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Hu
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D016922:Cellular Senescence; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000378:metabolism*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism*; D053605:Leukemia Inhibitory Factor / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2