LIF negatively regulates tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancers

Haiyang Yu, Xuetian Yue, Yuhan Zhao, Xiaoyan Li, Lihua Wu, Cen Zhang, Zhen Liu, Kevin Lin, Zijun Y. Xu-Monette, Ken H. Young, Juan Liu, Zhiyuan Shen, Zhaohui Feng () and Wenwei Hu ()
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Haiyang Yu: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey
Xuetian Yue: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey
Yuhan Zhao: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey
Xiaoyan Li: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey
Lihua Wu: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey
Cen Zhang: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey
Zhen Liu: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey
Kevin Lin: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey
Zijun Y. Xu-Monette: University of Texas MD Anderson Cancer Center
Ken H. Young: University of Texas MD Anderson Cancer Center
Juan Liu: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey
Zhiyuan Shen: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey
Zhaohui Feng: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey
Wenwei Hu: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6218

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