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

• Published in: Nature communications 2014-10, Vol.5 (1), p.5218-5218, Article 5218
• Main Authors: Yu, Haiyang, Yue, Xuetian, Zhao, Yuhan, Li, Xiaoyan, Wu, Lihua, Zhang, Cen, Liu, Zhen, Lin, Kevin, Xu-Monette, Zijun Y., Young, Ken H., Liu, Juan, Shen, Zhiyuan, Feng, Zhaohui, Hu, Wenwei
• Format: Article
• Language: English
• Subjects: 13; 13/2; 38; 38/89; 631/67/1059/2326; 631/67/1504/1885; 631/80/86; 64/60; 82/1; 82/51; 96/109; 96/31; 96/95; Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Cellular Senescence; Cohort Studies; Colorectal cancer; Colorectal Neoplasms - metabolism; Down-Regulation; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Genes; Humanities and Social Sciences; Humans; Inhibitor of Differentiation Protein 1 - metabolism; Leukemia; Leukemia Inhibitory Factor - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Nude; multidisciplinary; Neoplasm Transplantation; Oligonucleotide Array Sequence Analysis; Proteins; Proto-Oncogene Proteins c-mdm2 - metabolism; Regulation; Science; Science (multidisciplinary); STAT3 Transcription Factor - metabolism; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms6218

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. Leukaemia inhibitory factor (LIF) is a p53 target but its role in cancer is unclear. Here Hu et al. show that LIF confers chemoresistance in colorectal cancer cells by Stat3-mediated upregulation of inhibitor of DNA-binding 1, leading to MDM2 E3 ubiquitin ligase upregulation and p53 degradation.