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

被引：142

作者：

Yu, Haiyang ^{[1
]}

Yue, Xuetian ^{[1
]}

Zhao, Yuhan ^{[1
]}

Li, Xiaoyan ^{[1
,2
]}

Wu, Lihua ^{[1
,3
]}

Zhang, Cen ^{[1
]}

Liu, Zhen ^{[1
]}

Lin, Kevin ^{[1
]}

Xu-Monette, Zijun Y. ^{[4
]}

Young, Ken H. ^{[4
]}

Liu, Juan ^{[1
]}

Shen, Zhiyuan ^{[1
]}

Feng, Zhaohui ^{[1
]}

Hu, Wenwei ^{[1
]}

机构：

[1] Rutgers State Univ, Rutgers Canc Inst New Jersey, New Brunswick, NJ 08903 USA

[2] Shandong Univ, Qilu Hosp, Dept Breast Surg, Jinan 250012, Peoples R China

[3] Zhejiang Univ, Affiliated Hosp 1, Hangzhou 310003, Zhejiang, Peoples R China

[4] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

关键词：

LEUKEMIA INHIBITORY FACTOR; SINGLE NUCLEOTIDE POLYMORPHISM; UBIQUITIN-PROTEIN LIGASE; EMBRYONIC STEM-CELLS; BREAST-CANCER; COLON-CANCER; INDUCED APOPTOSIS; INITIATING CELLS; UP-REGULATION; EXPRESSION;

D O I：

10.1038/ncomms6218

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

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