Abstract 1223: LIF is a novel negative regulator of p53 in colorectal cancers

• Published in: Cancer research (Chicago, Ill.) Ill.), 2015-08, Vol.75 (15_Supplement), p.1223-1223
• Main Authors: Hu, Wenwei, Yu, Haiyang, Yue, Xuetian, Zhao, Yuhan, Zhang, Cen, Young, Ken, Liu, Juan, Feng, Zhaohui
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2015-1223

Leukemia inhibitory factor (LIF), a cytokine of the interleukin 6 superfamily,is involved in multiple biological functions. Recently, we identified that LIF is a p53 target gene which mediates the role of p53 in maternal implantation under normal physiological conditions in both mice and humans. However, to date, the role of LIF in tumorigenesis, especially colorectal cancers, is poorly understood. Here, we report that LIF is a negative regulator of p53; LIF downregulates p53 protein levels and function in transcriptional activity, apoptosis and senescence in human colorectal cancer cells. The downregulation of p53 by LIF is mediated by the activation of Stat3; blocking the Stat3 pathway largely abolishes the inhibitory effect of LIF on p53. We further identified that Stat3 transcriptionally induces ID1, the helix-loop-helix (HLH) protein inhibitor of differentiation and DNA binding to mediate its role in the negative regulation of p53. ID1 upregulates MDM2, a key negative regulator of p53, and promotes MDM2-mediated p53 protein degradation. We found that LIF is overexpressed in a large percentage of colorectal cancers. In turn, LIF overexpression promotes cellular resistance towards chemotherapeutic agents in cultured colorectal cancer cells and colorectal xenograft tumors in a largely p53-dependent manner. Furthermore, we found that overexpression of LIF is associated with a poor prognosis in colorectal 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 colorectal cancers. Targeting LIF, Stat3 as well as ID1 to reactivate p53 is a potential therapeutic strategy to enhance chemosensitivity in colorectal cancer, especially in tumors with LIF overexpression. Citation Format: Wenwei Hu, Haiyang Yu, Xuetian Yue, Yuhan Zhao, Cen Zhang, Ken Young, Juan Liu, Zhaohui Feng. LIF is a novel negative regulator of p53 in colorectal cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1223. doi:10.1158/1538-7445.AM2015-1223