Tumor suppressor p53 plays a crucial role in tumor suppression. Recently, we identified leukemia inhibitory factor (LIF) as a novel p53 target gene. To date, the role of LIF in tumorigenesis is poorly understood. Our following preliminary data strongly suggest that LIF is a novel negative regulator of p53 and plays an important role in colorectal cancer. 1) LIF is overexpressed in a high percentage of human colorectal cancers that we examined. 2) LIF down-regulates p53 protein levels and function in colorectal cancer cells, including HCT116 p53+/+ cells. 3) LIF promotes the proliferation of colorectal cancer cells, and the growth and angiogenesis of xenograft colorectal tumors. We hypothesize that LIF overexpression plays an important role in promoting tumorigenesis and therapeutic resistance in colorectal cancers, and the down-regulation of p53 function is an important underlying mechanism. In this proposed study, 1) we will investigate the down- regulation of p53 levels and function by LIF in colorectal cells in addition to HCT116 p53+/+ cells. 2) We will determine the mechanisms by which LIF down-regulates p53. Our preliminary studies strongly suggest that LIF down-regulates p53 function through the induction of specific p53 negative regulators in colorectal cells. To test this hypothesis, we will investigate whether endogenous LIF protein regulates the expression of these p53 negative regulators in colorectal cells. Furthermore, we will investigate the role and mechanisms of these p53 negative regulators in mediating the down-regulation of p53 by LIF in colorectal cells. 3) We will determine the role of LIF in promoting the growth, angiogenesis and therapeutic resistance in xenograft colorectal tumors. Furthermore, we will test the hypothesis that the down-regulation of p53 by LIF is an important mechanism for the promoting effect of LIF on tumorigenesis in xenograft colorectal tumors. 4) We will further investigate the mechanism accounting for LIF overexpression in both colorectal cancer cells and human colorectal cancer samples. The goal of this proposed study is to understand the role and molecular mechanisms of LIF in colorectal cancer. This study should greatly increase our understanding of molecular mechanisms of colorectal tumorigenesis;and furthermore, have the direct potential to develop LIF as an important tumor biomarker and a therapeutic target for colorectal cancers.

Public Health Relevance

The goal of this proposed study is to understand the role and molecular mechanism of LIF in colorectal cancers. It is our anticipation that this study will establish the important role of LIF overexpression in promoting tumorigenesis and therapeutic resistance in colorectal cancers, and provide the down- regulation of p53 by LIF as an important underlying mechanism. This study will have the direct potential to develop LIF as an important tumor biomarker and a therapeutic target for colorectal cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA160558-01A1
Application #
8295104
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Watson, Joanna M
Project Start
2012-09-01
Project End
2013-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$327,850
Indirect Cost
$120,350
Name
University of Medicine & Dentistry of NJ
Department
Pediatrics
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Zhang, Cen; Liu, Juan; Huang, Grace et al. (2016) Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression. Genes Dev 30:1956-70
Yue, Xuetian; Zhao, Yuhan; Huang, Grace et al. (2016) A novel mutant p53 binding partner BAG5 stabilizes mutant p53 and promotes mutant p53 GOFs in tumorigenesis. Cell Discov 2:16039
Zhang, Cen; Liu, Juan; Tan, Chunwen et al. (2016) microRNA-1827 represses MDM2 to positively regulate tumor suppressor p53 and suppress tumorigenesis. Oncotarget 7:8783-96
Zhang, Cen; Liu, Juan; Zhao, Yuhan et al. (2016) Glutaminase 2 is a novel negative regulator of small GTPase Rac1 and mediates p53 function in suppressing metastasis. Elife 5:e10727
Yue, Xuetian; Zhao, Yuhan; Zhang, Cen et al. (2016) Leukemia inhibitory factor promotes EMT through STAT3-dependent miR-21 induction. Oncotarget 7:3777-90
Yue, Xuetian; Zhao, Yuhan; Liu, Juan et al. (2015) BAG2 promotes tumorigenesis through enhancing mutant p53 protein levels and function. Elife 4:
Yue, Xuetian; Wu, Lihua; Hu, Wenwei (2015) The regulation of leukemia inhibitory factor. Cancer Cell Microenviron 2:
Liu, Juan; Zhang, Cen; Hu, Wenwei et al. (2015) Tumor suppressor p53 and its mutants in cancer metabolism. Cancer Lett 356:197-203
Wu, Lihua; Yu, Haiyang; Zhao, Yuhan et al. (2015) HIF-2α mediates hypoxia-induced LIF expression in human colorectal cancer cells. Oncotarget 6:4406-17
Zhao, Y; Zhang, C; Yue, X et al. (2015) Pontin, a new mutant p53-binding protein, promotes gain-of-function of mutant p53. Cell Death Differ 22:1824-36

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