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The Role of LIF, a Novel Negative Regulator of p53, in Colorectal Cancer

Award Number: R01CA160558
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2012
PERIOD OF PERFORMANCE END DATE: 06/30/2017

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The Role of LIF, a Novel Negative Regulator of p53, in Colorectal Cancer - DESCRIPTION (provided by applicant): 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	6	12/13/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $291,168 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	001	6	6/22/2017	NON-COMPETING CONTINUATION	$291,169
2017	2012	UMDNJ-ROBERT WOOD JOHNSON MEDICAL SCHOOL							Cancer Biology Research	000	1	5/8/2017	NEW	-$1
														Subtotal = $291,168

Issue Date FY: 2016 ( Subtotal = $291,169 )
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cancer Biology Research	000	5	6/3/2016	EXTENSION WITH OR WITHOUT FUNDS	$291,169
														Subtotal = $291,169

Issue Date FY: 2015 ( Subtotal = $291,169 )
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cancer Biology Research	000	4	6/5/2015	NON-COMPETING CONTINUATION	$291,169
														Subtotal = $291,169

Issue Date FY: 2014 ( Subtotal = $106,370 )
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cancer Biology Research	000	3	8/29/2014	NON-COMPETING CONTINUATION	$106,370
														Subtotal = $106,370

Issue Date FY: 2013 ( Subtotal = $310,130 )
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Cancer Biology Research	000	2	8/16/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$310,130
														Subtotal = $310,130

Issue Date FY: 2012 ( Subtotal = $327,850 )
2012	2012	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	1	5/25/2012	NEW	$327,850
														Subtotal = $327,850

Grand Total All Awards = $1,617,856

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The Role of LIF, a Novel Negative Regulator of p53, in Colorectal Cancer

Award Number: R01CA160558

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2012

PERIOD OF PERFORMANCE END DATE: 06/30/2017

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