Gastric cancer is the second most common cause of cancer-related deaths worldwide. There is growing evidence suggesting that cancer signaling networks are wired in a complex manner. This complexity is translated into poor clinical outcome, a common feature of gastric cancer. This wiring is not only important for maintaining cancer cell survival but also for providing supportive properties such as angiogenesis. The molecular targets that govern this interaction between the molecular signaling pathways that drive gastric tumorigenesis remain largely uncharacterized. Therefore, the identification of critical molecular targets, located at the hub of the signaling networks that bridge cancer signaling pathways, is a key step in understanding the biology of gastric cancer and improving our currently limited diagnostic, preventive, and therapeutic approaches. In the present proposal, we plan to pursue our novel finding that shows DARPP-32 at the interface of two key signaling pathways, NF-kB and STAT-3;thus playing a crucial role in the development and progression of the gastric tumorigenesis cascade. The proposal examines a novel hypothesis that transcription up-regulation of DARPP-32 by NF-kB connects cancer cell signaling pathways leading to activation of STAT3, thereby placing DARPP-32 as a bridge between two important signaling pathways amplifying their oncogenic signals promoting angiogenesis and tumorigenesis. We propose three specific aims to test our hypothesis.
The first aim will test the transcription regulation of DARPP-32 by NF-kB and examine the mechanisms by which DARPP-32 regulates STAT3 signaling. These studies will define the role of DARPP-32 as a bridge between two important oncogenic signaling pathways, NF-kB and STAT3.
In Aim 2, we will examine the biological outcome of the NF-kB - DARPP-32 - STAT3 axis, explore its role in regulating angiogenesis, and determine the therapeutic potential of targeting the DARPP-32 signaling axis.
The third aim, will determine the role of DARPP-32 in promoting gastric tumorigenesis using genetic mouse models of DARPP-32 overexpression and knockdown. We will also explore the histopathological and clinical significance of overexpression of NF-kB - DARPP-32 - STAT3 in fully annotated de-identified human gastric cancer tissue samples. Our studies are conceptually innovative and of critical significance given the fact that the overall 5-year survival for gastric cancer is only 20%. Upon completion of our studies, the results will have a significant impact on understanding the biology of gastric cancer affecting our diagnostic, prognostic, and possibly clinical management of this disease.

Public Health Relevance

Gastric cancer is one of the most prevalent cancers world-wide. In this proposal, we plan to characterize the molecular function(s) of DARPP-32, a frequently overexpressed gene in gastric cancer, in order to identify its biological, diagnostic, prognostic, and possibly therapeutic values.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093999-13
Application #
8743185
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Yassin, Rihab R,
Project Start
2001-07-01
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Nashville
State
TN
Country
United States
Zip Code
37212
Zhu, Shoumin; Soutto, Mohammed; Chen, Zheng et al. (2016) Helicobacter pylori-induced cell death is counteracted by NF-κB-mediated transcription of DARPP-32. Gut :
Belkhiri, Abbes; Zhu, Shoumin; El-Rifai, Wael (2016) DARPP-32: from neurotransmission to cancer. Oncotarget 7:17631-40
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Chen, Zheng; Zhu, Shoumin; Hong, Jun et al. (2016) Gastric tumour-derived ANGPT2 regulation by DARPP-32 promotes angiogenesis. Gut 65:925-34
Bhardwaj, Vikas; Noto, Jennifer M; Wei, Jinxiong et al. (2015) Helicobacter pylori bacteria alter the p53 stress response via ERK-HDM2 pathway. Oncotarget 6:1531-43
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Soutto, Mohammed; Peng, DunFa; Katsha, Ahmed et al. (2015) Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis. Gut 64:1028-39
Wei, Jinxiong; Noto, Jennifer M; Zaika, Elena et al. (2015) Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner. Gut 64:1040-8
Soutto, Mohammed; Romero-Gallo, Judith; Krishna, Uma et al. (2015) Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis. Oncotarget 6:17911-22
Belkhiri, Abbes; El-Rifai, Wael (2014) 5-Methylcytosine hydroxylation-mediated LINE-1 hypomethylation: a novel mechanism of proto-oncogenes activation in colorectal cancer? Gut 63:538-9

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