Pancreatic cancer is a highly aggressive malignancy and the fourth leading cause of cancer related death in the United States. Despite some recent progress in our understanding of the molecular progression of this disease, it is still not clearly understood what makes this cancer so aggressive and elusive. To make further progress, we need to identify novel gene targets and delineate their mechanisms of action in pancreatic cancer pathobiology. ETV4 is a transcription factor, which is overexpressed in multiple malignancies and has been shown to exhibit functional participation. However, no study so far has systematically examined its significance in pancreatic cancer. Our preliminary studies demonstrate, for the first time, that ETV4 is over- expressed in majority of pancreatic cancer cell lines and tumor tissues, and silencing of ETV4 suppresses growth of pancreatic cancer cells. Furthermore, ETV4 downregulation is associated with decreased migration, invasion and increased cell-cell interaction. Based on these promising observations, we hypothesize that ETV4 is a key determinant of pancreatic cancer growth and malignant phenotype. We plan to test this hypothesis in two specific aims.
In specific aim I, we will examine the pathological significance of ETV4 in pancreatic cancer cells through its ectopic overexpression in a poorly-tumorigenic and ETV4-nonexpressing cell line (BxPC3), and silencing in a highly tumorigenic and ETV4-overexpressing pancreatic cancer cell line (Colo357).
This aim will provide the information on the functional role of ETV4 in pancreatic cancer pathogenesis.
In specific aim II, we will investigate the expression and sub-cellular localization of ETV4 in human pancreatic tumors and normal pancreatic tissues by performing immunohistochemical (IHC) analysis.
This aim will support the clinical relevance of our experimental data and provide the information on the incidence of ETV4 expression in human pancreatic tumors and any association with tumor -stage and -grade. Taken together, the studies proposed in this pilot project will provide sufficien preliminary data on the function and incidence of ETV4 in pancreatic cancer. The resulting outcome will form the bases for future investigations to further define the mechanisms underlying the aberrant expression and functions of ETV4 in pancreatic cancer. Long -term goal of this project is to develop a novel ETV4-based therapeutic intervention approach for successful management of this lethal malignancy.

Public Health Relevance

Pancreatic cancer has the worst prognosis among all cancers thus underscoring the need to identify novel molecular targets that could lead to the development of more effective diagnostic and treatment strategies. The proposed pilot studies will provide novel information on the pathological role of ETV4 in pancreatic cancer and support its clinical relevance as a therapeutic target. The resulting information, in long term, will be useful for better disease management and thus enhance the life expectancy of patients diagnosed with this devastating and lethal malignancy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
5R03CA169829-02
Application #
8508226
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Yassin, Rihab R,
Project Start
2012-07-10
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$69,795
Indirect Cost
$22,795
Name
University of South Alabama
Department
Type
Schools of Medicine
DUNS #
172750234
City
Mobile
State
AL
Country
United States
Zip Code
36688
Tyagi, Nikhil; Deshmukh, Sachin K; Srivastava, Sanjeev K et al. (2018) ETV4 Facilitates Cell-Cycle Progression in Pancreatic Cells through Transcriptional Regulation of Cyclin D1. Mol Cancer Res 16:187-196
Deshmukh, Sachin Kumar; Singh, Ajay P; Singh, Seema (2018) ETV4: an emerging target in pancreatic cancer. Oncoscience 5:260-261
Tyagi, Nikhil; Marimuthu, Saravanakumar; Bhardwaj, Arun et al. (2016) p-21 activated kinase 4 (PAK4) maintains stem cell-like phenotypes in pancreatic cancer cells through activation of STAT3 signaling. Cancer Lett 370:260-7
Azim, Shafquat; Zubair, Haseeb; Srivastava, Sanjeev K et al. (2016) Deep sequencing and in silico analyses identify MYB-regulated gene networks and signaling pathways in pancreatic cancer. Sci Rep 6:28446
Tyagi, Nikhil; Arora, Sumit; Deshmukh, Sachin K et al. (2016) Exploiting Nanotechnology for the Development of MicroRNA-Based Cancer Therapeutics. J Biomed Nanotechnol 12:28-42
Deshmukh, Sachin K; Srivastava, Sanjeev K; Bhardwaj, Arun et al. (2015) Resistin and interleukin-6 exhibit racially-disparate expression in breast cancer patients, display molecular association and promote growth and aggressiveness of tumor cells through STAT3 activation. Oncotarget 6:11231-41
Srivastava, Sanjeev K; Bhardwaj, Arun; Arora, Sumit et al. (2015) MYB is a novel regulator of pancreatic tumour growth and metastasis. Br J Cancer 113:1694-703
Srivastava, Sanjeev K; Bhardwaj, Arun; Arora, Sumit et al. (2015) MicroRNA-345 induces apoptosis in pancreatic cancer cells through potentiation of caspase-dependent and -independent pathways. Br J Cancer 113:660-8
Srivastava, S K; Bhardwaj, A; Arora, S et al. (2015) Interleukin-8 is a key mediator of FKBP51-induced melanoma growth, angiogenesis and metastasis. Br J Cancer 112:1772-81
Khan, Mohammad Aslam; Srivastava, Sanjeev K; Bhardwaj, Arun et al. (2015) Gemcitabine triggers angiogenesis-promoting molecular signals in pancreatic cancer cells: Therapeutic implications. Oncotarget 6:39140-50

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