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.
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.
|Tyagi, Nikhil; Bhardwaj, Arun; Singh, Ajay P et al. (2014) p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-?B pathway. Oncotarget 5:8778-89|
|Srivastava, Sanjeev K; Arora, Sumit; Singh, Seema et al. (2014) MicroRNAs in pancreatic malignancy: progress and promises. Cancer Lett 347:167-74|
|Arora, Sumit; Swaminathan, Suresh K; Kirtane, Ameya et al. (2014) Synthesis, characterization, and evaluation of poly (D,L-lactide-co-glycolide)-based nanoformulation of miRNA-150: potential implications for pancreatic cancer therapy. Int J Nanomedicine 9:2933-42|
|Arora, Sumit; Bhardwaj, Arun; Singh, Seema et al. (2013) An undesired effect of chemotherapy: gemcitabine promotes pancreatic cancer cell invasiveness through reactive oxygen species-dependent, nuclear factor *B- and hypoxia-inducible factor 1*-mediated up-regulation of CXCR4. J Biol Chem 288:21197-207|
|Bhardwaj, Arun; Arora, Sumit; Prajapati, Vijay K et al. (2013) Cancer "stemness"- regulating microRNAs: role, mechanisms and therapeutic potential. Curr Drug Targets 14:1175-84|