Pancreatic cancer (PC) is a disease of insidious progression and high lethality. The survival of patients with PC is less than 5% over the period of 5 years. The etiology of PC is associated with inherited gene mutations and polymorphisms (genetic susceptibility), lifestyle-related factors, such as high caloric intake, high-fat diet and smoking. Despite epidemiological evidence suggesting an association of cigarette smoking with pancreatic malignancy, the molecular consequences of cigarette smoking and nicotine (an important constituent of cigarette smoke) leading to cancerous form of the pancreas are not clear. Recently, we have observed that cigarette smoke inhalation induces a chronic pancreatic inflammatory process with fibrosis and scarring of pancreatic structures. Furthermore, we have found altered expression of genes involved in the function of the pancreas in smoke-treated rats. In parallel studies, we detected MUC4 mucin in histologically identifiable intra-ductal lesions known as Pancreatic Intraepithelial Neoplasias (PanINs), and the expression of MUC4 increased progressively with .tumorigenic and malignant phenotype. The oncogenic potential of MUC4 was also observed in the NIH3T3 mouse fibroblast cells. Interestingly, our studies have also revealed that MUC4 regulates the expression of HER2 by post-transcriptional mechanism(s). The overall objective of this research proposal is to investigate the pathological consequences of cigarette smoking toward the initiation and progression of PC and to establish the regulatory mechanism(s) underlying the cigarette smoke- induced MUC4 expression and its role in the pathogenic process. Specifically, we aim to establish the role of cigarette smoke and nicotine in the etiology of pancreatic cancer and unravel the regulatory mechanism(s) underlying nicotine-induced MUC4 expression. We hypothesize that cigarette smoking contributes to the development of pancreatic cancer, and that MUC4 is an important component in the disease process. To test our hypothesis, we propose three specific aims.
In Aim 1, we will investigate the effect of cigarette-smoke/nicotine on pancreatic cancer growth by performing various functional assays in established pancreatic cancer cell lines and in an in-vitro human pancreatic cancer progression model.
Aim 2 will delineate the signaling pathways implicated in mediating the effect of nicotine on MUC4 expression alone and in collaboration with other inducers of MUC4.
In Aim 3, we will carry out studies in different mouse models that spontaneously develop pre-malignant and malignant pancreatic lesions to examine the effect of cigarette-smoke and nicotine in potentiating the early events of pancreatic carcinogenesis. We will also generate a mouse model in MUC4-null background to define the role of MUC4 in malignant disease initiation and progression. Taken together, these studies will establish the causal role of cigarette-smoke and nicotine in the etiology of lethal pancreatic cancer. Project Narrative The proposed research investigations are aimed at understanding the pathological consequences of cigarette smoking toward the development of pancreatic cancer and establishing the role of cigarette smoke-induced MUC4 expression in the pathogenic process. In preliminary studies, we have shown that cigarette smoke inhalation induces a chronic pancreatic inflammatory process in vivo and the treatment of pancreatic cancer cells in vitro with nicotine induces MUC4 expression, an aberrantly expressed mucin in majority of pancreatic cancer, which also possess transforming properties. The outcome of the proposed studies will establish the mechanistic role of cigarette smoke and nicotine in the etiology of lethal pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA133774-05
Application #
8205008
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Johnson, Ronald L
Project Start
2008-03-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$307,952
Indirect Cost
$66,220
Name
University of Nebraska Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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Momi, Navneet; Kaur, Sukhwinder; Rachagani, Satyanarayana et al. (2014) Smoking and microRNA dysregulation: a cancerous combination. Trends Mol Med 20:36-47
Torres, María P; Rachagani, Satyanarayana; Souchek, Joshua J et al. (2013) Novel pancreatic cancer cell lines derived from genetically engineered mouse models of spontaneous pancreatic adenocarcinoma: applications in diagnosis and therapy. PLoS One 8:e80580
Momi, N; Ponnusamy, M P; Kaur, S et al. (2013) Nicotine/cigarette smoke promotes metastasis of pancreatic cancer through α7nAChR-mediated MUC4 upregulation. Oncogene 32:1384-95

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