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.
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.
|Macha, M A; Rachagani, S; Pai, P et al. (2015) MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway. Oncogene 34:1698-708|
|Kumar, S; Torres, M P; Kaur, S et al. (2015) Smoking accelerates pancreatic cancer progression by promoting differentiation of MDSCs and inducing HB-EGF expression in macrophages. Oncogene 34:2052-60|
|Macha, Muzafar A; Krishn, Shiv Ram; Jahan, Rahat et al. (2015) Emerging potential of natural products for targeting mucins for therapy against inflammation and cancer. Cancer Treat Rev 41:277-88|
|Pandey, Poomy; Rachagani, Satyanarayana; Das, Srustidhar et al. (2015) Amyloid precursor-like protein 2 (APLP2) affects the actin cytoskeleton and increases pancreatic cancer growth and metastasis. Oncotarget 6:2064-75|
|Lakshmanan, Imayavaramban; Seshacharyulu, Parthasarathy; Haridas, Dhanya et al. (2015) Novel HER3/MUC4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells. Oncotarget 6:21085-99|
|Macha, Muzafar A; Seshacharyulu, Parthasarathy; Krishn, Shiv Ram et al. (2014) MicroRNAs (miRNAs) as biomarker(s) for prognosis and diagnosis of gastrointestinal (GI) cancers. Curr Pharm Des 20:5287-97|
|Kaur, Sukhwinder; Sharma, Neil; Krishn, Shiv Ram et al. (2014) MUC4-mediated regulation of acute phase protein lipocalin 2 through HER2/AKT/NF-?B signaling in pancreatic cancer. Clin Cancer Res 20:688-700|
|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 ?7nAChR-mediated MUC4 upregulation. Oncogene 32:1384-95|
Showing the most recent 10 out of 69 publications