The central hypothesis of this proposed study is that the MUC4 mucin contributes to the pathogenesis of pancreatic adenocarcinomas. Results of studies conducted in our laboratory and by other groups in the past few years have shown that MUC4 is overexpressed in pancreatic tumors compared to the normal pancreas. We have made significant progress in characterizing this biologically important molecule. The deduced structure of the encoded protein reveals traits that are typical of mucins and highlights the presence of multiple putative EGF domains, which may potentially confer important functions to the mature product. Furthermore, MUC4 is a membrane-anchored and highly glycosylated protein with an extended size that may exceed 2 pm over the cell surface, in which MUC4a is an extracellular mucin-type glycoprotein subunit, and MUC4 j3 is the transmembrane subunit. In consideration of the structural features of MUC4, as well as its frequent association with pancreatic adenocarcinomas, the need for an enhanced knowledge of the function(s) of this mucin cannot be overemphasized. During the previous funding period, we generated full-length MUC4 cDNA sequences, produced anti-MUC4 antibodies, and characterized a pancreatic tumor model (CDI8/HPAF) that showed regulated expression in vitro and in vivo. In the present proposal, our immediate objectives are to define the functions and regulatory mechanism(s) of MUC4 expression in pancreatic tumor cells. Our working hypothesis is that MUC4 is a multifunctional protein that promotes cell proliferation by signaling via its putative functional domains, and that confers anti-adhesive/adhesive properties to tumor cells owing to its unusually large size and extensive glycosylation. Additionally, we hypothesize that the regulation of MUC4 expression in pancreatic tumor cells is a complex process that entails the interplay of various biologically active factors such as IFN gamma and TGF beta 3. Specifically, we propose to: 1) Investigate if MUC4 expression contributes to the tumor growth and metastatic properties in pancreatic cancer cells by means of 'overexpression' and 'knockout' of the MUC4 gene. The roles of the structural components of MUC4 will also be examined. 2) Determine the mechanism(s) by which MUC4 expression can be regulated in pancreatic tumor cells. The CD18/HPAF pancreatic tumor cells will be used to investigate these mechanisms as MUC4 expression can be turned 'on' and 'off' in vitro and in vivo in these cells. Together, understanding the functions and mechanisms of regulated expression of MUC4 in pancreatic tumor cells can help to design diagnostics and therapeutic strategies for pancreatic cancer patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Pathology B Study Section (PTHB)
Program Officer
Sussman, Daniel J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Nebraska Medical Center
Schools of Medicine
United States
Zip Code
Kumar, Sushil; Cruz, Eric; Joshi, Suhasini et al. (2017) Genetic variants of mucins: unexplored conundrum. Carcinogenesis 38:671-679
Das, S; Rachagani, S; Sheinin, Y et al. (2016) Mice deficient in Muc4 are resistant to experimental colitis and colitis-associated colorectal cancer. Oncogene 35:2645-54
Joshi, Suhasini; Kumar, Sushil; Bafna, Sangeeta et al. (2015) Genetically engineered mucin mouse models for inflammation and cancer. Cancer Metastasis Rev 34:593-609
Higashi, Michiyo; Yokoyama, Seiya; Yamamoto, Takafumi et al. (2015) Mucin expression in endoscopic ultrasound-guided fine-needle aspiration specimens is a useful prognostic factor in pancreatic ductal adenocarcinoma. Pancreas 44:728-34
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
Yokoyama, Seiya; Kitamoto, Sho; Higashi, Michiyo et al. (2014) Diagnosis of pancreatic neoplasms using a novel method of DNA methylation analysis of mucin expression in pancreatic juice. PLoS One 9:e93760
Shibahara, Hiroaki; Higashi, Michiyo; Koriyama, Chihaya et al. (2014) Pathobiological implications of mucin (MUC) expression in the outcome of small bowel cancer. PLoS One 9:e86111
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
Kaur, Sukhwinder; Chakraborty, Subhankar; Baine, Michael J et al. (2013) Potentials of plasma NGAL and MIC-1 as biomarker(s) in the diagnosis of lethal pancreatic cancer. PLoS One 8:e55171

Showing the most recent 10 out of 140 publications