MUC13 mucin augments pancreatic tumorigenesis.
The high death rate of pancreatic cancer is attributed to the lack of reliable methods for early detection and underlying molecular mechanisms of its aggressive pathogenesis. Although MUC13, a newly identified transmembrane mucin, is known to be aberrantly expressed in ovarian and gastro-intestinal cancers, its role in pancreatic cancer is unknown. Herein, we investigated the expression profile and functions of MUC13 in pancreatic cancer progression. The expression profile of MUC13 in pancreatic cancer was investigated using a recently generated monoclonal antibody (clone PPZ0020) and pancreatic tissue microarrays. The expression of MUC13 was significantly (P < 0.005) higher in cancer samples compared with normal/nonneoplastic pancreatic tissues. For functional analyses, full-length MUC13 was expressed in MUC13 null pancreatic cancer cell lines, MiaPaca and Panc1. MUC13 overexpression caused a significant (P < 0.05) increase in cell motility, invasion, proliferation, and anchorage-dependent or -independent clonogenicity while decreasing cell-cell and cell-substratum adhesion. Exogenous MUC13 expression significantly (P < 0.05) enhanced pancreatic tumor growth and reduced animal survival in a xenograft mouse model. These tumorigenic characteristics correlated with the upregulation/phosphorylation of HER2, p21-activated kinase 1 (PAK1), extracellular signal-regulated kinase (ERK), Akt, and metastasin (S100A4), and the suppression of p53. Conversely, suppression of MUC13 in HPAFII pancreatic cancer cells by short hairpin RNA resulted in suppression of tumorigenic characteristics, repression of HER2, PAK1, ERK, and S100A4, and upregulation of p53. MUC13 suppression also significantly (P < 0.05) reduced tumor growth and increased animal survival. These results imply a role of MUC13 in pancreatic cancer and suggest its potential use as a diagnostic and therapeutic target.
Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD 57104, USA. subhash.chauhan@usd.edu
Subhash C
SC
Chauhan
Mara C
MC
Ebeling
Diane M
DM
Maher
Michael D
MD
Koch
Akira
A
Watanabe
Hiroyuki
H
Aburatani
Yuhlong
Y
Lio
Meena
M
Jaggi
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009077:Mucins / Q000276:immunology / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism
D000911:Antibodies, Monoclonal; D048049:Extracellular Signal-Regulated MAP Kinases; D009077:Mucins; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D016159:Tumor Suppressor Protein p53; D054462:p21-Activated Kinases; C429552:MUC13 protein, human; C077591:S100A4 protein, human; C508053:ERBB2 protein, human; C515903:PAK1 protein, human