Tumor-associated MUC 5 AC stimulates in vivo tumorigenicity of human pancreatic cancer

a high molecular weight glycoprotein, is overexpressed in the ductal region of human pancreatic cancer but is not detectable in the normal pancreas, suggesting its association with disease development. In the present study, we investigated the in vitro and in vivo effects of MUC5AC knockdown by short interfering RNA (siRNA) in the MUC5AC-overexpressing SW1990 and BxPC3 human pancreatic cancer cell lines in order to clarify its function. Significant decreases in the expression levels of MUC5AC mRNA and protein were observed in SW1990 and BxPC3 cells that had been stably transfected with a MUC5AC siRNA expression vector (SW1990/si-MUC5AC and BxPC3/si-MUC5AC cells) compared to those in cells transfected with an si-mock vector (SW1990/si-mock and BxPC3/si-mock cells). In in vitro studies, neither type of MUC5AC-knockdown cell showed any difference in cell survival, proliferation, or morphology from the si-mock cells or parental cells. However, in vivo xenograft studies demonstrated that MUC5AC knockdown significantly reduced the tumorigenicity and suppressed the tumor growth of si-MUC5AC cells compared to those of the si-mock cells. Immunohistochemical analysis revealed that CD45R/B220 + and Gr-1 + cells had infiltrated into the tumor tissue of the SW1990/si-MUC5AC cells. Furthermore, cancer-associated antigen specific antibodies were detected at high levels in the sera from the SW1990/si-MUC5AC cell-bearing mice. These results suggest that tumor-associated MUC5AC expressed on the surface of pancreatic cancer cells supports the escape of pancreatic cancer cells from immunosurveillance. The present findings highlight a new dimension of MUC5AC as a functional immuno-suppressive agent and its important role in pancreatic cancer progression.

[1]  J. Meza,et al.  MUC4, a multifunctional transmembrane glycoprotein, induces oncogenic transformation of NIH3T3 mouse fibroblast cells. , 2008, Cancer research.

[2]  B. Hémon,et al.  Transcription factor AP-2alpha represses both the mucin MUC4 expression and pancreatic cancer cell proliferation. , 2007, Carcinogenesis.

[3]  H. Takagi,et al.  Different progression of tumor xenografts between mucin-producing and mucin-non-producing mammary adenocarcinoma-bearing mice. , 2006, Cancer research.

[4]  P. Singh,et al.  RNA Interference Suppression of MUC1 Reduces the Growth Rate and Metastatic Phenotype of Human Pancreatic Cancer Cells , 2006, Clinical Cancer Research.

[5]  M. Oka,et al.  Increased expression of MUC1 in advanced pancreatic cancer , 2003, Journal of Gastroenterology.

[6]  S. Truant,et al.  Requirement of both mucins and proteoglycans in cell‐cell dissociation and invasiveness of colon carcinoma HT‐29 cells , 2003, International journal of cancer.

[7]  T. Sawada,et al.  Granulocyte-colony stimulating factor enhances chimeric antibody Nd2 dependent cytotoxicity against pancreatic cancer mediated by polymorphonuclear neutrophils. , 2002, International journal of oncology.

[8]  Kan Yang,et al.  Colorectal Cancer in Mice Genetically Deficient in the Mucin Muc2 , 2002, Science.

[9]  S. Crawley,et al.  MUC17, a novel membrane-tethered mucin. , 2002, Biochemical and biophysical research communications.

[10]  B. Yin,et al.  Molecular Cloning of the CA125 Ovarian Cancer Antigen , 2001, The Journal of Biological Chemistry.

[11]  G. Sutherland,et al.  MUC13, a Novel Human Cell Surface Mucin Expressed by Epithelial and Hemopoietic Cells* , 2001, The Journal of Biological Chemistry.

[12]  J. Ho.  Mucins in the diagnosis and therapy of pancreatic cancer. , 2000, Current pharmaceutical design.

[13]  D. Thornton,et al.  Physical characterization of the MUC5AC mucin: a highly oligomeric glycoprotein whether isolated from cell culture or in vivo from respiratory mucous secretions. , 2000, The Biochemical journal.

[14]  B. Fischer,et al.  Neutrophil elastase increases MUC5AC mRNA and protein expression in respiratory epithelial cells. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[15]  N. Moniaux,et al.  Complete sequence of the human mucin MUC4: a putative cell membrane-associated mucin. , 1999, The Biochemical journal.

[16]  N. Nowak,et al.  Chromosomal localization of a human mucin gene (MUC8) and cloning of the cDNA corresponding to the carboxy terminus. , 1997, American journal of respiratory cell and molecular biology.

[17]  J. Kalden,et al.  Preclinical studies with Fc(gamma)R bispecific antibodies and granulocyte colony-stimulating factor-primed neutrophils as effector cells against HER-2/neu overexpressing breast cancer. , 1997, Cancer research.

[18]  J. Davies,et al.  MUC5AC, but not MUC2, is a prominent mucin in respiratory secretions , 1996, Glycoconjugate Journal.

[19]  J. Davies,et al.  Different mucins are produced by the surface epithelium and the submucosa in human trachea: identification of MUC5AC as a major mucin from the goblet cells. , 1996, The Biochemical journal.

[20]  V. Debailleul,et al.  Human mucin genes: genomic organization and expression of MUC4, MUC5AC and MUC5B. , 1995, Biochemical Society transactions.

[21]  C. Balagué,et al.  Altered expression of MUC2, MUC4, and MUC5 mucin genes in pancreas tissues and cancer cell lines. , 1994, Gastroenterology.

[22]  Y. Kim,et al.  Molecular cloning of human intestinal mucin (MUC2) cDNA. Identification of the amino terminus and overall sequence similarity to prepro-von Willebrand factor. , 1994, The Journal of biological chemistry.

[23]  A. Biesbrock,et al.  Molecular cloning, sequence, and specificity of expression of the gene encoding the low molecular weight human salivary mucin (MUC7). , 1993, The Journal of biological chemistry.

[24]  W. Kuo,et al.  Human gastric mucin. Identification of a unique species by expression cloning. , 1993, The Journal of biological chemistry.

[25]  R. Lagacé,et al.  The human MUC2 intestinal mucin has cysteine-rich subdomains located both upstream and downstream of its central repetitive region. , 1992, The Journal of biological chemistry.

[26]  M. Ligtenberg,et al.  Suppression of cellular aggregation by high levels of episialin. , 1992, Cancer research.

[27]  D. Swallow,et al.  Molecular cloning of cDNAs derived from a novel human intestinal mucin gene. , 1990, Biochemical and biophysical research communications.

[28]  International Journal of Oncology , 2017 .

[29]  J. Meza,et al.  MUC 4 Mucin Potentiates Pancreatic Tumor Cell Proliferation , Survival , and Invasive Properties and Interferes with Its Interaction to Extracellular Matrix Proteins , 2007 .

[30]  A. Osterhaus,et al.  Granulocyte macrophage colony-stimulating factor expression in human herpetic stromal keratitis: implications for the role of neutrophils in HSK. , 2007, Investigative ophthalmology & visual science.

[31]  Michael A. Hollingsworth,et al.  Mucins in cancer: protection and control of the cell surface , 2004, Nature Reviews Cancer.

[32]  B. Fischer,et al.  Neutrophil elastase increases MUC5AC mRNA and protein expression in respiratory epithelial cells. , 1999, The American journal of physiology.

[33]  J. Sheehan,et al.  Mucous glycoproteins: a gel of a problem. , 1985, Essays in biochemistry.