MUC4 as a diagnostic marker in cancer.

BACKGROUND Mucins are high molecular mass glycoproteins whose role in diagnosis, prognosis and therapy is being increasingly recognized owing to their altered expression in a variety of carcinomas. MUC4, a membrane-bound mucin encoded by a gene located on chromosome locus 3q29, is aberrantly expressed in several cancers including those of the bile duct, breast, colon, esophagus, ovary, lung, prostate, stomach and pancreas. OBJECTIVE This review considers the potential use of the MUC4 expression pattern in the diagnosis and prognosis of various cancers. RESULTS/CONCLUSION MUC4 expression is a specific marker of epithelial tumors and its expression correlates positively with the degree of differentiation in several cancers. Importantly, MUC4 has emerged as a specific marker of dysplasia, being expressed in the earliest dysplastic lesions preceding several malignancies, including lethal pancreatic cancer. The presence of MUC4-specific antibodies in the serum and of the transcript in peripheral blood mononuclear cells of cancer patients raises the possibility of it emerging as a new diagnostic biomarker for bedside application in high-risk individuals and those with established cancer.

[1]  T. Irimura,et al.  Expression of Different Glycoforms of Membrane Mucin (MUC1) and Secretory Mucin (MUC2, MUC5AC and MUC6) in Pancreatic Neoplasms , 2003 .

[2]  K. Imai,et al.  New classification of pancreatic intraductal papillary–mucinous tumour by mucin expression: its relationship with potential for malignancy , 2002, The Journal of pathology.

[3]  F. Alameda,et al.  MUC4 expression is increased in dysplastic cervical disorders. , 2001, Human pathology.

[4]  M. Paparella,et al.  Characterization of mucins in human middle ear and Eustachian tube. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[5]  Gerd Schmitz,et al.  Aberrant intestinal expression and allelic variants of mucin genes associated with inflammatory bowel disease , 2006, Journal of Molecular Medicine.

[6]  S. Batra,et al.  Transcriptional regulation of human mucin MUC4 by bile acids in oesophageal cancer cells is promoter-dependent and involves activation of the phosphatidylinositol 3-kinase signalling pathway. , 2004, The Biochemical journal.

[7]  M. Copin,et al.  Mucin gene expression in intestinal epithelial cells in Crohn's disease , 2001, Gut.

[8]  M. Copin,et al.  Mucinous bronchioloalveolar carcinomas display a specific pattern of mucin gene expression among primary lung adenocarcinomas. , 2001, Human pathology.

[9]  M. Copin,et al.  Normal respiratory mucosa, precursor lesions and lung carcinomas: differential expression of human mucin genes. , 2001, Frontiers in bioscience : a journal and virtual library.

[10]  G J Strous,et al.  Mucin-type glycoproteins. , 1992, Critical reviews in biochemistry and molecular biology.

[11]  L. Alós,et al.  Expression of Membrane-Bound Mucins (MUC1 and MUC4) and Secreted Mucins (MUC2, MUC5AC, MUC5B, MUC6 and MUC7) in Mucoepidermoid Carcinomas of Salivary Glands , 2005, The American journal of surgical pathology.

[12]  S. Batra,et al.  Generation and Characterization of Anti-MUC4 Monoclonal Antibodies Reactive with Normal and Cancer Cells in Humans , 2004, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[13]  S. Batra,et al.  Retinoic Acid-dependent Transforming Growth Factor-β2-mediated Induction of MUC4 Mucin Expression in Human Pancreatic Tumor Cells Follows Retinoic Acid Receptor-α Signaling Pathway* , 2000, The Journal of Biological Chemistry.

[14]  C. Cherbut,et al.  MUC Genes Are Differently Expressed During Onset and Maintenance of Inflammation in Dextran Sodium Sulfate-Treated Mice , 2006, Digestive Diseases and Sciences.

[15]  C. Gomez-Fernandez,et al.  MUC4 (Sialomucin Complex) Expression in Salivary Gland Tumors and Squamous Cell Carcinoma of the Upper Aerodigestive Tract , 2001, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[16]  Sangeeta Bafna,et al.  Aberrant expression of transmembrane mucins, MUC1 and MUC4, in human prostate carcinomas , 2006, The Prostate.

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

[18]  King-Teh Lee,et al.  Altered Mucin Gene Expression in Stone-Containing Intrahepatic Bile Ducts and Cholangiocarcinomas , 2001, Digestive Diseases and Sciences.

[19]  J. Hanaoka,et al.  Analysis of MUC4 mucin expression in lung carcinoma cells and its immunogenicity , 2001, Cancer.

[20]  P. Fouret,et al.  MUC1, MUC2, MUC4, and MUC5AC Expression in Salivary Gland Mucoepidermoid Carcinoma: Diagnostic and Prognostic Implications , 2005, The American journal of surgical pathology.

[21]  D. Querleu,et al.  Mucin gene transcripts in benign and borderline mucinous tumours of the ovary: an in situ hybridization study , 2001, The Journal of pathology.

[22]  S. Batra,et al.  MUC4 expression is a novel prognostic factor in patients with invasive ductal carcinoma of the pancreas , 2005, Journal of Clinical Pathology.

[23]  Kohzoh Imai,et al.  MUC4 is a novel prognostic factor of intrahepatic cholangiocarcinoma‐mass forming type , 2004, Hepatology.

[24]  C. Degott,et al.  Mucin gene expression in intraductal papillary‐mucinous pancreatic tumours and related lesions , 2002, The Journal of pathology.

[25]  S. Batra,et al.  MUC4 Is a Novel Prognostic Factor of Extrahepatic Bile Duct Carcinoma , 2006, Clinical Cancer Research.

[26]  D. Zander,et al.  MUC4 expression in non-small cell lung carcinomas: relationship to tumor histology and patient survival. , 2007, Archives of pathology & laboratory medicine.

[27]  H. Friess,et al.  Mucin (MUC) gene expression in human pancreatic adenocarcinoma and chronic pancreatitis: a potential role of MUC4 as a tumor marker of diagnostic significance. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[28]  N. Moniaux,et al.  Human mucin gene MUC4: organization of its 5'-region and polymorphism of its central tandem repeat array. , 1998, The Biochemical journal.

[29]  S. Takao,et al.  Gene expression of gastric type mucin (MUC5AC) in pancreatic tumors: Its relationship with the biological behavior of the tumor , 1999, Pathology international.

[30]  I. Shih,et al.  MUC4 is upregulated in ovarian carcinoma effusions and differentiates carcinoma cells from mesothelial cells , 2007, Diagnostic cytopathology.

[31]  A. Janin,et al.  Abnormal mucus in cap polyposis , 1998, Gut.

[32]  S. Batra,et al.  Emerging roles of MUC4 in cancer: a novel target for diagnosis and therapy. , 2007, Cancer research.

[33]  P. Toselli,et al.  Expression of Membrane-associated Mucins MUC1 and MUC4 in Major Human Salivary Glands , 2002, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[34]  M. Gross,et al.  Molecular cloning and chromosomal localization of a novel human tracheo-bronchial mucin cDNA containing tandemly repeated sequences of 48 base pairs. , 1991, Biochemical and biophysical research communications.

[35]  S. Gendler,et al.  Structure and function of the cell surface (tethered) mucins. , 2008, Annual review of physiology.

[36]  P. Slootweg Atlas of Tumor Pathology: Tumors of the Upper Aerodigestive Tract and Ear. , 2000 .

[37]  P. Siersema,et al.  MUC4 is increased in high grade intraepithelial neoplasia in Barrett’s oesophagus and is associated with a proapoptotic Bax to Bcl-2 ratio , 2004, Journal of Clinical Pathology.

[38]  K. Hamilton-Nelson,et al.  MUC4 and ERBB2 expression in major and minor salivary gland mucoepidermoid carcinoma , 2004, Head & neck.

[39]  J. Cameron,et al.  MUC4 expression increases progressively in pancreatic intraepithelial neoplasia. , 2002, American journal of clinical pathology.

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

[41]  Christine A Iacobuzio-Donahue,et al.  Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologies. , 2003, Cancer research.

[42]  P. Singh,et al.  Cell surface-associated mucins in signal transduction. , 2006, Trends in cell biology.

[43]  J. Isola,et al.  Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line. , 2005, Cancer research.

[44]  M. Cummings,et al.  Expression of MUC1 and MUC2 mucins in epithelial ovarian tumours , 1997, The Journal of pathology.

[45]  D. Alderson,et al.  Mucin gene expression in Barrett's oesophagus: an in situ hybridisation and immunohistochemical study , 2000, Gut.

[46]  M. Hollingsworth,et al.  Human MUC4 mucin cDNA and its variants in pancreatic carcinoma. , 2000, Journal of biochemistry.

[47]  A. Jemal,et al.  Cancer Statistics, 2007 , 2007, CA: a cancer journal for clinicians.

[48]  Catalin C. Barbacioru,et al.  Double immunohistochemical staining with MUC4/p53 is useful in the distinction of pancreatic adenocarcinoma from chronic pancreatitis: a tissue microarray-based study. , 2007, Archives of pathology & laboratory medicine.

[49]  S. Randell,et al.  Mucin gene expression during differentiation of human airway epithelia in vitro. Muc4 and muc5b are strongly induced. , 1999, American journal of respiratory cell and molecular biology.

[50]  S. Batra,et al.  Structure, evolution, and biology of the MUC4 mucin , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[51]  K. Carraway,et al.  Expression and localization of Muc4/sialomucin complex (SMC) in the adult and developing rat intestine: Implications for Muc4/SMC function , 2005, Journal of cellular physiology.

[52]  C. Cordon-Cardo,et al.  Selection of tumor antigens as targets for immune attack using immunohistochemistry: protein antigens. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[53]  C. Lombardo,et al.  Pattern of mucin gene expression in normal and neoplastic lung tissues. , 1996, Anticancer research.

[54]  M. Pasdar,et al.  The importance of MUC1 cellular localization in patients with breast carcinoma , 2001, Cancer.

[55]  A. Corfield,et al.  Mucins and mucosal protection in the gastrointestinal tract: new prospects for mucins in the pathology of gastrointestinal disease , 2000, Gut.

[56]  C. A. Carraway,et al.  Muc4/sialomucin complex, the intramembrane ErbB2 ligand, in cancer and epithelia: to protect and to survive. , 2002, Progress in nucleic acid research and molecular biology.

[57]  T. Hong,et al.  Mucin mRNA expression in lung adenocarcinoma cell lines and tissues. , 1996, Oncology.

[58]  M. Bouvet Tumor Markers for Pancreatic Cancer: What Happens When Preoperative CA 19--9 is Undetectable? , 2004, Annals of Surgical Oncology.

[59]  K. Carraway,et al.  Presence of MUC4 in human milk and at the luminal surfaces of blood vessels , 2005, Journal of cellular physiology.

[60]  W. Frankel,et al.  Mucin profiles in signet-ring cell carcinoma. , 2009, Archives of pathology & laboratory medicine.

[61]  I. Gipson Mucins of the human endocervix. , 2001, Frontiers in bioscience : a journal and virtual library.

[62]  R. Dodge,et al.  Mucin gene expression in ovarian cancers. , 1998, Cancer research.

[63]  S. Batra,et al.  Multiple roles of mucins in pancreatic cancer, a lethal and challenging malignancy , 2004, British Journal of Cancer.

[64]  A. Belfiore,et al.  Differential expression of mucins 1–6 in papillary thyroid carcinoma: evidence for transformation‐dependent post‐translational modifications of MUC1 in situ , 2003, The Journal of pathology.

[65]  Barry J. Allen,et al.  MUC1, MUC2, MUC4, MUC5AC and MUC6 Expression in the Progression of Prostate Cancer , 2005, Clinical & Experimental Metastasis.

[66]  S. Batra,et al.  Aberrant Expression of MUC3 and MUC4 Membrane-Associated Mucins and Sialyl Lex Antigen in Pancreatic Intraepithelial Neoplasia , 2003, Pancreas.

[67]  Lynette M. Smith,et al.  Aberrant expression of MUC4 in ovarian carcinoma: diagnostic significance alone and in combination with MUC1 and MUC16 (CA125) , 2006, Modern Pathology.

[68]  I. Gipson,et al.  Alteration in goblet cell numbers and mucin gene expression in a mouse model of allergic conjunctivitis. , 2001, Investigative ophthalmology & visual science.

[69]  N. Hosten,et al.  Combined imaging techniques for pancreatic cancer , 2000, The Lancet.

[70]  T. Inatomi,et al.  Expression of secretory mucin genes by human conjunctival epithelia. , 1996, Investigative ophthalmology & visual science.

[71]  M. Copin,et al.  From normal respiratory mucosa to epidermoid carcinoma: Expression of human mucin genes , 2000, International journal of cancer.

[72]  S. Itzkowitz,et al.  Mucin gene expression in colonic tissues and cell lines. , 1992, Cancer research.

[73]  B. Fischer,et al.  Neutrophil elastase increases MUC4 expression in normal human bronchial epithelial cells. , 2003, American journal of physiology. Lung cellular and molecular physiology.

[74]  B. Warren,et al.  Expression of mucin genes in ulcerative colitis. , 1995, Biochemical Society transactions.

[75]  S. Batra,et al.  Biomarkers in Diagnosis of pancreatic carcinoma in fine-needle aspirates. , 2006, American journal of clinical pathology.

[76]  M. Rossignol,et al.  International differences in epidemiology of lung adenocarcinoma. , 1997, Lung cancer.

[77]  R. Bresalier,et al.  Mucins and mucin binding proteins in colorectal cancer , 2004, Cancer and Metastasis Reviews.

[78]  S. Batra,et al.  Diagnostic value of MUC4 immunostaining in distinguishing epithelial mesothelioma and lung adenocarcinoma , 2004, Modern Pathology.

[79]  C. Reis,et al.  Role of fucosyltransferases in the association between apomucin and Lewis antigen expression in normal and malignant gastric epithelium , 2000, Gut.

[80]  C. Morrison,et al.  The Mucin Expression Profile of Endometrial Carcinoma and Correlation With Clinical-Pathologic Parameters , 2007, Applied immunohistochemistry & molecular morphology : AIMM.

[81]  D. Kanduc,et al.  Genome‐wide transcriptional profiling in human squamous cell carcinoma of the skin identifies unique tumor‐associated signatures , 2006, The Journal of dermatology.

[82]  J. Triboulet,et al.  Mucin gene expression and cell differentiation in human normal, premalignant and malignant esophagus , 2000, International journal of cancer.

[83]  F. Escande,et al.  Alternative splicing generates a family of putative secreted and membrane-associated MUC4 mucins. , 2000, European journal of biochemistry.

[84]  K. Basso,et al.  Gene dosage alterations revealed by cDNA microarray analysis in cervical cancer: Identification of candidate amplified and overexpressed genes , 2007, Genes, chromosomes & cancer.

[85]  Dileepa S. Diyagama,et al.  A Molecular Diagnostic Test for Distinguishing Lung Adenocarcinoma from Malignant Mesothelioma Using Cells Collected from Pleural Effusions , 2006, Clinical Cancer Research.

[86]  K. Carraway,et al.  Detection of sialomucin complex (MUC4) in human ocular surface epithelium and tear fluid. , 2000, Investigative ophthalmology & visual science.

[87]  H. Höfler,et al.  Her-2/neu Gene Amplification, Elevated mRNA Expression, and Protein Overexpression in the Metaplasia-Dysplasia-Adenocarcinoma Sequence of Barrett’s Esophagus , 2001, Laboratory Investigation.

[88]  F. Alameda,et al.  Mucin Genes (MUC2, MUC4, MUC5AC, and MUC6) Detection in Normal and Pathological Endometrial Tissues , 2007, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[89]  F. Chaves,et al.  Levels of mucin gene expression in normal human conjunctival epithelium in vivo , 2003, Current eye research.

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

[91]  M. Copin,et al.  Expression of human mucin genes in respiratory, digestive, and reproductive tracts ascertained by in situ hybridization. , 1993, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[92]  T. Irimura,et al.  Expression of MUC1 and MUC2 mucin antigens in intrahepatic bile duct tumors: Its relationship with a new morphological classification of cholangiocarcinoma , 1999, Hepatology.

[93]  B. Leggett,et al.  Immunohistochemical Staining Patterns of MUC1, MUC2, MUC4, and MUC5AC Mucins in Hyperplastic Polyps, Serrated Adenomas, and Traditional Adenomas of the Colorectum , 1999, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[94]  I. Gipson,et al.  Mucin genes expressed by human female reproductive tract epithelia. , 1997, Biology of reproduction.

[95]  A. Volterra,et al.  Peroxynitrite Inhibits Glutamate Transporter Subtypes (*) , 1996, The Journal of Biological Chemistry.

[96]  H. Ishinaga,et al.  Mucin gene expression in the effusions of otitis media with effusion. , 2003, International journal of pediatric otorhinolaryngology.

[97]  S. Batra,et al.  MUC4 expression correlates with poor prognosis in small-sized lung adenocarcinoma. , 2007, Lung cancer.

[98]  I. Shih,et al.  Gene Expression Signatures Differentiate Ovarian/Peritoneal Serous Carcinoma from Diffuse Malignant Peritoneal Mesothelioma , 2006, Clinical Cancer Research.

[99]  A. Tzakis,et al.  Expression of MUC2 and MUC4 proteins and cytokines: early markers of intestinal graft rejection1,2 , 2003, Transplantation.

[100]  A. Zalewska,et al.  Structure and biosynthesis of human salivary mucins. , 2000, Acta biochimica Polonica.

[101]  C. Muir,et al.  Upper aerodigestive tract cancers , 1995, Cancer.

[102]  E. Petricoin,et al.  Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. , 2003, Cancer cell.

[103]  U. Manne,et al.  Mucinous expression in benign and neoplastic glandular lesions of the uterine cervix. , 2006, Archives of pathology & laboratory medicine.

[104]  J. F. Thompson,et al.  Sialomucin Complex, a Heterodimeric Glycoprotein Complex , 1996, The Journal of Biological Chemistry.

[105]  M. Makuuchi,et al.  Clinical significance of subcellular localization of KL-6 mucin in primary colorectal adenocarcinoma and metastatic tissues. , 2006, World journal of gastroenterology.

[106]  I. Ellis,et al.  Expression of mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and their prognostic significance in human breast cancer , 2005, Modern Pathology.