title: Deregulation of MUC4 in gastric adenocarcinoma: potential pathobiological implication in poorly differentiated non-signet ring cell type gastric cancer.
abstract: MUC4 is a large, heavily glycosylated transmembrane mucin, that is implicated in the pathogenesis of various types of cancers. To date, no extensive study has been done to check the expression and functional significance of MUC4 in different types of gastric adenocarcinomas. Here, we report the expression profile of MUC4 in gastric adenocarcinomas and its function in poorly differentiated gastric non-signet ring cell carcinoma (non-SRCC) type cells. Immunohistochemical analysis using tissue microarray (TMA) showed a significant difference in MUC4 expression between normal adjacent (n = 45) and gastric adenocarcinoma (n = 83; P < 0.001). MUC4 expression was not associated with tumour type, stage or with the degree of differentiation. To gain further insight into the significance of MUC4 expression in gastric non-SRCC cells, MUC4 was ectopically expressed in AGS, a poorly differentiated gastric non-signet ring cell line. The MUC4 overexpressing cells (AGS-MUC4) showed a significant increase (P < 0.005) in cell motility and a decrease in cellular aggregation as compared with the vector-transfected cells. Furthermore, in vivo tumorigenicity analysis revealed that animals transplanted with the MUC4 overexpressing cells (AGS-MUC4) had a greater incidence of tumours (83%) in comparison to empty vector control (17%). In addition, the expression of MUC4 resulted in enhanced expression of total cellular ErbB2 and phosphorylated ErbB2. In conclusion, our results showed that MUC4 is overexpressed in gastric adenocarcinoma tissues, and that it has a role in promoting aggressive properties in poorly differentiated gastric non-SRCC cells through the activation of the ErbB2 oncoprotein.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaho, NE 68198, USA.
authors.forename: S
authors.initials: S
authors.lastname: Senapati
authors.forename: P
authors.initials: P
authors.lastname: Chaturvedi
authors.forename: P
authors.initials: P
authors.lastname: Sharma
authors.forename: G
authors.initials: G
authors.lastname: Venkatraman
authors.forename: J L
authors.initials: JL
authors.lastname: Meza
authors.forename: W
authors.initials: W
authors.lastname: El-Rifai
authors.forename: H K
authors.initials: HK
authors.lastname: Roy
authors.forename: S K
authors.initials: SK
authors.lastname: Batra
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000556:secondary; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D018279:Carcinoma, Signet Ring Cell / Q000378:metabolism* / Q000556:secondary; D002454:Cell Differentiation; D002465:Cell Movement / Q000502:physiology; D005455:Fluorescent Antibody Technique; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D051379:Mice; D008819:Mice, Nude; D055264:Mucin-4 / Q000378:metabolism*; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology*; D046888:Tissue Array Analysis; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D055264:Mucin-4; D018719:Erb-b2 Receptor Tyrosine Kinases
references.citation: Nat Rev Cancer. 2005 May;5(5):341-54
references.pmid: 15864276
references.citation: Int J Cancer. 1998 Apr 17;79(2):133-8
references.pmid: 9583726
references.citation: Gastroenterology. 1997 Aug;113(2):455-64
references.pmid: 9247464
references.citation: Oncogene. 2000 Nov 20;19(49):5680-9
references.pmid: 11114748
references.citation: Oncogene. 2003 Sep 4;22(38):6107-10
references.pmid: 12955090
references.citation: Gastric Cancer. 2004;7(1):9-16
references.pmid: 15052434
references.citation: Gastroenterology. 1994 Jul;107(1):160-72
references.pmid: 8020658
references.citation: Br J Cancer. 2007 Aug 6;97(3):345-57
references.pmid: 17595659
references.citation: Br J Surg. 2003 Jan;90(1):95-101
references.pmid: 12520583
references.citation: Cancer Res. 1993 Feb 1;53(3):641-51
references.pmid: 7678777
references.citation: Am J Clin Pathol. 2002 May;117(5):791-6
references.pmid: 12090430
references.citation: Laryngoscope. 2004 Aug;114(8 Pt 2 Suppl 101):1-32
references.pmid: 15284539
references.citation: Biochem Biophys Res Commun. 2007 Mar 30;355(1):200-3
references.pmid: 17292332
references.citation: Acta Pathol Microbiol Scand. 1965;64:31-49
references.pmid: 14320675
references.citation: Cancer Res. 1995 Jun 15;55(12):2681-90
references.pmid: 7780985
references.citation: Adv Cancer Res. 1989;52:257-331
references.pmid: 2662714
references.citation: Gut. 2000 Sep;47(3):349-56
references.pmid: 10940270
references.citation: Cancer Detect Prev. 1995;19(2):173-82
references.pmid: 7750105
references.citation: Med J Aust. 1985 Feb 4;142(3):S5-6
references.pmid: 3969029
references.citation: Cancer Res. 1994 Apr 1;54(7 Suppl):1941s-1943s
references.pmid: 8137316
references.citation: Cancer Res. 2007 Jan 15;67(2):433-6
references.pmid: 17234748
references.citation: Eur J Cancer. 2008 May;44(7):1048-56
references.pmid: 18397823
references.citation: J Surg Oncol. 1999 Aug;71(4):214-9
references.pmid: 10440758
references.citation: Nat Rev Cancer. 2004 Jan;4(1):45-60
references.pmid: 14681689
references.citation: Mol Cancer Res. 2007 Apr;5(4):309-20
references.pmid: 17406026
references.citation: J Biol Chem. 2003 Sep 12;278(37):35458-64
references.pmid: 12826677
references.citation: Hepatology. 2004 Jan;39(1):220-9
references.pmid: 14752841
references.citation: Cancer Res. 1989 Dec 15;49(24 Pt 1):6966-71
references.pmid: 2582438
references.citation: Int J Cancer. 1998 Aug 21;79(4):402-10
references.pmid: 9699534
references.citation: Int J Cancer. 2003 May 10;104(6):683-94
references.pmid: 12640674
references.citation: Int J Cancer. 1989 Jun 15;43(6):1072-6
references.pmid: 2471698
references.citation: J Mammary Gland Biol Neoplasia. 1996 Apr;1(2):219-29
references.pmid: 10887495
references.citation: Pancreas. 2003 Apr;26(3):e48-54
references.pmid: 12657964
references.citation: J Histochem Cytochem. 2000 Mar;48(3):377-88
references.pmid: 10681391
references.citation: Cancer Res. 1983 Apr;43(4):1703-9
references.pmid: 6831414
references.citation: CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96
references.pmid: 18287387
references.citation: Mod Pathol. 2004 Feb;17(2):150-7
references.pmid: 14657954
references.citation: Curr Opin Cell Biol. 2005 Oct;17(5):559-64
references.pmid: 16098726
references.citation: Clin Cancer Res. 1998 Nov;4(11):2605-14
references.pmid: 9829723
references.citation: J Biol Chem. 1997 Dec 26;272(52):33245-54
references.pmid: 9407114
references.citation: Cancer Res. 2004 Jan 15;64(2):622-30
references.pmid: 14744777
references.citation: J Histochem Cytochem. 2000 Dec;48(12):1657-66
references.pmid: 11101634
references.citation: Hum Pathol. 1997 Sep;28(9):1056-65
references.pmid: 9308730
references.citation: Cancer Res. 2008 Apr 1;68(7):2065-70
references.pmid: 18381409
references.citation: Cancer. 1999 May 1;85(9):1894-902
references.pmid: 10223227
references.citation: Clin Cancer Res. 2001 Dec;7(12):4033-40
references.pmid: 11751498