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World Journal of Surgical Oncology

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Open Access 01-12-2012 | Research

Prognostic significance of muc4 expression in gallbladder carcinoma

Authors: Hyeon Kook Lee, Min-Sun Cho, Tae Hun Kim

Published in: World Journal of Surgical Oncology | Issue 1/2012

Abstract

Background

Mucins are high molecular glycoproteins and play protective and lubricating roles in various epithelial tissues. Deregulated expression of mucins is involved in carcinogenesis and tumor invasion. MUC4 expression has been identified as a poor prognostic factor in pancreatobiliary carcinomas. To date, the relation between MUC4 expression and prognosis in gallbladder carcinoma remains to be determined. Authors examined MUC4 expression in gallbladder carcinoma and investigated its impact on prognosis.

Methods

The expression profiles of MUC4, MUC1, MUC2 mucins in gallbladder carcinoma tissues from 63 patients were investigated using immunohistochemical staining.

Results

For gallbladder carcinoma, positive staining of MUC4, MUC1, and MUC2 was 55.6%, 81.0%, 28.6%, respectively. There was a significant correlation between the expression of MUC4 and the expression of MUC1 or MUC2 (p = 0.004, p = 0.009, respectively). Univariate analysis showed that MUC4 expression (p = 0.047), differentiation (p < 0.05), T-stage (p < 0.05) and lymph node metastasis (p < 0.001) were significantly associated with poor survival. Expression of MUC1 and MUC2 was not correlated to survival. The backward stepwise multivariate analysis showed that MUC4 expression (p = 0.039) and lymph node metastasis (p = 0.001) were significant independent risk factors. In combined assessment of MUC4 and MUC2 expression, MUC4 positive and MUC2 negative group showed a significantly worse outcome than MUC4 negative groups(MUC4-/MUC2+ and MUC4-/MUC2-) and MUC4/MUC2 co-expression group(MUC4+/MUC2+) (p < 0.05).

Conclusions

MUC4 expression in gallbladder carcinoma is an independent poor prognostic factor. Therefore, MUC4 expression may be a useful marker to predict the outcome of patients with surgically resected gallbladder carcinoma. MUC2 expression may have prognostic value when combined with MUC4 expression.

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Manfredi S, Benhamiche AM, Isambert N, Prost P, Jouve JL, Faivre J: Trends in incidence and management of gallbladder carcinoma: a population-based study in France. Cancer. 2000, 89: 757-762. 10.1002/1097-0142(20000815)89:4<757::AID-CNCR6>3.0.CO;2-H.CrossRefPubMed

Donohue JH: Present status of the diagnosis and treatment of gallbladder carcinoma. J Hepatobiliary Pancreat Surg. 2001, 8: 530-534. 10.1007/s005340100021.CrossRefPubMed

Kim WS, Choi DW, You DD, Ho CY, Heo JS, Choi SH: Risk factors influencing recurrence, patterns of recurrence, and the efficacy of adjuvant therapy after radical resection for gallbladder carcinoma. J Gastrointest Surg. 2010, 14: 679-687. 10.1007/s11605-009-1140-z.CrossRefPubMed

Rose MC, Voynow JA: Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev. 2006, 86: 245-278. 10.1152/physrev.00010.2005.CrossRefPubMed

Hollingsworth MA, Swanson BJ: Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 2004, 4: 45-60. 10.1038/nrc1251.CrossRefPubMed

Yonezawa S, Higashi M, Yamada N, Yokoyama S, Kitamoto S, Kitajima S, Goto M: Mucins in human neoplasms: clinical pathology, gene expression and diagnostic application. Pathol Int. 2011, 61: 697-716. 10.1111/j.1440-1827.2011.02734.x.CrossRefPubMed

Vermeer PD, Einwalter LA, Moninger TO, Rokhlina T, Kern JA, Zabner J, Welsh MJ: Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature. 2003, 422: 322-326. 10.1038/nature01440.CrossRefPubMed

Ho SB, Shekels LL, Toribara NW, Kim YS, Lyftogt C, Cherwitz DL, Niehans GA: Mucin gene expression in normal, preneoplastic and neoplastic human gastric epithelium. Cancer Res. 1995, 55: 2681-2690.PubMed

Ho SB, Niehans GA, Lyftogt C, Yan PS, Cherwitz DL, Gum ET, Dahiya R, Kim YS: Heterogenicity of mucin gene expression in normal and neoplastic tissues. Cancer Res. 1993, 53: 641-651.PubMed

10.

Higashi M, Yonezawa S, Ho JJ, Tanaka S, Irimura T, Kim YS, Sato E: Expression of MUC1 and MUC2 mucin antigens in intrahepatic bile duct tumors: its relationship with a new morphological classification of cholangiocarcinoma. Hepatology. 1999, 30: 1347-1355. 10.1002/hep.510300609.CrossRefPubMed

11.

Yonezawa S, Nakamura A, Horinouchi M, Sato E: The expression of several types of mucin is related to the biological behavior of pancreatic neoplasms. J Hepatobiliary Pancreat Surg. 2002, 9: 328-341. 10.1007/s005340200037.CrossRefPubMed

12.

Tamada S, Goto M, Nomoto M, Nagata K, Shimizu T, Tanaka S, Sakoda K, Imai K, Yonezawa S: Expression of MUC1 and MUC2 mucins in extrahepatic bile duct carcinomas: its relationship with tumor progression and prognosis. Pathol Int. 2002, 52: 713-723. 10.1046/j.1440-1827.2002.01414.x.CrossRefPubMed

13.

Porchet N, Nguyen VC, Dufosse J, Audie JP, Guyonnet-Duperat V, Gross MS, Denis C, Degand P, Bernheim A, Aubert JP: Molecular cloning and chromosomal localization of a novel human tracheo-bronchial mucin cDNA containing tandemly repeated sequences of 48 base pairs. Biochem Biophys Res Commun. 1991, 175: 414-422. 10.1016/0006-291X(91)91580-6.CrossRefPubMed

14.

Bafna S, Kaur S, Batra SK: Membrane-bound mucins: the mechanistic basis for alterations in the growth and survival of cancer cells. Oncogene. 2010, 29: 2893-2904. 10.1038/onc.2010.87.PubMedCentralCrossRefPubMed

15.

Chaturvedi P, Singh AP, Batra SK: Structure, evolution, and biology of the MUC4 mucin. FASEB J. 2008, 22: 966-981.PubMedCentralCrossRefPubMed

16.

Chauhan SC, Singh AP, Ruiz F, Johansson SL, Jain M, Smith LM, Moniaux N, Batra SK: Aberrant expression of MUC4 in ovarian carcinoma: diagnostic significance alone and in combination with MUC1 and MUC16 (CA125). Mod Pathol. 2006, 19: 1386-1394. 10.1038/modpathol.3800646.CrossRefPubMed

17.

Rakha EA, Boyce RW, Abd El-Rehim D, Kurien T, Green AR, Paish EC, Robertson JF, Ellis IO: Expression of mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and their prognostic significance in human breast cancer. Mod Pathol. 2005, 18: 1295-1304. 10.1038/modpathol.3800445.CrossRefPubMed

18.

Hanaoka J, Kontani K, Sawai S, Ichinose M, Tezuka N, Inoue S, Fujino S, Ohkubo I: Analysis of MUC4 mucin expression in lung carcinoma cells and its immunogenicity. Cancer. 2001, 92: 2148-2157. 10.1002/1097-0142(20011015)92:8<2148::AID-CNCR1557>3.0.CO;2-6.CrossRefPubMed

19.

Saitou M, Goto M, Horinouchi M, Tamada S, Nagata K, Hamada T, Osako M, Takao S, Batra SK, Aikou T, Imai K, Yonezawa S: MUC4 expression is a novel prognostic factor in patients with invasive ductal carcinoma of the pancreas. J Clin Pathol. 2005, 58: 845-852. 10.1136/jcp.2004.023572.PubMedCentralCrossRefPubMed

20.

Shibahara H, Tamada S, Higashi M, Goto M, Batra SK, Hollingsworth MA, Imai K, Yonezawa S: MUC4 is a novel prognostic factor of intrahepatic cholangiocarcinoma-mass forming type. Hepatology. 2004, 39: 220-229. 10.1002/hep.20031.CrossRefPubMed

21.

Tamada S, Shibahara H, Higashi M, Goto M, Batra SK, Imai K, Yonezawa S: MUC4 is a novel prognostic factor of extrahepatic bile duct carcinoma. Clin Cancer Res. 2006, 12: 4257-4264. 10.1158/1078-0432.CCR-05-2814.CrossRefPubMed

22.

Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DG, Morrow M: American joint committee on cancer: cancer staging manual. 2002, Chicago: Springer, 6CrossRef

23.

Vandenhaute B, Buisine MP, Debailleul V, Clément B, Moniaux N, Dieu MC, Degand P, Porchet N, Aubert JP: Mucin gene expression in biliary epithelial cells. J Hepatol. 1997, 27: 1057-1066. 10.1016/S0168-8278(97)80150-X.CrossRefPubMed

24.

Matull WR, Andreola F, Loh A, Adiguzel Z, Deheragoda M, Qureshi U, Batra SK, Swallow DM, Pereira SP: MUC4 and MUC5AC are highly specific tumour-associated mucins in biliary tract cancer. Br J Cancer. 2008, 98: 1675-1681. 10.1038/sj.bjc.6604364.PubMedCentralCrossRefPubMed

25.

Tsutsumida H, Goto M, Kitajima S, Kubota I, Hirotsu Y, Wakimoto J, Batra SK, Imai K, Yonezawa S: MUC4 expression correlates with poor prognosis in small sized lung adenocarcinoma. Lung Cancer. 2007, 55: 195-203. 10.1016/j.lungcan.2006.10.013.CrossRefPubMed

26.

Carraway KL, Perez A, Idris N, Jepson S, Arango M, Komatsu M, Haq B, Price-Schiavi SA, Zhang J, Carraway CA: Muc4/sialomucin complex, the intramembrane ErbB2 ligand, in cancer and epithelia: to protect and to survive. Prog Nucleic Acid Res Mol Biol. 2002, 71: 149-185.CrossRefPubMed

27.

Carraway KL, Theodoropoulos G, Kozloski GA, Carothers Carraway CA: Muc4/MUC4 functions and regulation in cancer. Future Oncol. 2009, 5: 1631-1640. 10.2217/fon.09.125.PubMedCentralCrossRefPubMed

28.

Miyahara N, Shoda J, Ishige K, Kawamoto T, Ueda T, Taki R, Ohkohchi N, Hyodo I, Thomas MB, Krishnamurthy S, Carraway KL, Irimura T: MUC4 interacts with ErbB2 in human gallbladder carcinoma: potential pathobiological implications. Eur J Cancer. 2008, 44: 1048-1056. 10.1016/j.ejca.2008.03.007.CrossRefPubMed

29.

Workman HC, Sweeney C, Carraway KL: The membrane mucin Muc4 inhibits apoptosis induced by multiple insults via ErbB2-dependent and ErbB2-independent mechanisms. Cancer Res. 2009, 69: 2845-2852. 10.1158/0008-5472.CAN-08-2089.PubMedCentralCrossRefPubMed

30.

Kufe DW: Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer. 2009, 9: 874-885. 10.1038/nrc2761.PubMedCentralCrossRefPubMed

31.

Yonezawa S, Goto M, Yamada N, Higashi M, Nomoto M: Expression profiles of MUC1, MUC2, and MUC4 mucins in human neoplasms and their relationship with biological behavior. Proteomics. 2008, 8: 3329-3341. 10.1002/pmic.200800040.CrossRefPubMed

32.

Ghosh M, Kamma H, Kawamoto T, Koike N, Miwa M, Kapoor VK, Krishnani N, Agrawal S, Ohkohchi N, Todoroki T: MUC 1 core protein as a marker of gallbladder malignancy. Eur J Surg Oncol. 2005, 31: 891-896. 10.1016/j.ejso.2005.03.008.CrossRefPubMed

33.

Yamato T, Sasaki M, Watanabe Y, Nakanuma Y: Expression of MUC1 and MUC2 mucin core proteins and their messenger RNA in gall bladder carcinoma: an immunohistochemical and in situ hybridization study. J Pathol. 1999, 188: 30-37. 10.1002/(SICI)1096-9896(199905)188:1<30::AID-PATH291>3.0.CO;2-Q.CrossRefPubMed

34.

Kashiwagi H, Kijima H, Dowaki S, Ohtani Y, Tobita K, Yamazaki H, Nakamura M, Ueyama Y, Tanaka M, Inokuchi S, Makuuchi H: MUC1 and MUC2 expression in human gallbladder carcinoma: a clinicopathological study and relationship with prognosis. Oncol Rep. 2001, 8: 485-489.PubMed

35.

Takagawa M, Muguruma N, Oguri K, Imoto Y, Okamoto K, Ii K, Ito S: Prediction of prognosis in gallbladder carcinoma by mucin and p53 immunohistochemistry. Dig Dis Sci. 2005, 50: 1410-1413. 10.1007/s10620-005-2854-8.CrossRefPubMed

36.

Osako M, Yonezawa S, Siddiki B, Huang J, Ho JJ, Kim YS, Sato E: Immunohistochemical study of mucin carbohydrates and core protein in human pancreatic tumors. Cancer. 1993, 71: 2191-2199. 10.1002/1097-0142(19930401)71:7<2191::AID-CNCR2820710705>3.0.CO;2-X.CrossRefPubMed

37.

Horinouchi M, Nagata K, Nakamura A, Goto M, Takao S, Sakamoto M, Fukushima N, Miwa A, Irimura T, Imai K, Sato E, Yonezawa : Expression of different glycoforms of membrane mucin(MUC1) and secretory mucin (MUC2, MUC5AC and MUC6) in pancreatic neoplasms. Acta Histochem Cytochem. 2003, 36: 443-453. 10.1267/ahc.36.443.CrossRef

Title: Prognostic significance of muc4 expression in gallbladder carcinoma
Authors: Hyeon Kook Lee
Min-Sun Cho
Tae Hun Kim
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: World Journal of Surgical Oncology / Issue 1/2012
Electronic ISSN: 1477-7819
DOI: https://doi.org/10.1186/1477-7819-10-224

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Springer Medicine

Prognostic significance of muc4 expression in gallbladder carcinoma

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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