Role of MUC20 overexpression as a predictor of recurrence and poor outcome in colorectal cancer

Journal of Translational Medicine

Xiang Du²  Xiaoyan Zhou³  Menghong Sun³  Weiqi Sheng³  Cong Tan³  Shujuan Ni³  Qifeng Wang³  Dali Li³  Yayun Chi⁴  Ping Wei³  Lisha Wang³  Xiuying Xiao¹ 

[1] Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China;Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China;Institute of Pathology, Fudan University, Shanghai, 200032, China;Breast Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

关键词: Recurrence;    Invasion;    Colorectal Cancer;    MUC20;   

Others  :  827380
DOI  :  10.1186/1479-5876-11-151

 received in 2013-03-31, accepted in 2013-06-13,  发布年份 2013

【 摘 要 】

Background

Colorectal cancer (CRC) remains one of the most common cancers worldwide. We observed that MUC20 was significantly up-regulated in CRC patients with poor prognosis based on the microarray analysis. However, little is known about the role of MUC20 in CRC.

Methods

Microarray experiments were performed on the Affymetrix U133 plus 2.0 GeneChip Array. The protein and mRNA levels of MUC20 were examined by immunohistochemistry (IHC) and Real-Time quantitative PCR (RT-qPCR) in CRC tissues and adjacent noncancerous tissues (ANCT). ShRNA and overexpression plasmids were used to regulate MUC20 expression in CRC cell lines in vitro; wound healing, Transwell migration assays, and Western blotting were used to detect migration and invasion changes.

Results

MUC20 was one of the up-regulated genes in CRC patients with poor prognosis by microarray. Using IHC and RT-qPCR, we showed that MUC20 expression was significantly higher in CRC tissues than in ANCT (P < 0.05). We further showed that MUC20 overexpression was correlated with recurrence and poor outcome (P < 0.05). The Kaplan-Meier survival curves indicated that disease-free survival (DFS) and overall survival (OS) were significantly worse in CRC patients with MUC20 overexpression. The Cox multivariate analysis revealed that MUC20 overexpression and TNM stage were independent prognostic factors. Elevated expression of MUC20 in cells promoted migration and invasion, whereas ShRNA-mediated knockdown inhibited these processes. In addition, Western blotting demonstrated that MUC20-induced invasion was associated with MMP-2, MMP-3, and E-cadherin.

Conclusions

Cumulatively, MUC20 may serve as an important predictor of recurrence and poor outcome for CRC patients. MUC20 overexpression could enhance migration and invasion abilities of CRC cells. Translation of its roles into clinical practice will need further investigation and additional test validation.

【 授权许可】

   
2013 Xiao et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Noura S, Ohue M, Shingai T, Kano S, Ohigashi H, Yano M, Ishikawa O, Takenaka A, Murata K, Kameyama M: Effects of intraperitoneal chemotherapy with mitomycin C on the prevention of peritoneal recurrence in colorectal cancer patients with positive peritoneal lavage cytology findings. Ann Surg Oncol 2011, 18:396-404.
• [2]Zhao L, Liu Y, Sun X, Peng K, Ding Y: Serum proteome analysis for profiling protein markers associated with lymph node metastasis in colorectal carcinoma. J Comp Pathol 2011, 144:187-194.
• [3]Ishizuka M, Kita J, Shimoda M, Kato M, Sawada T, Kubota K: Impact of grading of liver metastasis on postoperative outcome in patients with liver metastases from colorectal cancer. Hepatogastroenterology 2012, 59:54-58.
• [4]Mehlen P, Puisieux A: Metastasis: a question of life or death. Nat Rev Cancer 2006, 6:449-458.
• [5]Roessler S, Jia HL, Budhu A, Forgues M, Ye QH, Lee JS, Thorgeirsson SS, Sun Z, Tang ZY, Qin LX, Wang XW: A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients. Cancer Res 2010, 70:10202-10212.
• [6]Hollingsworth MA, Swanson BJ: Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer 2004, 4:45-60.
• [7]Kufe DW: Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer 2009, 9:874-885.
• [8]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.
• [9]Yonezawa S, Higashi M, Yamada N, Goto M: Precursor lesions of pancreatic cancer. Gut Liver 2008, 2:137-154.
• [10]Yonezawa S, Higashi M, Yamada N, Yokoyama S, Goto M: Significance of mucin expression in pancreatobiliary neoplasms. J Hepatobiliary Pancreat Sci 2010, 17:108-124.
• [11]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.
• [12]Kang H, Min BS, Lee KY, Kim NK, Kim SN, Choi J, Kim H: Loss of E-cadherin and MUC2 expressions correlated with poor survival in patients with stages II and III colorectal carcinoma. Ann Surg Oncol 2011, 18:711-719.
• [13]Byrd JC, Bresalier RS: Mucins and mucin binding proteins in colorectal cancer. Cancer Metastasis Rev 2004, 23:77-99.
• [14]Matsuda K, Masaki T, Watanabe T, Kitayama J, Nagawa H, Muto T, Ajioka Y: Clinical significance of MUC1 and MUC2 mucin and p53 protein expression in colorectal carcinoma. Jpn J Clin Oncol 2000, 30:89-94.
• [15]Higuchi T, Orita T, Nakanishi S, Katsuya K, Watanabe H, Yamasaki Y, Waga I, Nanayama T, Yamamoto Y, Munger W, Sun HW, Falk RJ, Jennette JC, Alcorta DA, Li H, Yamamoto T, Saito Y, Nakamura M: Molecular cloning, genomic structure, and expression analysis of MUC20, a novel mucin protein, up-regulated in injured kidney. J Biol Chem 2004, 279:1968-1979.
• [16]Higuchi T, Orita T, Katsuya K, Yamasaki Y, Akiyama K, Li H, Yamamoto T, Saito Y, Nakamura M: MUC20 suppresses the hepatocyte growth factor-induced Grb2-Ras pathway by binding to a multifunctional docking site of met. Mol Cell Biol 2004, 24:7456-7468.
• [17]Lin B, Utleg AG, Gravdal K, White JT, Halvorsen OJ, Lu W, True LD, Vessella R, Lange PH, Nelson PS, Hood L, Kalland KH, Akslen LA: WDR19 expression is increased in prostate cancer compared with normal cells, but low-intensity expression in cancers is associated with shorter time to biochemical failures and local recurrence. Clin Cancer Res 2008, 14:1397-1406.
• [18]Peng ZH, Wan DS, Li LR, Chen G, Lu ZH, Wu XJ, Kong LH, Pan ZZ: Expression of COX-2, MMP-2 and VEGF in stage II and III colorectal cancer and the clinical significance. Hepatogastroenterology 2011, 58:369-376.
• [19]Peng B, Cao L, Wang W, Xian L, Jiang D, Zhao J, Zhang Z, Wang X, Yu L: Polymorphisms in the promoter regions of matrix metalloproteinases 1 and 3 and cancer risk: a meta-analysis of 50 case-control studies. Mutagenesis 2010, 25:41-48.
• [20]Park KS, Kim SJ, Kim KH, Kim JC: Clinical characteristics of TIMP2, MMP2, and MMP9 gene polymorphisms in colorectal cancer. J Gastroenterol Hepatol 2011, 26:391-397.
• [21]Buda A, Pignatelli M: E-cadherin and the cytoskeletal network in colorectal cancer development and metastasis. Cell Commun Adhes 2011, 18:133-143.
• [22]Bertucci F, Salas S, Eysteries S, Nasser V, Finetti P, Ginestier C, Charafe-Jauffret E, Loriod B, Bachelart L, Montfort J, Victorero G, Viret F, Ollendorff V, Fert V, Giovaninni M, Delpero JR, Nguyen C, Viens P, Monges G, Birnbaum D, Houlgatte R: Gene expression profiling of colon cancer by DNA microarrays and correlation with histoclinical parameters. Oncogene 2004, 23:1377-1391.
• [23]Frederiksen CM, Knudsen S, Laurberg S, Orntoft TF: Classification of Dukes’ B and C colorectal cancers using expression arrays. J Cancer Res Clin Oncol 2003, 129:263-271.
• [24]Tureci O, Ding J, Hilton H, Bian H, Ohkawa H, Braxenthaler M, Seitz G, Raddrizzani L, Friess H, Buchler M, Sahin U, Hammer J: Computational dissection of tissue contamination for identification of colon cancer-specific expression profiles. FASEB J 2003, 17:376-385.
• [25]Lascorz J, Chen B, Hemminki K, Forsti A: Consensus pathways implicated in prognosis of colorectal cancer identified through systematic enrichment analysis of gene expression profiling studies. PLoS One 2011, 6:e18867.
• [26]Nannini M, Pantaleo MA, Maleddu A, Astolfi A, Formica S, Biasco G: Gene expression profiling in colorectal cancer using microarray technologies: results and perspectives. Cancer Treat Rev 2009, 35:201-209.
• [27]Wang Y, Jatkoe T, Zhang Y, Mutch MG, Talantov D, Jiang J, McLeod HL, Atkins D: Gene expression profiles and molecular markers to predict recurrence of Dukes’ B colon cancer. J Clin Oncol 2004, 22:1564-1571.
• [28]Sanz-Pamplona R, Berenguer A, Cordero D, Riccadonna S, Sole X, Crous-Bou M, Guino E, Sanjuan X, Biondo S, Soriano A, Jurman G, Capella G, Furlanello C, Moreno V: Clinical value of prognosis gene expression signatures in colorectal cancer: a systematic review. PLoS One 2012, 7:e48877.
• [29]Arango D, Laiho P, Kokko A, Alhopuro P, Sammalkorpi H, Salovaara R, Nicorici D, Hautaniemi S, Alazzouzi H, Mecklin JP, Jarvinen H, Hemminki A, Astola J, Schwartz SJ, Aaltonen LA: Gene-expression profiling predicts recurrence in Dukes’ C colorectal cancer. Gastroenterology 2005, 129:874-884.
• [30]Yamasaki M, Takemasa I, Komori T, Watanabe S, Sekimoto M, Doki Y, Matsubara K, Monden M: The gene expression profile represents the molecular nature of liver metastasis in colorectal cancer. Int J Oncol 2007, 30:129-138.
• [31]Vlad AM, Diaconu I, Gantt KR: MUC1 in endometriosis and ovarian cancer. Immunol Res 2006, 36:229-236.
• [32]Woenckhaus M, Merk J, Stoehr R, Schaeper F, Gaumann A, Wiebe K, Hartmann A, Hofstaedter F, Dietmaier W: Prognostic value of FHIT, CTNNB1, and MUC1 expression in non-small cell lung cancer. Hum Pathol 2008, 39:126-136.
• [33]Marin F, Bonet C, Munoz X, Garcia N, Pardo ML, Ruiz-Liso JM, Alonso P, Capella G, Sanz-Anquela JM, Gonzalez CA, Sala N: Genetic variation in MUC1, MUC2 and MUC6 genes and evolution of gastric cancer precursor lesions in a long-term follow-up in a high-risk area in Spain. Carcinogenesis 2012, 33:1072-1080.
• [34]Terada T: An immunohistochemical study of primary signet-ring cell carcinoma of the stomach and colorectum: II. Expression of MUC1, MUC2, MUC5AC, and MUC6 in normal mucosa and in 42 cases. Int J Clin Exp Pathol 2013, 6:613-621.
• [35]Kocer B, Soran A, Erdogan S, Karabeyoglu M, Yildirim O, Eroglu A, Bozkurt B, Cengiz O: Expression of MUC5AC in colorectal carcinoma and relationship with prognosis. Pathol Int 2002, 52:470-477.
• [36]Bu XD, Li N, Tian XQ, Li L, Wang JS, Yu XJ, Huang PL: Altered expression of MUC2 and MUC5AC in progression of colorectal carcinoma. World J Gastroenterol 2010, 16:4089-4094.
• [37]Chen CH, Wang SW, Chen CW, Huang MR, Hung JS, Huang HC, Lin HH, Chen RJ, Shyu MK, Huang MC: MUC20 overexpression predicts poor prognosis and enhances EGF-induced malignant phenotypes via activation of the EGFR-STAT3 pathway in endometrial cancer. Gynecol Oncol 2013, 128:560-567.
• [38]Vekony H, Leemans CR, Ylstra B, Meijer GA, van der Waal I, Bloemena E: Salivary gland carcinosarcoma: oligonucleotide array CGH reveals similar genomic profiles in epithelial and mesenchymal components. Oral Oncol 2009, 45:259-265.
• [39]Yoon SO, Park SJ, Yun CH, Chung AS: Roles of matrix metalloproteinases in tumor metastasis and angiogenesis. J Biochem Mol Biol 2003, 36:128-137.
• [40]Hsu HH, Liu CJ, Shen CY, Chen YJ, Chen LM, Kuo WH, Lin YM, Chen RJ, Tsai CH, Tsai FJ, Huang CY: p38alpha MAPK mediates 17beta-estradiol inhibition of MMP-2 and -9 expression and cell migration in human LoVo colon cancer cells. J Cell Physiol 2012, 227:3648-3660.
• [41]Damodharan U, Ganesan R, Radhakrishnan UC: Expression of MMP2 and MMP9 (gelatinases A and B) in human colon cancer cells. Appl Biochem Biotechnol 2011, 165:1245-1252.
• [42]McColgan P, Sharma P: Polymorphisms of matrix metalloproteinases 1, 2, 3 and 9 and susceptibility to lung, breast and colorectal cancer in over 30,000 subjects. Int J Cancer 2009, 125:1473-1478.
• [43]Palacios F, Tushir JS, Fujita Y, D’Souza-Schorey C: Lysosomal targeting of E-cadherin: a unique mechanism for the down-regulation of cell-cell adhesion during epithelial to mesenchymal transitions. Mol Cell Biol 2005, 25:389-402.
• [44]Tsanou E, Peschos D, Batistatou A, Charalabopoulos A, Charalabopoulos K: The E-cadherin adhesion molecule and colorectal cancer. A global literature approach. Anticancer Res 2008, 28:3815-3826.
• [45]Miladi-Abdennadher I, Abdelmaksoud-Dammak R, Ayed-Guerfali DB, Ayadi L, Khabir A, Amouri A, Frikha F, Tahri N, Ellouz S, Frikha M, Sellami-Boudawara T, Mokdad-Gargouri R: Expression of COX-2 and E-cadherin in Tunisian patients with colorectal adenocarcinoma. Acta Histochem 2011, 114:577-581.