Correlation of Wnt5a expression with histopathological grade/stage in urothelial carcinoma of the bladder

Diagnostic Pathology

Scott Jenkinson²  Masato Nakazawa¹  Karen Coschigano³  Colin Brockett³  Danielle Greco³  Seth Crouser³  Ramiro Malgor³ 

[1] Office of Research and Grants, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA;Department of Specialty Medicine, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA;Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701-2979, USA

关键词: Cell migration;    Urothelial carcinoma;    Wnt5a;    Bladder cancer;   

Others  :  805497
DOI  :  10.1186/1746-1596-8-139

 received in 2013-04-26, accepted in 2013-08-01,  发布年份 2013

【 摘 要 】

Background

Bladder cancer, including urothelial carcinoma (UC), is the most common malignancy of the urinary tract and the fourth most frequent cancer overall in men. Wnt5a, a member of the Wnt family of proteins, has been shown to have contradictory roles in the pathogenesis of many cancers, acting either as tumor suppressor or tumor promoter. The objective of this study was to investigate the expression and role of Wnt5a in the pathogenesis of UC and suggest possible clinical applications for diagnosis, prognosis and treatment.

Methods

We characterized the expression of Wnt5a in 33 human UC samples using immunohistochemistry. The samples were obtained via transurethral resection, immediately fixed in formalin and then embedded in paraffin. The correlation between Wnt5a immunoreactivity, histological grade, and pathological stage of the tumor was analyzed. The expression of Wnt5a mRNA as well as the effect of Wnt5a on cell migration was also evaluated in two UC cell lines, T24 and J82, and a normal urothelial cell line.

Results

Our immunohistochemical results revealed that Wnt5a staining intensity correlated positively with the histological grade and pathological stage of the UC. Wnt5a mRNA expression differed widely in the three urothelial cell lines, with high levels in one carcinoma cell line and low levels in the other cell line in comparison to the normal urothelial cell line. Migration increased in both UC cell lines in response to Wnt5a treatment.

Conclusions

Our results show that the Wnt5a pathway may play a role in the pathogenesis of UC and suggest that Wnt5a may serve as an additional, complementary diagnostic/prognostic marker for UC.

Virtual slide

http://www.diagnosticpathology.diagnomx.eu/vs/1952312091979566 webcite

【 授权许可】

   
2013 Malgor et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Foster CS, Ross JS: Pathology of the Urinary Bladder. 1st edition. Saunders: Philadelphia, PA; 2004:183-190. 199–209; 247–267
• [2]Kausch I, Bohle A: Bladder cancer. II. Molecular aspects and diagnosis. Eur Urol 2001, 39(5):498-506.
• [3]DeVita VT, Lawrence TS, Rosenberg SA: Cancer Principles & Practice of Oncology. 9th edition. 2011, 241-243. 1183–1189
• [4]American Cancer Society: Cancer Facts & Figures 2013. Atlanta: American Cancer Society Inc.; 2013.
• [5]Dale TC: Signal transduction by the Wnt family of ligands. Biochem J 1998, 329(Pt 2):209-223.
• [6]Nishita M, Enomoto M, Yamagata K, Minami Y: Cell/tissue-tropic functions of Wnt5a signaling in normal and cancer cells. Trends Cell Biol 2010, 20(6):346-354.
• [7]Dejmek J, Dejmek A, Safholm A, Sjolander A, Andersson T: Wnt-5a protein expression in primary dukes B colon cancers identifies a subgroup of patients with good prognosis. Cancer Res 2005, 65(20):9142-9146.
• [8]McCall KD, Harii N, Lewis CJ, Malgor R, Kim WB, Saji M, Kohn AD, Moon RT, Kohn LD: High basal levels of functional toll-like receptor 3 (TLR3) and noncanonical Wnt5a are expressed in papillary thyroid cancer and are coordinately decreased by phenylmethimazole together with cell proliferation and migration. Endocrinology 2007, 148(9):4226-4237.
• [9]Blumenthal A, Ehlers S, Lauber J, Buer J, Lange C, Goldmann T, Heine H, Brandt E, Reiling N: The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation. Blood 2006, 108(3):965-973.
• [10]Christman MA 2nd, Goetz DJ, Dickerson E, McCall KD, Lewis CJ, Benencia F, Silver MJ, Kohn LD, Malgor R: Wnt5a is expressed in murine and human atherosclerotic lesions. Am J Physiol Heart Circ Physiol 2008, 294(6):H2864-H2870.
• [11]Shiina H, Igawa M, Shigeno K, Terashima M, Deguchi M, Yamanaka M, Ribeiro-Filho L, Kane CJ, Dahiya R: Beta-catenin mutations correlate with over expression of C-myc and cyclin D1 Genes in bladder cancer. J Urol 2002, 168(5):2220-2226.
• [12]Kastritis E, Murray S, Kyriakou F, Horti M, Tamvakis N, Kavantzas N, Patsouris ES, Noni A, Legaki S, Dimopoulos MA, et al.: Somatic mutations of adenomatous polyposis coli gene and nuclear b-catenin accumulation have prognostic significance in invasive urothelial carcinomas: evidence for Wnt pathway implication. Int J Cancer 2009, 124(1):103-108.
• [13]Wissmann C, Wild PJ, Kaiser S, Roepcke S, Stoehr R, Woenckhaus M, Kristiansen G, Hsieh JC, Hofstaedter F, Hartmann A, et al.: WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer. J Pathol 2003, 201(2):204-212.
• [14]Urakami S, Shiina H, Enokida H, Hirata H, Kawamoto K, Kawakami T, Kikuno N, Tanaka Y, Majid S, Nakagawa M, et al.: Wnt antagonist family genes as biomarkers for diagnosis, staging, and prognosis of renal cell carcinoma using tumor and serum DNA. Clin Cancer Res 2006, 12(23):6989-6997.
• [15]Urakami S, Shiina H, Enokida H, Kawakami T, Tokizane T, Ogishima T, Tanaka Y, Li LC, Ribeiro-Filho LA, Terashima M, et al.: Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt/beta-catenin signaling pathway. Clin Cancer Res 2006, 12(2):383-391.
• [16]Costa VL, Henrique R, Ribeiro FR, Carvalho JR, Oliveira J, Lobo F, Teixeira MR, Jeronimo C: Epigenetic regulation of Wnt signaling pathway in urological cancer. Epigenetics 2010, 5(4):343-351.
• [17]McDonald SL, Silver A: The opposing roles of Wnt-5a in cancer. Br J Cancer 2009, 101(2):209-214.
• [18]Weeraratna AT, Jiang Y, Hostetter G, Rosenblatt K, Duray P, Bittner M, Trent JM: Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell 2002, 1(3):279-288.
• [19]Schwartz AL, Malgor R, Dickerson E, Weeraratna AT, Slominski A, Wortsman J, Harii N, Kohn AD, Moon RT, Schwartz FL, et al.: Phenylmethimazole decreases Toll-like receptor 3 and noncanonical Wnt5a expression in pancreatic cancer and melanoma together with tumor cell growth and migration. Clin Cancer Res 2009, 15(12):4114-4122.
• [20]Kurayoshi M, Oue N, Yamamoto H, Kishida M, Inoue A, Asahara T, Yasui W, Kikuchi A: Expression of Wnt-5a is correlated with aggressiveness of gastric cancer by stimulating cell migration and invasion. Cancer Res 2006, 66(21):10439-10448.
• [21]Blanc E, Goldschneider D, Douc-Rasy S, Benard J, Raguenez G: Wnt-5a gene expression in malignant human neuroblasts. Cancer Lett 2005, 228(1–2):117-123.
• [22]Kremenevskaja N, von Wasielewski R, Rao AS, Schofl C, Andersson T, Brabant G: Wnt-5a has tumor suppressor activity in thyroid carcinoma. Oncogene 2005, 24(13):2144-2154.
• [23]Ying J, Li H, Yu J, Ng KM, Poon FF, Wong SC, Chan AT, Sung JJ, Tao Q: WNT5A exhibits tumor-suppressive activity through antagonizing the Wnt/beta-catenin signaling, and is frequently methylated in colorectal cancer. Clin Cancer Res 2008, 14(1):55-61.
• [24]Olson DJ, Gibo DM, Saggers G, Debinski W, Kumar R: Reversion of uroepithelial cell tumorigenesis by the ectopic expression of human wnt-5a. Cell Growth Differ 1997, 8(4):417-423.
• [25]Masters JR, Hepburn PJ, Walker L, Highman WJ, Trejdosiewicz LK, Povey S, Parkar M, Hill BT, Riddle PR, Franks LM: Tissue culture model of transitional cell carcinoma: characterization of twenty-two human urothelial cell lines. Cancer Res 1986, 46(7):3630-3636.
• [26]Andersen CL, Jensen JL, Orntoft TF: Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res 2004, 64(15):5245-5250.
• [27]Chen YB, Tu JJ, Kao J, Zhou XK, Chen YT: Survivin as a useful adjunct marker for the grading of papillary urothelial carcinoma. Arch Pathol Lab Med 2008, 132(2):224-231.
• [28]Coleman JF, Hansel DE: Utility of diagnostic and prognostic markers in urothelial carcinoma of the bladder. Adv Anat Pathol 2009, 16(2):67-78.
• [29]Wang S, Xue S, Dai Y, Yang J, Chen Z, Fang X, Zhou W, Wu W, Li Q: Reduced expression of microRNA-100 confers unfavorable prognosis in patients with bladder cancer. Diagn Pathol 2012, 7:159. BioMed Central Full Text
• [30]Bahadir B, Behzatoglu K, Bektas S, Bozkurt ER, Ozdamar SO: CD10 expression in urothelial carcinoma of the bladder. Diagn Pathol 2009, 4:38. BioMed Central Full Text
• [31]Tadin T, Krpina K, Stifter S, Babarovic E, Fuckar Z, Jonjic N: Lower cyclooxygenase-2 expression is associated with recurrence of solitary non-muscle invasive bladder carcinoma. Diagn Pathol 2012, 7:152. BioMed Central Full Text
• [32]Masckauchan TN, Agalliu D, Vorontchikhina M, Ahn A, Parmalee NL, Li CM, Khoo A, Tycko B, Brown AM, Kitajewski J: Wnt5a signaling induces proliferation and survival of endothelial cells in vitro and expression of MMP-1 and Tie-2. Mol Biol Cell 2006, 17(12):5163-5172.
• [33]Coffelt SB, Tal AO, Scholz A, De Palma M, Patel S, Urbich C, Biswas SK, Murdoch C, Plate KH, Reiss Y, et al.: Angiopoietin-2 regulates gene expression in TIE2-expressing monocytes and augments their inherent proangiogenic functions. Cancer Res 2010, 70(13):5270-5280.
• [34]Voutsadakis IA: The ubiquitin-proteasome system and signal transduction pathways regulating Epithelial Mesenchymal transition of cancer. J Biomed Sci 2012, 19:67. BioMed Central Full Text
• [35]Huang CL, Liu D, Nakano J, Ishikawa S, Kontani K, Yokomise H, Ueno M: Wnt5a expression is associated with the tumor proliferation and the stromal vascular endothelial growth factor–an expression in non-small-cell lung cancer. Journal of clinical oncology: 2005, 23(34):8765-8773.
• [36]Bui TD, O’Brien T, Crew J, Cranston D, Harris AL: High expression of Wnt7b in human superficial bladder cancer vs invasive bladder cancer. Br J Cancer 1998, 77(2):319-324.
• [37]Mikels AJ, Nusse R: Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS Biol 2006, 4(4):e115.
• [38]Gordon MD, Nusse R: Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem 2006, 281(32):22429-22433.