Alternating expression levels of WWOX tumor suppressor and cancer-related genes in patients with bladder cancer

The aim of the present study was to determine the roles of the WWOX tumor suppressor and cancer-related genes in bladder tumor carcinogenesis. Reverse transcription-quantitative polymerase chain reaction was used to analyze the status of WWOX promoter methylation (using MethylScreen™ technology) and loss of heterozygosity (LOH) in papillary urothelial cancer tissues. The associations between the expression levels of the following tumorigenesis-related genes were also assessed: The WWOX tumor suppressor gene, the MKI67 proliferation gene, the BAX, BCL2 and BIRC5 apoptotic genes, the EGFR signal transduction gene, the VEGF vascular endothelial growth factor gene, and the CCND1 and CCNE1 cell cycle genes. The results reveal a high frequency of LOH in intron 1 in the WWOX gene, as well as an association between reduced WWOX expression levels and increased promoter methylation. In addition, the present study demonstrates that in bladder tumors, apoptosis is inhibited by increased expression levels of the BCL2 gene. A correlation between the proliferation indices of the MKI67 and the BIRC5 genes was also revealed. Furthermore, the expression levels of VEGF were identified to be positively associated with those of the EGFR gene.

[1]  M. Nowakowska,et al.  Genetic alterations of WWOX in Wilms' tumor are involved in its carcinogenesis. , 2012, Oncology reports.

[2]  J. Zhen,et al.  Aberrant Expression of WWOX Protein in Epithelial Ovarian Cancer: A Clinicopathologic and Immunohistochemical Study , 2012, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[3]  H. Miyake,et al.  Expression of cell cycle-associated proteins in non-muscle-invasive bladder cancer: correlation with intravesical recurrence following transurethral resection. , 2011, Urologic oncology.

[4]  K. Yanagihara,et al.  Loss of WW domain-containing oxidoreductase expression in the progression and development of gastric carcinoma: clinical and histopathologic correlations , 2010, Virchows Archiv.

[5]  A. Bednarek,et al.  LABORATORY INVESTIGATION- HUMAN/ANIMAL TISSUE Molecular analysis of WWOX expression correlation , 2022 .

[6]  K. Moon,et al.  Prognostic value of apoptosis-related markers in urothelial cancer of the upper urinary tract. , 2009, Human pathology.

[7]  G. Stein,et al.  Targeted ablation of the WW domain-containing oxidoreductase tumor suppressor leads to impaired steroidogenesis. , 2009, Endocrinology.

[8]  Stefano Volinia,et al.  The WWOX Tumor Suppressor Is Essential for Postnatal Survival and Normal Bone Metabolism* , 2008, Journal of Biological Chemistry.

[9]  A. Llombart‐Bosch,et al.  Low levels of WWOX protein immunoexpression correlate with tumour grade and a less favourable outcome in patients with urinary bladder tumours , 2008, Histopathology.

[10]  Wun-Jae Kim,et al.  Molecular biomarkers in urothelial bladder cancer , 2008, Cancer science.

[11]  C. Croce,et al.  Association of Wwox with ErbB4 in breast cancer. , 2007, Cancer research.

[12]  Y. Lotan,et al.  Survivin expression is associated with bladder cancer presence, stage, progression, and mortality , 2007 .

[13]  Y. Pekarsky,et al.  Physical association with WWOX suppresses c-Jun transcriptional activity. , 2006, Cancer research.

[14]  Ram H Datar,et al.  Molecular pathways in invasive bladder cancer: new insights into mechanisms, progression, and target identification. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  Y. Lotan,et al.  Correlation of cyclin D1 and E1 expression with bladder cancer presence, invasion, progression, and metastasis. , 2006, Human pathology.

[16]  R. Montironi,et al.  Apoptotic and proliferation indexes in primary superficial bladder tumors. , 2006, Cancer Letters.

[17]  J. Ludes-Meyers,et al.  WWOX protein expression in normal human tissues , 2006, Journal of Molecular Histology.

[18]  D. Iliopoulos,et al.  A role for the WWOX gene in prostate cancer. , 2006, Cancer research.

[19]  N. Sato,et al.  Expression and antigenicity of survivin, an inhibitor of apoptosis family member, in bladder cancer: implications for specific immunotherapy. , 2006, Urology.

[20]  Xia Ding,et al.  PKA-mediated protein phosphorylation regulates ezrin-WWOX interaction. , 2006, Biochemical and biophysical research communications.

[21]  Y. Pekarsky,et al.  WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function. , 2005, Cancer research.

[22]  Dimitrios Iliopoulos,et al.  Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer , 2005, Oncogene.

[23]  Haidong Wang,et al.  The expression and significance of survivin mRNA in urinary bladder carcinomas , 2004, Journal of Cancer Research and Clinical Oncology.

[24]  Y. Pekarsky,et al.  Loss of WWOX Expression in Gastric Carcinoma , 2004, Clinical Cancer Research.

[25]  C. Croce,et al.  The Tumor Suppressor Gene WWOX at FRA16D Is Involved in Pancreatic Carcinogenesis , 2004, Clinical Cancer Research.

[26]  Y. Pekarsky,et al.  Functional association between Wwox tumor suppressor protein and p73, a p53 homolog. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[27]  C. Croce,et al.  WW domain containing oxidoreductase gene expression is altered in non-small cell lung cancer. , 2003, Cancer research.

[28]  G. Horgan,et al.  Relative expression software tool (REST©) for group-wise comparison and statistical analysis of relative expression results in real-time PCR , 2002 .

[29]  C. Croce,et al.  Genetic alterations of the tumor suppressor gene WWOX in esophageal squamous cell carcinoma. , 2002, Cancer research.

[30]  D. Yoon,et al.  Genetic mapping and DNA sequence-based analysis of deleted regions on chromosome 16 involved in progression of bladder cancer from occult preneoplastic conditions to invasive disease , 2001, Oncogene.

[31]  E. Messing,et al.  Molecular mechanisms and pathways in bladder cancer development and progression. , 2000, Cancer control : journal of the Moffitt Cancer Center.

[32]  A. Bednarek,et al.  WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer. , 2000, Cancer research.

[33]  L. Lacombe,et al.  Predictive value of cell cycle markers p53, MDM2, p21, and Ki-67 in superficial bladder tumor recurrence. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[34]  Wei Chen,et al.  [Apoptosis and expression of PCNA in superficial transitional cell bladder cancer as related to recurrence]. , 1998, Zhonghua wai ke za zhi [Chinese journal of surgery].

[35]  V. Bilim,et al.  Variable Bcl-2 phenotype in benign and malignant lesions of urothelium. , 1998, Cancer letters.

[36]  T. Tzai,et al.  Significance of urinary epidermal growth factor and its receptor expression in human bladder cancer. , 1997, Anticancer research.

[37]  A. Harris,et al.  Vascular endothelial growth factor is a predictor of relapse and stage progression in superficial bladder cancer. , 1997, Cancer research.

[38]  A. Sahin,et al.  Deletion map of chromosome 16q in ductal carcinoma in situ of the breast: refining a putative tumor suppressor gene region. , 1996, Cancer research.

[39]  H. Shiina,et al.  Immunohistochemical analysis of bcl-2 expression in transitional cell carcinoma of the bladder. , 1996, Journal of clinical pathology.

[40]  A. Knudson.  Hereditary cancer, oncogenes, and antioncogenes. , 1985, Cancer research.

[41]  M. Bennett,et al.  EPIDERMAL-GROWTH-FACTOR RECEPTORS IN HUMAN BLADDER CANCER: COMPARISON OF INVASIVE AND SUPERFICIAL TUMOURS , 1985, The Lancet.

[42]  Q. Lu,et al.  Cigarette smoking extract causes hypermethylation and inactivation of WWOX gene in T-24 human bladder cancer cells. , 2012, Neoplasma.

[43]  F. Real,et al.  Molecular biology of bladder cancer , 2007, Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico.

[44]  K. Chu,et al.  The expression of vascular endothelial growth factor in transitional cell carcinoma of urinary bladder is correlated with cancer progression. , 2004, Urologic oncology.

[45]  L. Frati,et al.  Expression and prognostic significance of LIVIN, SURVIVIN and other apoptosis-related genes in the progression of superficial bladder cancer. , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[46]  E. Berg,et al.  World Health Organization Classification of Tumours , 2002 .

[47]  A. Harris.  Letter: Vitamin-C-induced hyperoxaluria. , 1976, Lancet.