Abstract
WWOX is a putative tumor suppressor gene that spans approximately a 1 Mb genomic region and is the site for the second most common chromosomal fragile site, FRA16D at 16q23. Various studies have focused on the expression of WWOX in human cancer mostly at the RNA level, but little is known about the normal pattern of WWOX protein expression in non-neoplastic tissues. In this study, a comprehensive analysis of WWOX protein expression in normal tissues was performed by means of immunohistochemistry utilizing a very specific anti-WWOX polyclonal antibody. We analyzed tissue cores of human samples representing more than 30 organs, using various tissue microarray (TMA) slides. Due to the potential role of WWOX in sex-steroid metabolism, whole sections from hormonally regulated organs like breast, ovaries, testes and prostate were also analyzed. The results from our study indicate that WWOX is preferentially highly expressed in secretory epithelial cells of reproductive, endocrine and exocrine organs, as well as in ductal epithelial cells from specific segments of the urinary system. Interestingly, we also observed significant WWOX protein expression in various cell types of neural origin including neurons, ependymal cells and astrocytes. No expression of WWOX was detected in adipose, connective, and lymphoid tissues, myelinized structures and blood vessels. By better defining the topographic distribution of WWOX in normal tissues this study provides some insight on the potential physiological role of this novel protein.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aqeilan RI, Donati V, Palamarchuk A, Trapasso F, Kaou M, Pekarsky Y, Sudol M, Croce CM (2005) WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function. Cancer Res 65 (15):6764–6772, Aug 1
Bednarek AK, Laflin KJ, Daniel RL, Liao Q, Hawkins KA, Aldaz CM (2000a) WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1,a region frequently affected in breast cancer. Cancer Res 60:2140–2145
Bednarek AK, Keck-Waggoner CL, Daniel RL, Laflin KJ, Bergsagel PL, Kiguchi K, Brenner AJ, Aldaz CM (2001b) WWOX, the FRA16D gene, behaves as a suppressor of tumor growth. Cancer Res 61:8068–8073
Duax WL, Ghosh D (1997) Structure and function of steroid dehydrogenases involved in hypertension, fertility, and cancer. Steroids 62:95–100
Gourley C, Paige AJ, Taylor KJ, Scott D, Francis NJ, Rush R, Aldaz CM, Smyth JF, Gabra H (2005) WWOX mRNA expression profile in epithelial ovarian cancer supports the role of WWOX variant 1 as a tumour suppressor, although the role of variant 4 remains unclear. Int J Oncol 26(6):1681–1689, Jun
Guler G, Uner A, Guler N, Han SY, Iliopoulos D, McCue P, Huebner K (2005) Concordant loss of fragile gene expression early in breast cancer development. Pathol Int 55(8):471–478, Aug
Iliopoulos D, Guler G, Han SY, Johnston D, Druck T, McCorkell KA, Palazzo J, McCue PA, Baffa R, Huebner K (2005a) Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer. Oncogene 24(9):1625–1633, Feb 24
Iliopoulos D, Guler G, Han SY, Druck T, Ottey M, McCorkell KA, Huebner K (2006b) Roles of FHIT and WWOX fragile genes in cancer. Cancer Lett 232(1):27–36, Jan 28
Ishii H, Vecchione A, Furukawa Y, Sutheesophon K, Han SY, Druck T, Kuroki T, Trapasso F, Nishimura M, Saito Y, Ozawa K, Croce CM, Huebner K (2003) Expression of FRA16D/WWOX and FRA3B/FHIT genes in hematopoietic malignancies. Mol Cancer Res 1:940–947
Jin C, Ge L, Ding X, Chen Y, Zhu H, Ward T, Wu F, Cao X, Wang Q, Yao X (2006) PKA-mediated protein phosphorylation regulates ezrin-WWOX interaction. Biochem Biophys Res Commun 341(3):784–791, Mar 17
Kallberg Y, Oppermann U, Jornvall H, Persson B (2002) Short-chain dehydrogenase/reductase (SDR) relationships: a large family with eight clusters common to human, animal, and plant genomes. Protein Sci 11(3):636–641, Mar
Krummel KA, Roberts LR, Kawakami M, Glover TW, Smith DI (2000) the characterization of the common fragile site FRA16D and its involvement in multiple myeloma translocations. Genomics 69:37–46
Kuroki T, Trapasso F, Shiraishi T, Alder H, Mimori K, Mori M, Croce CM (2002) Genetic alterations of the tumor suppressor gene WWOX in esophageal squamous cell Carcinoma. Cancer Res 62:2258–2260
Ludes-Meyers JH, Bednarek AK, Popescu NC, Bedford M, Aldaz CM (2003a) WWOX, the common chromosomal fragile site, FRA16D, cancer gene. Cytogenet Genome Res 100:101–110
Ludes-Meyers JH, Kil H, Bednarek AK, Drake J, Bedford MT, Aldaz CM (2004b) WWOX binds the specific proline-rich ligand PPXY: identification of candidate interacting proteins. Oncogene 23(29):5049–5055, Jun 24
Nunez MI, Ludes-Meyers J, Abba MC, Kil H, Abbey NW, Page RE, Sahin A, Klein-Szanto A, Aldaz CM (2005a) Frequent loss of WWOX expression in breast cancer: correlation with estrogen receptor status. Breast Cancer Res Treat 89(2):99–105
Nunez MI, Rosen DG, Ludes-Meyers JH, Abba MC, Kil H, Page R, Klein-Szanto AJ, Godwin AK, Liu J, Mills GB, Aldaz CM (2005b) WWOX protein expression varies among ovarian carcinoma histotypes and correlates with less favorable outcome. BMC Cancer 5(1):64, Jun 27
O’keefe LV, Richards RI (2006) Common chromosomal fragile sites and cancer: focus on FRA16D. Cancer Lett 232(1):37–47, Jan 28
Paige AJ, Taylor KJ, Stewart A, Sgouros JG, Gabra H, Sellar GC, Smyth JF, Porteous DJ, Watson JE (2000a) A 700-kb physical map of a region of 16q23.2 homozygously deleted in multiple cancers and spanning the common fragile site FRA16D. Cancer Res 60:1690–1697
Paige AJ, Taylor KJ, Taylor C, Hillier SG, Farrington S, Scott D, Porteous DJ, Smyth JF, Gabra H, Watson JE (2001b) WWOX: a candidate tumor suppressor gene involved in multiple tumor types. Proc Natl Acad Sci U S A 98:11417–11422
Park SW, Ludes-Meyers J, Zimonjic DB, Durkin ME, Popescu NC, Aldaz CM (2004) Frequent downregulation and loss of WWOX gene expression in human hepatocellular carcinoma. Br J Cancer 91:753–759
Pimenta FJ, Gomes DA, Perdigao PF, Barbosa AA, Romano-Silva MA, Gomez MV, Aldaz CM, De Marco L, Gomez RS (2006) Characterization of the tumor suppressor gene WWOX in primary human oral squamous cell carcinomas. Int J Cancer 118(5):1154–1158, Mar 1
Pluciennik E, Kusinska R, Potemski P, Kubiak R, Kordek R, Bednarek AK (2006) WWOX-the FRA16D cancer gene: expression correlation with breast cancer progression and prognosis. Eur J Surg Oncol 32(2):153–157, Mar
Smith DI, Zhu Y, McAvoy S, Kuhn R (2006) Common fragile sites, extremely large genes, neural development and cancer. Cancer Lett 232(1):48–57, Jan 28
Watanabe A, Hippo Y, Taniguchi H, Iwanari H, Yashiro M, Hirakawa K, Kodama T, Aburatani H (2003) An opposing view on WWOX protein function as a tumor suppressor. CancerRes 63:8629–8633
Acknowledgements
The authors gratefully acknowledge Nancy W. Abbey for technical assistance, Joi Holcomb for the elaboration of photo composites, Dr. Mario A. Luna and Dr. Daniel G. Rosen for critical reading. RO1 CA 102444 supported this project.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nunez, M.I., Ludes-Meyers, J. & Aldaz, C.M. WWOX protein expression in normal human tissues. J Mol Hist 37, 115–125 (2006). https://doi.org/10.1007/s10735-006-9046-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10735-006-9046-5