Reduced expression of the WW domain‑containing oxidoreductase in human hematopoietic malignancies

Luo,Lingqing; Chen,Yan; Cheng,Xiao; Lin,Yazhen; Fu,Xiaodan; Li,Dan; Cui,Zhaolei; Lin,Donghong

doi:10.3892/ol.2016.4495

Reduced expression of the WW domain‑containing oxidoreductase in human hematopoietic malignancies

Authors:
- Lingqing Luo
- Yan Chen
- Xiao Cheng
- Yazhen Lin
- Xiaodan Fu
- Dan Li
- Zhaolei Cui
- Donghong Lin
View Affiliations

Affiliations: Department of Clinical Laboratory, Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Provincial Cancer Hospital, Teaching Hospital of Fujian Medical University, Fuzhou, Fujian 350014, P.R. China, Department of Cardiovasology, Affiliated Mindong Hospital, Fujian Medical University, Fuan, Fujian 355000, P.R. China, Department of Clinical Laboratory, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou, Fujian 350004, P.R. China
Published online on: April 26, 2016 https://doi.org/10.3892/ol.2016.4495
Pages: 4083-4088

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The role of the WW domain‑containing oxidoreductase (WWOX) gene in multiple types of solid human cancers has been documented extensively thus far. Recently, we investigated the in vitro effects of WWOX overexpression and observed marked growth arrest in human leukemia cells; however, the clinical characterization of WWOX in leukemia remains poorly investigated. The present study evaluated the WWOX expression profiles of 182 patients with leukemia of different types and 5 leukemic cell lines, using reverse transcription‑polymerase chain reaction and immunofluorescence analysis. The results found that WWOX mRNA and WWOX protein expression was significantly reduced or absent in the leukemia cases and cell lines compared with paired controls. The WWOX‑positive rate was also lower in the leukemia cases compared with the rate of the normal controls. Notably, the WWOX level was reduced in newly diagnosed and relapsed cases, or in chronic myelogenous leukemia in the blastic phase, yet elevated in remission samples. Moreover, WWOX‑negative cases exhibited WWOX expression restoration following induced remission. These findings suggest that WWOX may contribute to the occurrence and development of leukemia, and that it has potential to be a good biomarker or predictor for leukemia therapy.

View Figures

View References

1	Bednarek AK, Laflin KJ, Daniel RL, Liao Q, Hawkins KA and Aldaz CM: 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. 2000.PubMed/NCBI
2	Iliopoulos D, Guler G, Han SY, Johnston D, Druck T, McCorkell KA, Palazzo J, McCue PA, Baffa R and Huebner K: Fragile genes as biomarkers: Epigenetic control of WWOX and FHIT in lung, breast and bladder cancer. Oncogene. 24:1625–1633. 2005. View Article : Google Scholar : PubMed/NCBI
3	Lan C, Chenggang W, Yulan B, Xiaohui D, Junhui Z and Xiao W: Aberrant expression of WWOX protein in epithelial ovarian cancer: A clinicopathologic and immunohistochemical study. Int J Gynecol Pathol. 31:125–132. 2012. View Article : Google Scholar : PubMed/NCBI
4	Ekizoglu S, Muslumanoglu M, Dalay N and Buyru N: Genetic alterations of the WWOX gene in breast cancer. Med Oncol. 29:1529–1535. 2012. View Article : Google Scholar : PubMed/NCBI
5	Guo W, Wang G, Dong Y, Guo Y, Kuang G and Dong Z: Decreased expression of WWOX in the development of esophageal squamous cell carcinoma. Mol Carcinog. 52:265–274. 2013. View Article : Google Scholar : PubMed/NCBI
6	Hu BS, Tan JW, Zhu GH, Wang DF, Zhou X and Sun ZQ: WWOX induces apoptosis and inhibits proliferation of human hepatoma cell line SMMC-7721. World J Gastroenterol. 18:3020–3026. 2012. View Article : Google Scholar : PubMed/NCBI
7	Nakayama S, Semba S, Maeda N, Matsushita M, Kuroda Y and Yokozaki H: Hypermethylation-mediated reduction of WWOX expression in intraductal papillary mucinous neoplasms of the pancreas. Br J Cancer. 100:1438–1443. 2009. View Article : Google Scholar : PubMed/NCBI
8	Huang C, Tian Y, Peng R, et al: Down-regulation of WWOX is associated with poor prognosis in patients with intrahepatic cholangiocarcinoma after Curative Resection. J Gastroenterol Hepatol. 30:421–433. 2015. View Article : Google Scholar : PubMed/NCBI
9	Göthlin Eremo A, Wegman P, Stål O, Nordenskjöld B, Fornander T and Wingren S: Wwox expression may predict benefit from adjuvant tamoxifen in randomized breast cancer patients. Oncol Rep. 29:1467–1474. 2013.PubMed/NCBI
10	Cancemi L, Romei C, Bertocchi S, Tarrini G, Spitaleri I, Cipollini M, Landi D, Garritano S, Pellegrini G, Cristaudo A, et al: Evidences that the polymorphism Pro-282-Ala within the tumor suppressor gene WWOX is a new risk factor for differentiated thyroid carcinoma. Int J Cancer. 129:2816–2824. 2011. View Article : Google Scholar : PubMed/NCBI
11	Ishii H, Vecchione A, Furukawa Y, Sutheesophon K, Han SY, Druck T, Kuroki T, Trapasso F, Nishimura M, Saito Y, et al: Expression of FRA16D/WWOX and FRA3B/FHIT genes in hematopoietic malignancies. Mol Cancer Res. 1:940–947. 2003.PubMed/NCBI
12	Ishii H and Furukawa Y: Alterations of common chromosome fragile sites in hematopoietic malignancies. Int J Hematol. 79:238–242. 2004. View Article : Google Scholar : PubMed/NCBI
13	Chen X, Zhang H, Li P, Yang Z, Qin L and Mo W: Gene expression of WWOX, FHIT and p73 in acute lymphoblastic leukemia. Oncol Lett. 6:963–969. 2013.PubMed/NCBI
14	Cui Z, Lin D, Cheng F, Luo L, Kong L, Xu J, Hu J and Lan F: The role of the WWOX gene in leukemia and its mechanisms of action. Oncol Rep. 29:2154–2162. 2013.PubMed/NCBI
15	Lin D, Cui Z, Kong L, Cheng F, Xu J and Lan F: p73 participates in WWOX-mediated apoptosis in leukemia cells. Int J Mol Med. 31:849–854. 2013.PubMed/NCBI
16	Zhang H, Kong L, Cui Z, Du W, He Y, Yang Z, Wang L and Chen X: The WWOX gene inhibits the growth of U266 multiple myeloma cells by triggering the intrinsic apoptotic pathway. Int J Mol Med. 34:804–809. 2014.PubMed/NCBI
17	Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR and Sultan C: Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 33:451–458. 1976. View Article : Google Scholar : PubMed/NCBI
18	Chen J, Odenike O and Rowley JD: Leukaemogenesis: More than mutant genes. Nat Rev Cancer. 10:23–36. 2010. View Article : Google Scholar : PubMed/NCBI
19	Aqeilan RI and Croce CM: WWOX in biological control and tumorigenesis. J Cell Physiol. 212:307–310. 2007. View Article : Google Scholar : PubMed/NCBI
20	Gardenswartz A and Aqeilan RI: WW domain-containing oxidoreductase's role in myriad cancers: Clinical significance and future implications. Exp Biol Med (Maywood). 239:253–263. 2014. View Article : Google Scholar : PubMed/NCBI
21	Guo W, Dong Z, Dong Y, Guo Y, Kuang G and Yang Z: Genetic and epigenetic alterations of WWOX in the development of gastric cardia adenocarcinoma. Environ Mol Mutagen. 54:112–123. 2013. View Article : Google Scholar : PubMed/NCBI
22	Guler G, Uner A, Guler N, Han SY, Iliopoulos D, McCue P and Huebner K: Concordant loss of fragile gene expression early in breast cancer development. Pathol Int. 55:471–478. 2005. View Article : Google Scholar : PubMed/NCBI
23	Diniz MG, Borges ER, Pimenta FJ, De Mesquita Netto AC, De Marco L, Gomez RS and Gomes CC: Evidence of molecular alterations in the tumour suppressor gene WWOX in benign and malignant bone related lesions of the jaws. Oncol Rep. 25:499–502. 2011.PubMed/NCBI
24	Maeda N, Semba S, Nakayama S, Yanagihara K and Yokozaki H: Loss of WW domain-containing oxidoreductase expression in the progression and development of gastric carcinoma: Clinical and histopathologic correlations. Virchows Arch. 457:423–432. 2010. View Article : Google Scholar : PubMed/NCBI
25	Chen X, Li P, Yang Z and Mo WN: Expression of fragile histidine triad (FHIT) and WW-domain oxidoreductase gene (WWOX) in nasopharyngeal carcinoma. Asian Pac J Cancer Prev. 14:165–171. 2013. View Article : Google Scholar : PubMed/NCBI
26	Donati V, Fontanini G, Dell'Omodarme M, Prati MC, Nuti S, Lucchi M, Mussi A, Fabbri M, Basolo F, Croce CM and Aqeilan RI: WWOX expression in different histologic types and subtypes of non-small cell lung cancer. Clin Cancer Res. 13:884–891. 2007. View Article : Google Scholar : PubMed/NCBI
27	Nunez MI, Rosen DG, Ludes-Meyers JH, Abba MC, Kil H, Page R, Klein-Szanto AJ, Godwin AK, Liu J, Mills GB and Aldaz CM: WWOX protein expression varies among ovarian carcinoma histotypes and correlates with less favorable outcome. BMC Cancer. 5:642005. View Article : Google Scholar : PubMed/NCBI
28	Yan H, Yu N and Tong J: Effects of 5-Aza-2′-deoxycytidine on the methylation state and function of the WWOX gene in the HO-8910 ovarian cancer cell line. Oncol Lett. 6:845–849. 2013.PubMed/NCBI
29	Göthlin Eremo A, Wegman P, Stål O, Nordenskjöld B, Fornander T and Wingren S: Wwox expression may predict benefit from adjuvant tamoxifen in randomized breast cancer patients. Oncol Rep. 29:1467–1474. 2013.PubMed/NCBI
30	Guler G, Iliopoulos D, Guler N, Himmetoglu C, Hayran M and Huebner K: Wwox and Ap2gamma expression levels predict tamoxifen response. Clin Cancer Res. 13:6115–6121.. 2007. View Article : Google Scholar : PubMed/NCBI