Exploring the mechanism of WWOX growth inhibitory effects on oral squamous cell carcinoma

Yang,Wei; Wang,Xiao‑Ming; Yuan,Hong‑Yan; Liu,Zhi‑Hui; Gao,Shuang; Peng,Liang

doi:10.3892/ol.2017.5850

Exploring the mechanism of WWOX growth inhibitory effects on oral squamous cell carcinoma

Authors:
- Wei Yang
- Xiao‑Ming Wang
- Hong‑Yan Yuan
- Zhi‑Hui Liu
- Shuang Gao
- Liang Peng
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Affiliations: School of Laboratory Medicine, Beihua University, Jilin City, Jilin 132013, P.R. China, Department of Pathology, Jilin Province People's Hospital, Changchun, Jilin 132001, P.R. China, Department of Immunology, College of Basic Medical Science, Jilin University, Changchun, Jilin 132001, P.R. China, Department of Stomatology, Taizhou Municipal Hospital, Taizhou, Zhejiang 318000, P.R. China
Published online on: March 13, 2017 https://doi.org/10.3892/ol.2017.5850
Pages: 3198-3204

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Abstract

Oral squamous cell carcinoma (OSCC) is one of the most common types of head and neck neoplasms in the world. Patients diagnosed with OSCC exhibit a poor prognosis. WW domain-containing oxidoreductase (WWOX), as a candidate tumor-suppressor gene, is involved in the genesis and progression of tumors. The deletion of the WWOX gene has been identified in OSCC and oral leukoplakia, but the function and mechanism of WWOX in OSCC remain unknown. Therefore, the present study investigated the role of WWOX in oral squamous carcinoma cells. The results revealed that an elevation of WWOX expression had an inhibitory effect on the growth of three types of oral squamous carcinoma cells, with the most evident effect occurring in Tca8113 cells. Also, in the Tca8113 cells, WWOX overexpression significantly inhibited colony formation, and induced apoptosis and cell cycle arrest. Microarray analysis, reverse transcription-quantitative polymerase chain reaction and western blotting methods detected that WWOX overexpression contributed to the differential expression of the genes involved in mediating the extracellular‑signal regulated protein kinase/mitogen‑activated protein kinase (ERK/MAPK) signaling pathway. These results suggest that the tumor‑suppressor function of the WWOX gene may be associated with the modulation of the ERK/MAPK signaling pathway, thus providing a novel target for OSCC therapy.

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1	Minicucci EM, da Silva GN and Salvadori DM: Relationship between head and neck cancer therapy and some genetic endpoints. World J Clin Oncol. 5:93–102. 2014. View Article : Google Scholar : PubMed/NCBI
2	Ratajczak-Wrona W, Jablonska E, Antonowicz B, Dziemianczyk D and Grabowska SZ: Levels of biological markers of nitric oxide in serum of patients with squamous cell carcinoma of the oral cavity. Int J Oral Sci. 5:141–145. 2013. View Article : Google Scholar : PubMed/NCBI
3	Rivera C and Venegas B: Histological and molecular aspects of oral squamous cell carcinoma (Review). Oncol Lett. 8:7–11. 2014.PubMed/NCBI
4	Warnakulasuriya S: Living with oral cancer: Epidemiology with particular reference to prevalence and life-style changes that influence survival. Oral Oncol. 46:407–410. 2010. View Article : Google Scholar : PubMed/NCBI
5	Giannola LI, De Caro V, Giandalia G, Siragusa MG, Paderni C, Campisi G and Florena AM: 5-Fluorouracil buccal tablets for locoregional chemotherapy of oral squamous cell carcinoma: Formulation, drug release and histological effects on reconstituted human oral epithelium and porcine buccal mucosa. Curr Drug Deliv. 7:109–117. 2010. View Article : Google Scholar : PubMed/NCBI
6	Lewandowska U, Zelazowski M, Seta K, Byczewska M, Pluciennik E and Bednarek AK: WWOX, the tumour suppressor gene affected in multiple cancers. J Physiol Pharmacol. 60:(Supp l). S47–S56. 2009.
7	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
8	Pimenta FJ, Cordeiro GT, Pimenta LG, Viana MB, Lopes J, Gomez MV, Aldaz CM, De-Marco L and Gomez RS: Molecular alterations in the tumor suppressor gene WWOX in oral leukoplakias. Oral Oncol. 44:753–758. 2008. View Article : Google Scholar : PubMed/NCBI
9	Pimenta FJ, Gomes DA, Perdigão PF, Barbosa AA, Romano-Silva MA, Gomez MV, Aldaz CM, De Marco L and Gomez RS: Characterization of the tumor suppressor gene WWOX in primary human oral squamous cell carcinomas. Int J Cance. 118:1154–1158. 2006. View Article : Google Scholar
10	Pimenta FJ, Cordeiro GT, Pimenta LG, Viana MB, Lopes J, Gomez MV, Aldaz CM, De Marco L and Gomez RS: Molecular alterations in the tumor suppressor gene WWOX in oral leukoplakias. Oral Onco. 44:753–758. 2008. View Article : Google Scholar
11	Kabbout M, Garcia MM, Fujimoto J, Liu DD, Woods D, Chow CW, Mendoza G, Momin AA, James BP, Solis L, et al: ETS2 mediated tumor suppressive function and MET oncogene inhibition in human non-small cell lung cancer. Clin Cancer Res. 19:3383–3395. 2013. View Article : Google Scholar : PubMed/NCBI
12	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
13	Aqeilan RI, Abu-Remaileh M and Abu-Odeh M: The common fragile site FRA16D gene product WWOX: Roles in tumor suppression and genomic stability. Cell Mol Life Sci. 71:4589–4599. 2014. View Article : Google Scholar : PubMed/NCBI
14	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
15	Qu J, Lu W, Li B, Lu C and Wan X: WWOX induces apoptosis and inhibits proliferation in cervical cancer and cell lines. Int J Mol Med. 31:1139–1147. 2013.PubMed/NCBI
16	Lin JT, Li HY, Chang NS, Lin CH, Chen YC and Lu PJ: WWOX suppresses prostate cancer cell progression through cyclin D1-mediated cell cycle arrest in the G1 phase. Cell Cycle. 14:408–416. 2015. View Article : Google Scholar : PubMed/NCBI
17	Whelan JT, Hollis SE, Cha DS, Asch AS and Lee MH: Post-transcriptional regulation of the Ras-ERK/MAPK signaling pathway. J Cell Physiol. 227:1235–1241. 2012. View Article : Google Scholar : PubMed/NCBI
18	Wang Z, Reinach PS, Zhang F, Vellonen KS, Urtti A, Turner H and Wolosin JM: DUSP5 and DUSP6 modulate corneal epithelial cell proliferation. Mol Vis. 16:1696–1704. 2010.PubMed/NCBI
19	Okudela K, Yazawa T, Woo T, Sakaeda M, Ishii J, Mitsui H, Shimoyamada H, Sato H, Tajiri M, Ogawa N, et al: Down-regulation of DUSP6 expression in lung cancer: Its mechanism and potential role in carcinogenesis. Am J Pathol. 175:867–881. 2009. View Article : Google Scholar : PubMed/NCBI
20	Li W, Song L, Ritchie AM and Melton DW: Increased levels of DUSP6 phosphatase stimulate tumourigenesis in a molecularly distinct melanoma subtype. Pigment Cell Melanoma Res. 25:188–199. 2012. View Article : Google Scholar : PubMed/NCBI
21	Nunes-Xavier CE, Tárrega C, Cejudo-Marín R, Frijhoff J, Sandin A, Ostman A and Pulido R: Differential up-regulation of MAP kinase phosphatases MKP3/DUSP6 and DUSP5 by Ets2 and c-Jun converge in the control of the growth arrest versus proliferation response of MCF-7 breast cancer cells to phorbol ester. J Biol Chem. 285:26417–26430. 2010. View Article : Google Scholar : PubMed/NCBI
22	Mori Sequeiros Garcia M, Gorostizaga A, Brion L, González-Calvar SI and Paz C: cAMP-activated Nr4a1 expression requires ERK activity and is modulated by MAPK phosphatase-1 in MA-10 Leydig cells. Mol Cell Endocrinol. 408:45–52. 2015. View Article : Google Scholar : PubMed/NCBI
23	Liu PY, Sheu JJ, Lin PC, Lin CT, Liu YJ, Ho LI, Chang LF, Wu WC, Chen SR, Chen J, et al: Expression of Nur77 induced by an n-butylidenephthalide derivative promotes apoptosis and inhibits cell growth in oral squamous cell carcinoma. Invest New Drugs. 30:79–89. 2012. View Article : Google Scholar : PubMed/NCBI
24	Thompson J and Winoto A: During negative selection, Nur77 family proteins translocate to mitochondria where they associate with Bcl-2 and expose its proapoptotic BH3 domain. J Exp Med. 205:1029–1036. 2008. View Article : Google Scholar : PubMed/NCBI
25	Zhang P, Jia R, Ying L, Liu B, Qian G, Fan X and Ge S: WWOX-mediated apoptosis in A549 cells mainly involves the mitochondrial pathway. Mol Med Rep. 6:121–124. 2012.PubMed/NCBI
26	Feng S, Zhou L, Nice EC and Huang C: Fibroblast growth factor receptors: Multifactorial-contributors to tumor initiation and progression. Histol Histopathol. 30:13–31. 2015.PubMed/NCBI
27	Katoh M and Nakagama H: FGF receptors: Cancer biology and therapeutics. Med Res Rev. 34:280–300. 2014. View Article : Google Scholar : PubMed/NCBI
28	Mathur A, Ware C, Davis L, Gazdar A, Pan BS and Lutterbach B: FGFR2 is amplified in the NCI-H716 colorectal cancer cell line and is required for growth and survival. PLoS One. 9:e985152014. View Article : Google Scholar : PubMed/NCBI
29	Matsuda Y, Yoshimura H, Suzuki T, Uchida E, Naito Z and Ishiwata T: Inhibition of fibroblast growth factor receptor 2 attenuates proliferation and invasion of pancreatic cancer. Cancer Sci. 105:1212–1219. 2014. View Article : Google Scholar : PubMed/NCBI