Downregulation of glutathione peroxidase 3 is associated with lymph node metastasis and prognosis in cervical cancer

Zhang,Xianglan; Zheng,Zhenlong; Yingji,Shen; Kim,Hyeyeon; Jin,Renshun; Renshu,Li; Lee,Doo Young; Roh,Mi Ryung; Yang,Sanghwa

doi:10.3892/or.2014.3152

Downregulation of glutathione peroxidase 3 is associated with lymph node metastasis and prognosis in cervical cancer

Authors:
- Xianglan Zhang
- Zhenlong Zheng
- Shen Yingji
- Hyeyeon Kim
- Renshun Jin
- Li Renshu
- Doo Young Lee
- Mi Ryung Roh
- Sanghwa Yang
View Affiliations

Affiliations: Department of Pathology, Yanbian University Hospital, Yanji, Jilin, P.R. China, Department of Dermatology, Yanbian University Hospital, Yanji, Jilin, P.R. China, Department of Gynecology, Maternal and Child Health Hospital, Dalian, Liaoning, P.R. China, Department of Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea, Department of Anesthesia and Pain, Yanbian University Hospital, Yanji, Jilin, P.R. China, Oral Cancer Research Institute, College of Dentistry, Yonsei University, Seoul, Republic of Korea, Department of Dermatology, Yonsei University College of Medicine, Seoul, Republic of Korea, National Creative Research Initiatives Center for Inflammatory Response Modulation, Yonsei University, Seoul, Republic of Korea
Published online on: April 23, 2014 https://doi.org/10.3892/or.2014.3152
Pages: 2587-2592

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

Glutathione peroxidase 3 (GPX3) is a member of the glutathione peroxidase family of selenoproteins and is one of the key defensive enzymes against oxidative damages to host cells. Downregulation of GPX3 due to its promoter hypermethylation has been documented in several different types of cancer, indicating that GPX3 functions as a possible tumor suppressor. In the present study, we showed that GPX3 is also significantly downregulated in cervical cancer tissues compared to normal cervical tissues by qRT-PCR analyses and immunohistostainings. GPX3 expression was significantly related to lymph node metastasis and prognosis in cervical cancer patients. Treatment of cervical cancer cells with 5-aza-2'-deoxycytidine restored the expression of GPX3 and methylation-specific PCR (MSP) confirmed the CpG methylation of the GPX3 gene. Our results indicate that promoter methylation is one of the major causes of GPX3 downregulation in cervical cancer and GPX3 could serve as a predictive biomarker for lymph node metastasis and prognosis of cervical cancer.

View Figures

View References

1	Lodygin D, Epanchintsev A, Menssen A, Diebold J and Hermeking H: Functional epigenomics identifies genes frequently silenced in prostate cancer. Cancer Res. 65:4218–4227. 2005. View Article : Google Scholar : PubMed/NCBI
2	Brigelius-Flohé R and Kipp A: Glutathione peroxidases in different stages of carcinogenesis. Biochim Biophys Acta. 1790:1555–1568. 2009.PubMed/NCBI
3	Yu YP, Yu G, Tseng G, et al: Glutathione peroxidase 3, deleted or methylated in prostate cancer, suppresses prostate cancer growth and metastasis. Cancer Res. 67:8043–8050. 2007. View Article : Google Scholar : PubMed/NCBI
4	Mikata R, Yokosuka O, Fukai K, et al: Analysis of genes upregulated by the demethylating agent 5-aza-2′-deoxycytidine in gastric cancer cell lines. Int J Cancer. 119:1616–1622. 2006.
5	Lee OJ, Schneider-Stock R, McChesney PA, Kuester D, Roessner A, Vieth M, Moskaluk CA and El-Rifai W: Hypermethylation and loss of expression of glutathione peroxidase-3 in Barrett’s tumorigenesis. Neoplasia. 7:854–861. 2005.PubMed/NCBI
6	Peng DF, Razvi M, Chen H, et al: DNA hypermethylation regulates the expression of members of the Mu-class glutathione S-transferases and glutathione peroxidases in Barrett’s adenocarcinoma. Gut. 58:5–15. 2009.PubMed/NCBI
7	Zhang X1, Yang JJ, Kim YS, Kim KY, Ahn WS and Yang S: An 8-gene signature, including methylated and down-regulated glutathione peroxidase 3, of gastric cancer. Int J Oncol. 36:405–414. 2010.PubMed/NCBI
8	Saga Y, Ohwada M, Suzuki M, et al: Glutathione peroxidase 3 is a candidate mechanism of anticancer drug resistance of ovarian clear cell adenocarcinoma. Oncol Rep. 20:1299–1303. 2008.PubMed/NCBI
9	Yang ZL, Yang L, Zou Q, et al: Positive ALDH1A3 and negative GPX3 expressions are biomarkers for poor prognosis of gallbladder cancer. Dis Markers. 35:163–172. 2013. View Article : Google Scholar : PubMed/NCBI
10	Kaiser MF, Johnson DC, Wu P, et al: Global methylation analysis identifies prognostically important epigenetically inactivated tumour suppressor genes in multiple myeloma. Blood. 122:219–226. 2013. View Article : Google Scholar
11	El Haddad M, Jean E, Turki A, et al: Glutathione peroxidase 3, a new retinoid target gene, is crucial for human skeletal muscle precursor cell survival. J Cell Sci. 125:6147–6156. 2012.PubMed/NCBI
12	Barrett CW, Ning W, Chen X, et al: Tumor suppressor function of the plasma glutathione peroxidase gpx3 in colitis-associated carcinoma. Cancer Res. 73:1245–1255. 2013. View Article : Google Scholar : PubMed/NCBI
13	Fitzpatrick JM, Schulman C, Zlotta AR and Schröder FH: Prostate cancer: a serious disease suitable for prevention. BJU Int. 103:864–870. 2009. View Article : Google Scholar : PubMed/NCBI
14	Lu J and Holmgren A: Selenoproteins. J Biol Chem. 284:723–727. 2009. View Article : Google Scholar
15	Yang X, Deignan JL, Qi H, et al: Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks. Nat Genet. 41:415–423. 2009. View Article : Google Scholar : PubMed/NCBI
16	Bachtiary B, Boutros PC, Pintilie M, et al: Gene expression profiling in cervical cancer: an exploration of intratumor heterogeneity. Clin Cancer Res. 12:5632–5640. 2006. View Article : Google Scholar : PubMed/NCBI
17	He Y, Wang Y, Li P, Zhu S, Wang J and Zhang S: Identification of GPX3 epigenetically silenced by CpG methylation in human esophageal squamous cell carcinoma. Dig Dis Sci. 56:681–688. 2011.
18	Scotto L, Narayan G, Nandula SV, et al: Identification of copy number gain and overexpressed genes on chromosome arm 20q by an integrative genomic approach in cervical cancer: potential role in progression. Genes Chromosomes Cancer. 47:755–765. 2008. View Article : Google Scholar : PubMed/NCBI
19	Baylin SB and Ohm JE: Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction? Nat Rev Cancer. 6:107–116. 2006. View Article : Google Scholar : PubMed/NCBI
20	Esteller M: Epigenetics in cancer. N Engl J Med. 358:1148–1159. 2008. View Article : Google Scholar
21	Jones PA and Baylin SB: The fundamental role of epigenetic events in cancer. Nat Rev Genet. 3:415–428. 2002.PubMed/NCBI
22	Christman JK: 5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene. 21:5483–5495. 2002.
23	Brigelius-Flohé R: Glutathione peroxidases and redox-regulated transcription factors. Biol Chem. 387:1329–1335. 2006.PubMed/NCBI
24	Clark LC, Combs GF Jr, Turnbull BW, et al: Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA. 276:1957–1963. 1996. View Article : Google Scholar
25	Dobosy JR, Roberts JL, Fu VX and Jarrard DF: The expanding role of epigenetics in the development, diagnosis and treatment of prostate cancer and benign prostatic hyperplasia. J Urol. 177:822–831. 2007. View Article : Google Scholar : PubMed/NCBI
26	Jee CD, Kim MA, Jung EJ, Kim J and Kim WH: Identification of genes epigenetically silenced by CpG methylation in human gastric carcinoma. Eur J Cancer. 45:1282–1293. 2009. View Article : Google Scholar : PubMed/NCBI
27	Maynard S, Schurman SH, Harboe C, de Souza-Pinto NC and Bohr VA: Base excision repair of oxidative DNA damage and association with cancer and aging. Carcinogenesis. 30:2–10. 2009. View Article : Google Scholar : PubMed/NCBI