PRDX1 and PRDX6 are repressed in papillary thyroid carcinomas via BRAF V600E-dependent and -independent mechanisms

Nicolussi,Arianna; D'Inzeo,Sonia; Mincione,Gabriella; Buffone,Amelia; Di Marcantonio,Maria  Carmela; Cotellese,Roberto; Cichella,Annadomenica; Capalbo,Carlo; Di Gioia,Cira; Nardi,Francesco; Giannini,Giuseppe; Coppa,Anna

doi:10.3892/ijo.2013.2208

PRDX1 and PRDX6 are repressed in papillary thyroid carcinomas via BRAF V600E-dependent and -independent mechanisms

Authors:
- Arianna Nicolussi
- Sonia D'Inzeo
- Gabriella Mincione
- Amelia Buffone
- Maria Carmela Di Marcantonio
- Roberto Cotellese
- Annadomenica Cichella
- Carlo Capalbo
- Cira Di Gioia
- Francesco Nardi
- Giuseppe Giannini
- Anna Coppa
View Affiliations

Affiliations: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy, Department of Experimental and Clinical Sciences, ‘G. d'Annunzio’ University Foundation, Chieti-Pescara, Italy , Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy, Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy
Published online on: December 5, 2013 https://doi.org/10.3892/ijo.2013.2208
Pages: 548-556

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

Many clinical studies highlight the dichotomous role of PRDXs in human cancers, where they can exhibit strong tumor-suppressive or tumor-promoting functions. Recent evidence suggests that lower expression of PRDXs correlates with cancer progression in colorectal cancer (CRC) or in esophageal squamous carcinoma. In the thyroid, increased levels of PRDX1 has been described in follicular adenomas and carcinomas, as well as in thyroiditis, while reduced levels of PRDX6 has been found in follicular adenomas. We studied the expression of PRDX1 and PRDX6, in a series of thyroid tissue samples, covering different thyroid diseases, including 13 papillary thyroid carcinomas (PTCs). Our results show that PRDX1 and PRDX6 are significantly reduced in all PTCs compared to normal tissues, to non-neoplastic tissue (MNG) or follicular neoplasms. This reduction is strongly evident in PTCs harboring BRAF V600E (31% of our cases). Using TPC-1 and BCPAP and FRTL-5 cell lines, we demonstrate for the first time that the presence of BRAF V600E is responsible of the hypoexpression of PRDX1 and PRDX6 both at mRNA and protein levels. Finally, independently of BRAF status, we observe an interesting correlation between the tumor size, the presence of lymph node metastasis and the lowest PRDX1 and PRDX6 levels. Therefore, these data indicate that PRDX1 and PRDX6 expression not only may play a key role in papillary thyroid carcinogenesis via a BRAF V600E-dependent mechanism, but their determination could be considered as potential tumor marker for indicating tumor progression in PTCs, independently of BRAF status.

View Figures

View References

1.	Senthil N and Manoharan S: Lipid peroxidation and antioxidants status in patients with papillary thyroid carcinoma in India. Asia Pac J Clin Nutr. 13:391–395. 2004.PubMed/NCBI
2.	Akinci M, Kosova F, Cetin B, Sepici A, Altan N, Aslan S and Cetin A: Oxidant/antioxidant balance in patients with thyroid cancer. Acta Cir Bras. 23:551–554. 2008. View Article : Google Scholar : PubMed/NCBI
3.	Lassoued S, Mseddi M, Mnif F, Abid M, Guermazi F, Masmoudi H, El Feki A and Attia H: A comparative study of the oxidative profile in Graves’ disease, Hashimoto’s thyroiditis, and papillary thyroid cancer. Biol Trace Elem Res. 138:107–115. 2010.PubMed/NCBI
4.	De Deken X, Wang D, Dumont JE and Miot F: Characterization of ThOX proteins as components of the thyroid H(2)O(2)-generating system. Exp Cell Res. 273:187–196. 2002.PubMed/NCBI
5.	Schweizer U, Chiu J and Köhrle J: Peroxides and peroxide-degrading enzymes in the thyroid. Antioxid Redox Signal. 10:1577–1592. 2008. View Article : Google Scholar : PubMed/NCBI
6.	Edgar RS, Green EW, Zhao Y, van Ooijen G, Olmedo M, Qin X, Xu Y, Pan M, Valekunja UK, Feeney KA, Maywood ES, Hastings MH, Baliga NS, Merrow M, Millar AJ, Johnson CH, Kyriacou CP, O’Neill JS and Reddy AB: Peroxiredoxins are conserved markers of circadian rhythms. Nature. 485:459–464. 2012.PubMed/NCBI
7.	Turner-Ivey B, Manevich Y, Schulte J, Kistner-Griffin E, Jezierska-Drutel A, Liu Y and Neumann CA: Role for Prdx1 as a specific sensor in redox-regulated senescence in breast cancer. Oncogene. View Article : Google Scholar : 2013, [Epub ahead of print].
8.	Manevich Y and Fisher AB: Peroxiredoxin 6, a 1-Cys peroxiredoxin, functions in antioxidant defense and lung phospholipid metabolism. Free Radic Biol Med. 38:1422–1432. 2005. View Article : Google Scholar : PubMed/NCBI
9.	Hofmann B, Hecht HJ and Flohé L: Peroxiredoxins. Biol Chem. 383:347–364. 2002. View Article : Google Scholar : PubMed/NCBI
10.	Wood ZA, Schröder E, Robin Harris J and Poole LB: Structure, mechanism and regulation of peroxiredoxins. Trends Biochem Sci. 28:32–40. 2003. View Article : Google Scholar : PubMed/NCBI
11.	Neumann CA, Krause DS, Carman CV, Das S, Dubey DP, Abraham JL, Bronson RT, Fujiwara Y, Orkin SH and van Etten RA: Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression. Nature. 424:561–565. 2003. View Article : Google Scholar : PubMed/NCBI
12.	Egler RA, Fernandes E, Rothermund K, Sereika S, De Souza-Pinto N, Jaruga P, Dizdaroglu M and Prochownik EV: Regulation of reactive oxygen species, DNA damage, and c-Myc function by peroxiredoxin 1. Oncogene. 24:8038–8050. 2005. View Article : Google Scholar : PubMed/NCBI
13.	Neumann CA and Fang Q: Are peroxiredoxins tumor suppressors? Curr Opin Pharmacol. 7:375–380. 2007. View Article : Google Scholar : PubMed/NCBI
14.	Lehtonen ST, Svensk AM, Soini Y, Pääkkö P, Hirvikoski P, Kang SW, Säily M and Kinnula VL: Peroxiredoxins, a novel protein family in lung cancer. Int J Cancer. 111:514–521. 2004. View Article : Google Scholar : PubMed/NCBI
15.	Park JH, Kim YS, Lee HL, Shim JY, Lee KS, Oh YJ, Shin SS, Choi YH, Park KJ, Park RW and Hwang SC: Expression of peroxiredoxin and thioredoxin in human lung cancer and paired normal lung. Respirology. 11:269–275. 2006. View Article : Google Scholar : PubMed/NCBI
16.	Kim JH, Bogner PN, Baek SH, Ramnath N, Liang P, Kim HR, Andrews C and Park YM: Up-regulation of peroxiredoxin 1 in lung cancer and its implication as a prognostic and therapeutic target. Clin Cancer Res. 14:2326–2333. 2008. View Article : Google Scholar : PubMed/NCBI
17.	Goncalves K, Sullivan K and Phelan S: Differential expression and function of peroxiredoxin 1 and peroxiredoxin 6 in cancerous MCF-7 and noncancerous MCF-10A breast epithelial cells. Cancer Invest. 30:38–47. 2012. View Article : Google Scholar : PubMed/NCBI
18.	Hoshino I, Matsubara H, Akutsu Y, Nishimori T, Yoneyama Y, Murakami K, Sakata H, Matsushita K and Ochiai T: Tumor suppressor Prdx1 is a prognostic factor in esophageal squamous cell carcinoma patients. Oncol Rep. 18:867–871. 2007.PubMed/NCBI
19.	Kinnula VL, Lehtonen S, Sormunen R, Kaarteenaho-Wiik R, Kang SW, Rhee SG and Soini Y: Overexpression of peroxiredoxins I, II, III, V, and VI in malignant mesothelioma. J Pathol. 196:316–323. 2002. View Article : Google Scholar : PubMed/NCBI
20.	Fujita Y, Nakanishi T, Hiramatsu M, Mabuchi H, Miyamoto Y, Miyamoto A, Shimizu A and Tanigawa N: Proteomics-based approach identifying autoantibody against peroxiredoxin VI as a novel serum marker in esophageal squamous cell carcinoma. Clin Cancer Res. 12:6415–6420. 2006. View Article : Google Scholar
21.	Park CK, Kim JH, Moon MJ, Jung JH, Lim SY, Park SH, Kim DG, Jung HW, Cho BK and Paek SH: Investigation of molecular factors associated with malignant transformation of oligodendroglioma by proteomic study of a single case of rapid tumor progression. J Cancer Res Clin Oncol. 134:255–262. 2008. View Article : Google Scholar : PubMed/NCBI
22.	Karihtala P, Mantyniemi A, Kang SW, Kinnula VL and Soini Y: Peroxiredoxins in breast carcinoma. Clin Cancer Res. 9:3418–3424. 2003.PubMed/NCBI
23.	Rolfs F, Huber M, Gruber F, Böhm F, Pfister HJ, Bochkov VN, Tschachler E, Dummer R, Hohl D, Schäfer M and Werner S: Dual role of the antioxidant enzyme peroxiredoxin 6 in skin carcinogenesis. Cancer Res. 73:3460–3469. 2013. View Article : Google Scholar : PubMed/NCBI
24.	Yanagawa T, Ishikawa T, Ishii T, Tabuchi K, Iwasa S, Bannai S, Omura K, Suzuki H and Yoshida H: Peroxiredoxin I expression in human thyroid tumors. Cancer Lett. 145:127–132. 1999. View Article : Google Scholar : PubMed/NCBI
25.	Sofiadis A, Becker S, Hellman U, Hultin-Rosenberg L, Dinets A, Hulchiy M, Zedenius J, Wallin G, Foukakis T, Höög A, Auer G, Lehtiö J and Larsson C: Proteomic profiling of follicular and papillary thyroid tumors. Eur J Endocrinol. 166:657–667. 2012. View Article : Google Scholar : PubMed/NCBI
26.	Leenhardt L, Grosclaude P and Chérié-Challine L: Thyroid Cancer Committee. Increased incidence of thyroid carcinoma in France: a true epidemic or thyroid nodule management effects? Report from the French Thyroid Cancer Committee Thyroid. 14:1056–1060. 2004.PubMed/NCBI
27.	Davies L and Welch HG: Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA. 295:2164–2167. 2006.
28.	Mazzaferri EL: Management of low-risk differentiated thyroid cancer. Endocr Pract. 13:498–512. 2007. View Article : Google Scholar : PubMed/NCBI
29.	Roti E, Degli Uberti EC, Bondanelli M and Braverman LE: Thyroid papillary microcarcinoma: a descriptive and meta-analysis study. Eur J Endocrinol. 159:659–673. 2008. View Article : Google Scholar : PubMed/NCBI
30.	Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, Zhu Z, Giannini R, Salvatore G, Fusco A, Santoro M, Fagin JA and Nikiforov YE: BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab. 88:5399–5404. 2003. View Article : Google Scholar : PubMed/NCBI
31.	Xing M: Prognostic utility of BRAF mutation in papillary thyroid cancer. Mol Cell Endocrinol. 321:86–93. 2010. View Article : Google Scholar : PubMed/NCBI
32.	Xing M: Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 13:184–199. 2013. View Article : Google Scholar : PubMed/NCBI
33.	Lazzereschi D, Ranieri A, Mincione G, Taccogna S, Nardi F and Colletta G: Human malignant thyroid tumors displayed reduced levels of transforming growth factor beta receptor type II messenger RNA and protein. Cancer Res. 57:2071–2076. 1997.
34.	Ambesi-Impiombato FS, Parks LA and Coon HG: Culture of hormone-dependent functional epithelial cells from rat thyroids. Proc Natl Acad Sci USA. 77:3455–3459. 1980. View Article : Google Scholar : PubMed/NCBI
35.	D’Inzeo S, Nicolussi A, Donini CF, Zani M, Mancini P, Nardi F and Coppa A: A novel human Smad4 mutation is involved in papillary thyroid carcinoma progression. Endocr Relat Cancer. 19:39–55. 2012.PubMed/NCBI
36.	Schweppe RE, Klopper JP, Korch C, Pugazhenthi U, Benezra M, Knauf JA, Fagin JA, Marlow LA, Copland JA, Smallridge RC and Haugen BR: Deoxyribonucleic acid profiling analysis of 40 human thyroid cancer cell lines reveals cross-contamination resulting in cell line redundancy and misidentification. J Clin Endocrinol Metab. 93:4331–4341. 2008. View Article : Google Scholar
37.	D’Inzeo S, Nicolussi A, Ricci A, Mancini P, Porcellini A, Nardi F and Coppa A: Role of reduced expression of SMAD4 in papillary thyroid carcinoma. J Mol Endocrinol. 45:229–244. 2010.PubMed/NCBI
38.	Nicolussi A, D’Inzeo S, Gismondi A and Coppa A: Reduction of invasive potential in K-ras-transformed thyroid cells by restoring of TGF-beta pathway. Clin Exp Metastasis. 23:237–248. 2006. View Article : Google Scholar : PubMed/NCBI
39.	Meireles AM, Preto A, Rocha AS, Rebocho AP, Máximo V, Pereira-Castro I, Moreira S, Feijão T, Botelho T, Marques R, Trovisco V, Cirnes L, Alves C, Velho S, Soares P and Sobrinho-Simões M: Molecular and genotypic characterization of human thyroid follicular cell carcinoma-derived cell lines. Thyroid. 17:707–715. 2007. View Article : Google Scholar : PubMed/NCBI
40.	Poncin S, Colin IM and Gérard AC: Minimal oxidative load: a prerequisite for thyroid cell function. J Endocrinol. 201:161–167. 2009. View Article : Google Scholar : PubMed/NCBI
41.	Maier J, van Steeg H, van Oostrom C, Paschke R, Weiss RE and Krohn K: Iodine deficiency activates antioxidant genes and causes DNA damage in the thyroid gland of rats and mice. Biochim Biophys Acta. 1773:990–999. 2007. View Article : Google Scholar : PubMed/NCBI
42.	Gérard AC, Many MC, Daumerie Ch, Knoops B and Colin IM: Peroxiredoxin 5 expression in the human thyroid gland. Thyroid. 15:205–209. 2005.PubMed/NCBI
43.	Xing M: Oxidative stress: a new risk factor for thyroid cancer. Endocr Relat Cancer. 19:C7–C11. 2012. View Article : Google Scholar : PubMed/NCBI
44.	Wang D, Feng JF, Zeng P, Yang YH, Luo J and Yang YW: Total oxidant/antioxidant status in sera of patients with thyroid cancers. Endocr Relat Cancer. 18:773–782. 2011. View Article : Google Scholar : PubMed/NCBI
45.	Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, Beller U, Westra WH, Ladenson PW and Sidransky D: BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst. 95:625–627. 2003. View Article : Google Scholar : PubMed/NCBI
46.	Fukushima T, Suzuki S, Mashiko M, Ohtake T, Endo Y, Takebayashi Y, Sekikawa K, Hagiwara K and Takenoshita S: BRAF mutations in papillary carcinomas of the thyroid. Oncogene. 22:6455–6457. 2003. View Article : Google Scholar : PubMed/NCBI
47.	Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE and Fagin JA: High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RASBRAF signaling pathway in papillary thyroid carcinoma. Cancer Res. 63:1454–1457. 2003.PubMed/NCBI
48.	Xu X, Quiros RM, Gattuso P, Ain KB and Prinz RA: High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Res. 63:4561–4567. 2003.PubMed/NCBI
49.	Frasca F, Nucera C, Pellegriti G, Gangemi P, Attard M, Stella M, Loda M, Vella V, Giordano C, Trimarchi F, Mazzon E, Belfiore A and Vigneri R: BRAF (V600E) mutation and the biology of papillary thyroid cancer. Endocr Relat Cancer. 15:191–205. 2008. View Article : Google Scholar : PubMed/NCBI
50.	Watanabe R, Hayashi Y, Sassa M, Kikumori T, Imai T, Kiuchi T and Murata Y: Possible involvement of BRAFV600E in altered gene expression in papillary thyroid cancer. Endocr J. 56:407–414. 2009. View Article : Google Scholar : PubMed/NCBI
51.	Hu S, Liu D, Tufano RP, Carson KA, Rosenbaum E, Cohen Y, Holt EH, Kiseljak-Vassiliades K, Rhoden KJ, Tolaney S, Condouris S, Tallini G, Westra WH, Umbricht CB, Zeiger MA, Califano JA, Vasko V and Xing M: Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int J Cancer. 119:2322–2329. 2006. View Article : Google Scholar : PubMed/NCBI
52.	Guan H, Ji M, Hou P, Liu Z, Wang C, Shan Z, Teng W and Xing M: Hypermethylation of the DNA mismatch repair gene hMLH1 and its association with lymph node metastasis and T1799A BRAF mutation in patients with papillary thyroid cancer. Cancer. 113:247–255. 2008. View Article : Google Scholar : PubMed/NCBI
53.	Riesco-Eizaguirre G, Rodríguez I, De la Vieja A, Costamagna E, Carrasco N, Nistal M and Santisteban P: The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. Cancer Res. 69:8317–8325. 2009. View Article : Google Scholar
54.	Knauf JA, Sartor MA, Medvedovic M, Lundsmith E, Ryder M, Salzano M, Nikiforov YE, Giordano TJ, Ghossein RA and Fagin JA: Progression of BRAF-induced thyroid cancer is associated with epithelial-mesenchymal transition requiring concomitant MAP kinase and TGFβ signaling. Oncogene. 30:3153–3162. 2011.PubMed/NCBI
55.	Ji D, Li M, Zhan T, Yao Y, Shen J, Tian H, Zhang Z and Gu J: Prognostic role of serum AZGP1, PEDF and PRDX2 in colorectal cancer patients. Carcinogenesis. 34:1265–1272. 2013. View Article : Google Scholar
56.	Park YH, Kim SU, Lee BK, Kim HS, Song IS, Shin HJ, Han YH, Chang KT, Kim JM, Lee DS, Kim YH, Choi CM, Kim BY and Yu DY: Prx I suppresses K-ras-driven lung tumorigenesis by opposing redox-sensitive ERK/cyclin D1 pathway. Antioxid Redox Signal. 19:482–496. 2013. View Article : Google Scholar : PubMed/NCBI