Open Access

Iodine promotes thyroid cancer development via SPANXA1 through the PI3K/AKT signalling pathway

  • Authors:
    • Xiaoyao Yang
    • Jingxue Sun
    • Jun Han
    • Lulu Sun
    • Hongzhi Wang
    • Dexin Zhang
    • Qingxiao Fang
    • Jiapeng Liu
    • Hong Qiao
  • View Affiliations

  • Published online on: May 21, 2019     https://doi.org/10.3892/ol.2019.10391
  • Pages: 637-644
  • Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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


Abstract

The aim of this study was to examine the impact of iodine on the development of thyroid cancer cells and to detect the underlying mechanisms. It was observed that proliferation was promoted and apoptosis was inhibited in cells treated with iodine at a specific concentration. This treatment group was then selected for further analysis, to investigate how iodine affects the development of thyroid cancer cells. It was reported that sperm protein associated with the nucleus, X‑linked, family member A1 (SPANXA1) expression in iodine‑treated cells was significantly upregulated. Furthermore, downregulation of SPANXA1 inhibited cell proliferation, migration and invasion, and promoted cell apoptosis. These results suggested that SPANXA1 played an important role in iodine‑treated thyroid cancer cells. Novel associations between SPANXA1 and thyroid cancer were described in the current study. In addition, SPANXA1 gene silencing resulted in the downregulation of PI3K and phosphorylated (p)AKT expression in iodine‑treated thyroid cancer cells, whereas iodine treatment alone resulted in upregulated PI3K and p‑AKT expression. Inhibiting PI3K further suppressed cell proliferation and contributed to apoptosis, even in the presence of SPANXA1 at high levels. As a consequence, PI3K/AKT may be one of the key signalling pathways by which iodine promotes thyroid cancer development in association with SPANXA1. In addition, our results further suggested that patients with thyroid cancer may need to avoid high‑iodine intake.

References

1 

Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI

2 

Nikiforov YE, Steward DL, Robinson-Smith TM, Haugen BR, Klopper JP, Zhu Z, Fagin JA, Falciglia M, Weber K and Nikiforova MN: Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J Clin Endocrinol Metab. 94:2092–2098. 2009. View Article : Google Scholar : PubMed/NCBI

3 

Ahn HS, Kim HJ and Welch HG: Korea's thyroid-cancer ‘epidemic’-screening and overdiagnosis. N Engl J Med. 371:1765–1767. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Oh CM, Won YJ, Jung KW, Kong HJ, Cho H, Lee JK, Lee DH and Lee KH; Community of Population-Based Regional Cancer Registries, : Cancer statistics in Korea: Incidence, mortality, survival, and prevalence in 2013. Cancer Res Treat. 48:436–450. 2016. View Article : Google Scholar : PubMed/NCBI

5 

Davies L and Welch HG: Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg. 140:317–322. 2014. View Article : Google Scholar : PubMed/NCBI

6 

Solis OE, Mehta RI, Lai A, Mehta RI, Farchoukh LO, Green RM, Cheng JC, Natarajan S, Vinters HV, Cloughesy T and Yong WH: Rosette-forming glioneuronal tumor: A pineal region case with IDH1 and IDH2 mutation analyses and literature review of 43 cases. J Neurooncol. 102:477–484. 2011. View Article : Google Scholar : PubMed/NCBI

7 

Zarkesh M, Zadeh-Vakili A, Akbarzadeh M, Fanaei SA, Hedayati M and Azizi F: The role of matrix metalloproteinase-9 as a prognostic biomarker in papillary thyroid cancer. BMC Cancer. 18:11992018. View Article : Google Scholar : PubMed/NCBI

8 

Choi C, Thi Thao Tran N, Van Ngu T, Park SW, Song MS, Kim SH, Bae YU, Ayudthaya PDN, Munir J, Kim E, et al: Promotion of tumor progression and cancer stemness by MUC15 in thyroid cancer via the GPCR/ERK and integrin-FAK signaling pathways. Oncogenesis. 7:852018. View Article : Google Scholar : PubMed/NCBI

9 

Kim M, Jeon MJ, Oh HS, Park S, Song DE, Sung TY, Kim TY, Chung KW, Kim WB, Shong YK, et al: Prognostic implication of N1b classification in the eighth edition of the tumor-node-metastasis staging system of differentiated thyroid cancer. Thyroid. 28:496–503. 2018. View Article : Google Scholar : PubMed/NCBI

10 

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

11 

Kim S, Chung JK, Min HS, Kang JH, Park DJ, Jeong JM, Lee DS, Park SH, Cho BY, Lee S and Lee MC: Expression patterns of glucose transporter-1 gene and thyroid specific genes in human papillary thyroid carcinoma. Nucl Med Mol Imaging. 48:91–97. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Kitahara CM: New evidence on the association between prediagnostic thyroid-stimulating hormone levels and thyroid cancer risk. Cancer Epidemiol Biomarkers Prev. 26:1163–1164. 2017. View Article : Google Scholar : PubMed/NCBI

13 

Williams D: Radiation carcinogenesis: Lessons from Chernobyl. Oncogene. 27 (Suppl 2):S9–S18. 2008. View Article : Google Scholar : PubMed/NCBI

14 

Pellegriti G, Frasca F, Regalbuto C, Squatrito S and Vigneri R: Worldwide increasing incidence of thyroid cancer: Update on epidemiology and risk factors. J Cancer Epidemiol. 2013:9652122013. View Article : Google Scholar : PubMed/NCBI

15 

Teng W, Shan Z, Teng X, Guan H, Li Y, Teng D, Jin Y, Yu X, Fan C, Chong W, et al: Effect of iodine intake on thyroid diseases in China. N Engl J Med. 354:2783–2793. 2006. View Article : Google Scholar : PubMed/NCBI

16 

Kim JS: Reply to: Papillary thyroid microcarcinoma in developing country scenario with endemic iodine deficiency. Surgery. 162:1912017. View Article : Google Scholar : PubMed/NCBI

17 

Zamrazil V, Cerovska J, Bílek R, Simecková A, Vrbíková J, Dvoráková M, Hníková O, Janecková M and Tomiska F: The effect of insufficient iodine intake on the size and function of the thyroid gland. Bratisl Lek Listy. 96:609–612. 1995.(In Czech). PubMed/NCBI

18 

Fiore E, Latrofa F and Vitti P: Iodine, thyroid autoimmunity and cancer. Eur Thyroid J. 4:26–35. 2015. View Article : Google Scholar : PubMed/NCBI

19 

Liu XH, Chen GG, Vlantis AC and van Hasselt CA: Iodine mediated mechanisms and thyroid carcinoma. Crit Rev Clin Lab Sci. 46:302–318. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Dijkstra B, Prichard RS, Lee A, Kelly LM, Smyth PP, Crotty T, McDermott EW, Hill AD and O'Higgins N: Changing patterns of thyroid carcinoma. Ir J Med Sci. 176:87–90. 2007. View Article : Google Scholar : PubMed/NCBI

21 

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

22 

Gerard AC, Humblet K, Wilvers C, Poncin S, Derradji H, de Ville de Goyet C, Abou-el-Ardat K, Baatout S, Sonveaux P, Denef JF and Colin IM: Iodine-deficiency-induced long lasting angiogenic reaction in thyroid cancers occurs via a vascular endothelial growth factor-hypoxia inducible factor-1-dependent, but not a reactive oxygen species-dependent, pathway. Thyroid. 22:699–708. 2012. View Article : Google Scholar : PubMed/NCBI

23 

Aschebrook-Kilfoy B, Grogan RH, Ward MH, Kaplan E and Devesa SS: Follicular thyroid cancer incidence patterns in the United States, 1980–2009. Thyroid. 23:1015–1021. 2013. View Article : Google Scholar : PubMed/NCBI

24 

Sun R, Wang J, Li X, Li L, Yang J, Ren Y, Xi Y and Sun C: Effect of iodine intake on p14ARF and p16INK4a expression in thyroid papillary carcinoma in rats. Med Sci Monit. 21:2288–2293. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Guan H, Ji M, Bao R, Yu H, Wang Y, Hou P, Zhang Y, Shan Z, Teng W and Xing M: Association of high iodine intake with the T1799A BRAF mutation in papillary thyroid cancer. J Clin Endocrinol Metab. 94:1612–1617. 2009. View Article : Google Scholar : PubMed/NCBI

26 

Saiselet M, Floor S, Tarabichi M, Dom G, Hébrant A, van Staveren WC and Maenhaut C: Thyroid cancer cell lines: An overview. Front Endocrinol (Lausanne). 3:1332012. View Article : Google Scholar : PubMed/NCBI

27 

Cao X, Ma W, Liu L, Xu J, Wang H, Li X, Wang J, Zhang J, Wang Z and Gu Y: Analysis of potassium iodate reduction in tissue homogenates using high performance liquid chromatography-inductively coupled plasma-mass spectrometry. J Trace Elem Med Biol. 32:1–6. 2015. View Article : Google Scholar : PubMed/NCBI

28 

Wang F, Wang Y, Wang L, Wang X, Sun C, Xing M and Zhao W: Strong association of high urinary iodine with thyroid nodule and papillary thyroid cancer. Tumour Biol. 35:11375–11379. 2014. View Article : Google Scholar : PubMed/NCBI

29 

Zhang YY, Liu ZB, Ye XG and Ren WM: Iodine regulates G2/M progression induced by CCL21/CCR7 interaction in primary cultures of papillary thyroid cancer cells with RET/PTC expression. Mol Med Rep. 14:3941–3946. 2016. View Article : Google Scholar : PubMed/NCBI

30 

Salemi M, Calogero AE, Vicari E, Migliore E, Zaccarello G, Cosentino A, Amore M, Tricoli D, Castiglione R, Bosco P and Rappazzo G: A high percentage of skin melanoma cells expresses SPANX proteins. Am J Dermatopathol. 31:182–186. 2009. View Article : Google Scholar : PubMed/NCBI

31 

Wang Z, Zhang Y, Liu H, Salati E, Chiriva-Internati M and Lim SH: Gene expression and immunologic consequence of SPAN-Xb in myeloma and other hematologic malignancies. Blood. 101:955–960. 2003. View Article : Google Scholar : PubMed/NCBI

32 

Maine EA, Westcott JM, Prechtl AM, Dang TT, Whitehurst AW and Pearson GW: The cancer-testis antigens SPANX-A/C/D and CTAG2 promote breast cancer invasion. Oncotarget. 7:14708–14726. 2016. View Article : Google Scholar : PubMed/NCBI

33 

Salemi M, Calogero AE, Zaccarello G, Castiglione R, Cosentino A, Campagna C, Vicari E and Rappazzo G: Expression of SPANX proteins in normal prostatic tissue and in prostate cancer. Eur J Histochem. 54:e412010. View Article : Google Scholar : PubMed/NCBI

34 

Zendman AJ, Zschocke J, van Kraats AA, de Wit NJ, Kurpisz M, Weidle UH, Ruiter DJ, Weiss EH and van Muijen GN: The human SPANX multigene family: Genomic organization, alignment and expression in male germ cells and tumor cell lines. Gene. 309:125–133. 2003. View Article : Google Scholar : PubMed/NCBI

35 

Yu K, Ganesan K, Tan LK, Laban M, Wu J, Zhao XD, Li H, Leung CH, Zhu Y, Wei CL, et al: A precisely regulated gene expression cassette potently modulates metastasis and survival in multiple solid cancers. PLoS Genet. 4:e10001292008. View Article : Google Scholar : PubMed/NCBI

36 

Roth RB, Hevezi P, Lee J, Willhite D, Lechner SM, Foster AC and Zlotnik A: Gene expression analyses reveal molecular relationships among 20 regions of the human CNS. Neurogenetics. 7:67–80. 2006. View Article : Google Scholar : PubMed/NCBI

37 

Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C and Gonzalez-Baron M: PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 30:193–204. 2004. View Article : Google Scholar : PubMed/NCBI

38 

Dillon RL, White DE and Muller WJ: The phosphatidyl inositol 3-kinase signaling network: Implications for human breast cancer. Oncogene. 26:1338–1345. 2007. View Article : Google Scholar : PubMed/NCBI

39 

Wen D, Deng L, Zhou M, Guo S, Shang L, Xu G and Dong S: A biofuel cell with a single-walled carbon nanohorn-based bioanode operating at physiological condition. Biosens Bioelectron. 25:1544–1547. 2010. View Article : Google Scholar : PubMed/NCBI

40 

Liu R, Liu D, Trink E, Bojdani E, Ning G and Xing M: The Akt-specific inhibitor MK2206 selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathway. J Clin Endocrinol Metab. 96:E577–E585. 2011. View Article : Google Scholar : PubMed/NCBI

41 

Xing M: Genetic alterations in the phosphatidylinositol-3 kinase/Akt pathway in thyroid cancer. Thyroid. 20:697–706. 2010. View Article : Google Scholar : PubMed/NCBI

42 

Uddin S, Bavi P, Siraj AK, Ahmed M, Al-Rasheed M, Hussain AR, Ahmed M, Amin T, Alzahrani A, Al-Dayel F, et al: Leptin-R and its association with PI3K/AKT signaling pathway in papillary thyroid carcinoma. Endocr Relat Cancer. 17:191–202. 2010. View Article : Google Scholar : PubMed/NCBI

43 

Ma Y, Qin H and Cui Y: MiR-34a targets GAS1 to promote cell proliferation and inhibit apoptosis in papillary thyroid carcinoma via PI3K/Akt/Bad pathway. Biochem Biophys Res Commun. 441:958–963. 2013. View Article : Google Scholar : PubMed/NCBI

44 

Xu J, Cai J, Jin X, Yang J, Shen Q, Ding X and Liang Y: PIG3 plays an oncogenic role in papillary thyroid cancer by activating the PI3K/AKT/PTEN pathway. Oncol Rep. 34:1424–1430. 2015. View Article : Google Scholar : PubMed/NCBI

45 

Serrano-Nascimento C, da Silva Teixeira S, Nicola JP, Nachbar RT, Masini-Repiso AM and Nunes MT: The acute inhibitory effect of iodide excess on sodium/iodide symporter expression and activity involves the PI3K/AKT signalling pathway. Endocrinology. 155:1145–1156. 2014. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

July 2019
Volume 18 Issue 1

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Yang, X., Sun, J., Han, J., Sun, L., Wang, H., Zhang, D. ... Qiao, H. (2019). Iodine promotes thyroid cancer development via SPANXA1 through the PI3K/AKT signalling pathway. Oncology Letters, 18, 637-644. https://doi.org/10.3892/ol.2019.10391
MLA
Yang, X., Sun, J., Han, J., Sun, L., Wang, H., Zhang, D., Fang, Q., Liu, J., Qiao, H."Iodine promotes thyroid cancer development via SPANXA1 through the PI3K/AKT signalling pathway". Oncology Letters 18.1 (2019): 637-644.
Chicago
Yang, X., Sun, J., Han, J., Sun, L., Wang, H., Zhang, D., Fang, Q., Liu, J., Qiao, H."Iodine promotes thyroid cancer development via SPANXA1 through the PI3K/AKT signalling pathway". Oncology Letters 18, no. 1 (2019): 637-644. https://doi.org/10.3892/ol.2019.10391