Serum WNT-induced secreted protein 1 level as a potential biomarker for thyroid nodules

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Gulhan Duman
Baris Sariakcali


Background. Thyroid nodule (TN) is a common thyroid disease worldwide, and it has increased significantly last decades. Most TNs are usually incidental findings of asymptomatic, benign lesions discovered by imaging modalities performed for reasons unrelated to thyroid diseases. The purpose of this study was to investigate the value of serum WNT-induced secreted protein 1 (WISP1) level as a supporting biomarker to perform differential diagnosis of benign and non-benign thyroid nodules. Materials and methods. The study was completed with the 89 patients undergone fine needle aspiration biopsy and 43 controls. The patients were composed of 96 (72.7 %) females and 36 (27.3 %) males. And they were divided into 2 group according to the Bethesda cytological evaluation as Benign (Bethesda 2) and Non-Benign (Bethesda 3–6) groups. Their serum WISP1 levels were measured by an ELISA method. Results. There were 58 (43.9 %) patients in Benign (Bethesda 2) and 31 (23.5 %) in non-Benign (Bethesda 3–6) groups. In the contrary nodule size was bigger in the Non-benign group than that benign group (p = 0.006). The serum WISP1 level in the Benign (Bethesda 2) group was significantly higher than that in the and Non-Benign (Bethesda 3–6) group, and controls (p < 0). The difference between benign and non-benign group accordingly to their echogenicitiy was significant (p < 0.05). In benign group there was 76.9 % mixed echoic nodules, 76.7 % isoechoic nodules 68.4 % isohypoechoic nodules and 35.7 % hypoechoic nodules. In the non-benign group, the highest hypoechoic echo (64.3 %), the least mixed echo (23.1 %), while in the benign group, the most mixed echo (76.9 %), the least hypoechoic echo (35.7 %) was present. There was no relation between WISP1 levels and echogenicity with Kruskal-Wallis H test. Conclusions. According to the preliminary results of current study, addition of serum WISP1 measurement to the differential diagnostic work-up of thyroid nodules patients may provide supportive information. In thyroid nodules patients with Benign (Bethesda 2) category of cytological evaluation, a higher level of serum WISP1 may support cytological diagnosis.

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How to Cite
Duman, G., and B. Sariakcali. “Serum WNT-Induced Secreted Protein 1 Level As a Potential Biomarker for Thyroid Nodules”. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (Ukraine), vol. 17, no. 3, June 2021, pp. 226-33, doi:10.22141/2224-0721.17.3.2021.232652.
Original Researches


Al Dawish MA, Robert AA, Muna A, et al. Bethesda System for Reporting Thyroid Cytopathology: A three-year study at a tertiary care referral center in Saudi Arabia. World J Clin Oncol. 2017 Apr 10;8(2):151-157. doi:10.5306/wjco.v8.i2.151.

Janczak D, Pawlowski W, Dorobisz T, et al. An evaluation of the diagnostic efficacy of fine needle aspiration biopsy in patients operated for a thyroid nodular goiter. Onco Targets Ther. 2016 Sep 22;9:5819-5823. doi:10.2147/OTT.S111275.

Dean DS, Gharib H. Epidemiology of thyroid nodules. Best Pract Res Clin Endocrinol Metab. 2008 Dec;22(6):901-911. doi:10.1016/j.beem.2008.09.019.

Bomeli SR, LeBeau SO, Ferris RL. Evaluation of a thyroid nodule. Otolaryngol Clin North Am. 2010 Apr;43(2):229-238, vii. doi:10.1016/j.otc.2010.01.002.

Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016 Jan;26(1):1-133. doi:10.1089/thy.2015.0020.

Yang J, Schnadig V, Logrono R, Wasserman PG. Fine-needle aspiration of thyroid nodules: a study of 4703 patients with histologic and clinical correlations. Cancer. 2007 Oct 25;111(5):306-315. doi:10.1002/cncr.22955.

Baloch ZW, LiVolsi VA, Asa SL, et al. Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol. 2008 Jun;36(6):425-437. doi:10.1002/dc.20830.

Meko JB, Norton JA. Large cystic/solid thyroid nodules: a potential false-negative fine-needle aspiration. Surgery. 1995 Dec;118(6):996-1003; discussion 1003-4. doi:10.1016/s0039-6060(05)80105-9.

Shin JJ, Caragacianu D, Randolph GW. Impact of thyroid nodule size on prevalence and post-test probability of malignancy: a systematic review. Laryngoscope. 2015 Jan;125(1):263-272. doi:10.1002/lary.24784.

Hsiao SJ, Nikiforov YE. Molecular approaches to thyroid cancer diagnosis. Endocr Relat Cancer. 2014 Oct;21(5):T301-313. doi:10.1530/ERC-14-0166.

Özdamar Oİ, Acar GÖ, Özen F, Zenginkinet T. Assessment of BRAF V600E, KRAS, NRAS and EGFR mutations in papillary thyroid carcinoma and Hashimoto thyroiditis. ENT Updates. 2020;10(2):300-305. doi:10.32448/entupdates.711666.

Wang W, Chang J, Jia B, Liu J. The blood biomarkers of thyroid cancer. Cancer Manag Res. 2020 Jul 6;12:5431-5438. doi:10.2147/CMAR.S261170.

Chiang KC, Yeh CN, Chung LC, et al. WNT-1 inducible signaling pathway protein-1 enhances growth and tumorigenesis in human breast cancer. Sci Rep. 2015 Mar 3;5:8686. doi:10.1038/srep08686.

Deng W, Fernandez A, McLaughlin SL, Klinke DJ 2nd. WNT1-inducible signaling pathway protein 1 (WISP1/CCN4) stimulates melanoma invasion and metastasis by promoting the epithelial-mesenchymal transition. J Biol Chem. 2019 Apr 5;294(14):5261-5280. doi:10.1074/jbc.RA118.006122.

Jia S, Qu T, Feng M, et al. Association of Wnt1-inducible signaling pathway protein-1 with the proliferation, migration and invasion in gastric cancer cells. Tumour Biol. 2017;39(6):1010428317699755. doi:10.1177/1010428317699755.

Evranos B, Polat SB, Baser H, et al. Bethesda classification is a valuable guide for fine needle aspiration reports and highly predictive especially for diagnosing aggressive variants of papillary thyroid carcinoma. Cytopathology. 2017 Aug;28(4):259-267. doi:10.1111/cyt.12384.

Arora N, Scognamiglio T, Zhu B, Fahey TJ 3rd. Do benign thyroid nodules have malignant potential? An evidence-based review. World J Surg. 2008 Jul;32(7):1237-1246. doi:10.1007/s00268-008-9484-1.

Russ G, Bonnema SJ, Erdogan MF, Durante C, Ngu R, Leenhardt L. European Thyroid Association Guidelines for Ultrasound Malignancy Risk Stratification of Thyroid Nodules in Adults: The EU-TIRADS. Eur Thyroid J. 2017 Sep;6(5):225-237. doi:10.1159/000478927.

Bongiovanni M, Spitale A, Faquin WC, Mazzucchelli L, Baloch ZW. The Bethesda System for Reporting Thyroid Cytopathology: a meta-analysis. Acta Cytol. 2012;56(4):333-339. doi:10.1159/000339959.

Ha EJ, Baek JH, Na DG. Risk stratification of thyroid nodules on ultrasonography: current status and perspectives. Thyroid. 2017 Dec;27(12):1463-1468. doi:10.1089/thy.2016.0654.

Meng Z, Tan J, Zhang G, et al. Evaluation of serum midkine as a biomarker in differentiated thyroid cancer. Life Sci. 2015 Jun 1;130:18-24. doi:10.1016/j.lfs.2015.02.028.

Hu Z, Zhao P, Zhang K, Zang L, Liao H, Ma W. Evaluation of Serum Vascular Adhesion Protein-1 as a Potential Biomarker in Thyroid Cancer. Int J Endocrinol. 2016;2016:6312529. doi:10.1155/2016/6312529.

Cibas ES, Ali SZ. The 2017 Bethesda System for Reporting Thyroid Cytopathology. Thyroid. 2017 Nov;27(11):1341-1346. doi:10.1089/thy.2017.0500.

Kleiman DA, Beninato T, Soni A, Shou Y, Zarnegar R, Fahey TJ 3rd. Does bethesda category predict aggressive features in malignant thyroid nodules? Ann Surg Oncol. 2013 Oct;20(11):3484-3490. doi:10.1245/s10434-013-3076-5.

Pennica D, Swanson TA, Welsh JW, et al. WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14717-14722. doi:10.1073/pnas.95.25.14717.

Xu L, Corcoran RB, Welsh JW, Pennica D, Levine AJ. WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene. Genes Dev. 2000 Mar 1;14(5):585-595.

Maiese K. WISP1: Clinical insights for a proliferative and restorative member of the CCN family. Curr Neurovasc Res. 2014;11(4):378-389. doi:10.2174/1567202611666140912115107.

Gurbuz I, Chiquet-Ehrismann R. CCN4/WISP1 (WNT1 inducible signaling pathway protein 1): a focus on its role in cancer. Int J Biochem Cell Biol. 2015 May;62:142-146. doi:10.1016/j.biocel.2015.03.007.

Wu J, Long Z, Cai H, et al. High expression of WISP1 in colon cancer is associated with apoptosis, invasion and poor prognosis. Oncotarget. 2016 Aug 2;7(31):49834-49847. doi:10.18632/oncotarget.10486.

Taghavi A, Akbari ME, Hashemi-Bahremani M, et al. Gene expression profiling of the 8q22-24 position in human breast cancer: TSPYL5, MTDH, ATAD2 and CCNE2 genes are implicated in oncogenesis, while WISP1 and EXT1 genes may predict a risk of metastasis. Oncol Lett. 2016 Nov;12(5):3845-3855. doi:10.3892/ol.2016.5218.

Nagai Y, Watanabe M, Ishikawa S, et al. Clinical significance of Wnt-induced secreted protein-1 (WISP-1/CCN4) in esophageal squamous cell carcinoma. Anticancer Res. 2011 Mar;31(3):991-997.

Davies SR, Davies ML, Sanders A, Parr C, Torkington J, Jiang WG. Differential expression of the CCN family member WISP-1, WISP-2 and WISP-3 in human colorectal cancer and the prognostic implications. Int J Oncol. 2010 May;36(5):1129-1136. doi:10.3892/ijo_00000595.

Shao H, Cai L, Grichnik JM, Livingstone AS, Velazquez OC, Liu ZJ. Activation of Notch1 signaling in stromal fibroblasts inhibits melanoma growth by upregulating WISP-1. Oncogene. 2011 Oct 20;30(42):4316-4326. doi:10.1038/onc.2011.142.

Soon LL, Yie TA, Shvarts A, Levine AJ, Su F, Tchou-Wong KM. Overexpression of WISP-1 down-regulated motility and invasion of lung cancer cells through inhibition of Rac activation. J Biol Chem. 2003 Mar 28;278(13):11465-11470. doi:10.1074/jbc.M210945200.

Mueller MM, Fusenig NE. Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 2004 Nov;4(11):839-849. doi:10.1038/nrc1477.

Rupp C, Scherzer M, Rudisch A, et al. IGFBP7, a novel tumor stroma marker, with growth-promoting effects in colon cancer through a paracrine tumor-stroma interaction. Oncogene. 2015 Feb 12;34(7):815-825. doi:10.1038/onc.2014.18.

Bauer M, Su G, Casper C, He R, Rehrauer W, Friedl A. Heterogeneity of gene expression in stromal fibroblasts of human breast carcinomas and normal breast. Oncogene. 2010 Mar 25;29(12):1732-1740. doi:10.1038/onc.2009.463.

Tanaka S, Sugimachi K, Kameyama T, et al. Human WISP1v, a member of the CCN family, is associated with invasive cholangiocarcinoma. Hepatology. 2003 May;37(5):1122-1129. doi:10.1053/jhep.2003.50187.

Ono M, Inkson CA, Sonn R, et al. WISP1/CCN4: a potential target for inhibiting prostate cancer growth and spread to bone. PLoS One. 2013 Aug 14;8(8):e71709. doi:10.1371/journal.pone.0071709.

Feng M, Jia S. Dual effect of WISP-1 in diverse pathological processes. Chin J Cancer Res. 2016 Dec;28(6):553-560. doi:10.21147/j.issn.1000-9604.2016.06.01.