Document Type : Original Article(s)

Authors

1 Department of Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

2 Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Zagazig University, Zagazig, Egypt

3 Department of Medical Oncology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

4 Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Abstract

Background: There is an ongoing need for targeted therapy and systemic treatment protocols for papillary thyroid carcinoma (PTC) patients. Yes activated protein-1 (YAP-1) has been found to control many targets of Hippo pathway. Annexin family is a huge family playing many roles in cellular processes. Annexin A10 (ANXA10) is a member of annexin family. Uncoordinated-5D (UNC5D), a recently discovered Unc5 family member which is found in normal tissues and downregulated in cancer cell lines and tissues. Aim of the study was to assess the expression of YAP-1, ANXA10, and UNC5D in PTC and in non-neoplastic tissues of thyroid gland using immunohistochemistry to evaluate their clinical significance and prognostic values in PTC patients.
Method: In the present prospective study, we took samples from 60 patients with PTC and 30 samples from non-neoplastic thyroid tissues for YAP-1, ANXA10, and UNC5D immunohistochemistry. All the patients were followed up for assessment of the prognostic, clinical, and pathological of their expression.
Results: Upregulation of YAP-1 and ANXA10 in addition to downregulation of UNC5D was found in PTC tissues more than non-neoplastic thyroid tissues. In PTC tissues, there were positive associations between high YAP-1 and ANXA10 expression, low UNC5D expression, tumor size (P = 0.022, 0.011, 0.014), presence of lymph node metastases (P = 0.005, < 0.001, 0.008), and inferior disease-free survival rate (P = 0.003, 0.01, 0.03).
Conclusion: Upregulation of YAP-1 and ANXA10 expression and downregulation of UNC5D was associated with bad clincopathological criteria, disease progression, high incidence of disease recurrence, and poor survival.

Keywords

How to cite this article:

Elsayed WSH, Harb OA, Obaya AA, Elsayed DH, Gertallah LM, Mawla WA, et al. Expressions of YAP-1, ANXA10, and UNC5D in tissues of papillary thyroid carcinoma; prognostic, pathological, and clinical significance. Middle East J Cancer. 2023;14(1):29-40. doi: 10.30476/mejc.2022.89869.1551.

  1. Singh Ospina N, Iñiguez-Ariza NM, Castro MR. Thyroid nodules: diagnostic evaluation based on thyroid cancer risk assessment. BMJ. 2020;368:l6670. doi: 10.1136/bmj.l6670.
  2. Kitahara CM, Sosa JA. The changing incidence of thyroid cancer. Nat Rev Endocrinol. 2016;12(11):646- 53. doi: 10.1038/nrendo.2016.110.
  3. Vuong HG, Odate T, Duong UNP, Mochizuki K, Nakazawa T, Katoh R, et al. Prognostic importance of solid variant papillary thyroid carcinoma: A systematic review and meta-analysis. Head Neck. 2018;40(7):1588-97.
  4. Liu Z, Zeng W, Maimaiti Y, Ming J, Guo Y, Liu Y, et al. High expression of yes-activated protein-1 in papillary thyroid carcinoma correlates with poor prognosis. Appl Immunohistochem Mol Morphol. 2019;27(1):59-64.
  5. Ye S, Eisinger-Mathason TS. Targeting the Hippo pathway: Clinical implications and therapeutics. Pharmacol Res. 2016;103:270-8. doi: 10.1016/j.phrs. 2015.11.025.
  6. Wang Z, Wu Y, Wang H, Pajonczyk D, Rescher U. Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. Proc Natl Acad Sci USA. 2014;111: 89-98. doi: 10.1073/pnas.1319190110.
  7. Liu X, Yang M, Guo Y, Lu X. Annexin A10 is a novel prognostic biomarker of papillary thyroid cancer. Ir J Med Sci. 2021;190(1):59-65. doi: 10.1007/s11845- 020-02263-x.
  8. Schloer S, Pajonczyk D, Rescher U. Annexins in translational research: Hidden treasures to be found. Int J Mol Sci. 2018;19(6):1781. doi: 10.3390/ijms 19061781.
  9. Foo SL, Yap G, Cui J, Lim LHK. Annexin-A1 - A blessing or a curse in cancer? Trends Mol Med. 2019;25(4):315-27. doi: 10.1016/j.molmed.2019. 02.004.
  10. Engelkamp D. Cloning of three mouse Unc5 genes and their expression patterns at mid-gestation. Mech Dev. 2002;118(1-2):191-7. doi: 10.1016/s0925- 4773(02)00248-4.
  11. Zhu Y, Li Y, Haraguchi S, Yu M, Ohira M, Ozaki T, et al. Dependence receptor UNC5D mediates nerve growth factor depletion-induced neuroblastoma regression. J Clin Invest. 2013;123(7):2935-47. doi: 10.1172/JCI65988.
  12. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, 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;26(1):1-133. doi: 10.1089/thy. 2015.0020.
  13. Boin A, Couvelard A, Couderc C, Brito I, Filipescu D, Kalamarides M, et al. Proteomic screening identifies a YAP-driven signaling network linked to tumor cell proliferation in human schwannomas. Neuro Oncol. 2014;16(9):1196-209. doi: 10.1093/neuonc/nou020.
  14. Bai N, Zhang C, Liang N, Zhang Z, Chang A, Yin J, et al. Yes-associated protein (YAP) increases chemosensitivity of hepatocellular carcinoma cells by modulation of p53. Cancer Biol Ther. 2013;14(6):511-20. doi: 10.4161/cbt.24345.
  15. Yuan M, Tomlinson V, Lara R, Holliday D, Chelala C, Harada T, et al. Yes-associated protein (YAP) functions as a tumor suppressor in breast. Cell Death Differ. 2008;15(11):1752-9. doi: 10.1038/cdd.2008.108.
  16. Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 2007;21(21):2747-61. doi: 10.1101/gad.1602907.
  17. Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R, et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol. 2007;17(23):2054-60. doi: 10.1016/j.cub.2007.10.039. Erratum in: Curr Biol. 2007;17(23):2094.
  18. Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, et al. Elucidation of a universal sizecontrol mechanism in Drosophila and mammals. Cell. 2007;130(6):1120-33. doi: 10.1016/j.cell.2007.07.019.
  19. Zhao B, Lei QY, Guan KL. The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Curr Opin Cell Biol. 2008;20(6):638-46. doi: 10.1016/j.ceb.2008.10.001.
  20. Xia Y, Chang T, Wang Y, Liu Y, Li W, Li M, et al. YAP promotes ovarian cancer cell tumorigenesis and is indicative of a poor prognosis for ovarian cancer patients. PLoS One. 2014;9(3):e91770. doi: 10.1371/journal.pone.0091770. Erratum in: PLoS One. 2016;11(3):e0152712.
  21. Jeong W, Kim SB, Sohn BH, Park YY, Park ES, Kim SC, et al. Activation of YAP1 is associated with poor prognosis and response to taxanes in ovarian cancer. Anticancer Res. 2014;34(2):811-7.
  22. Wang L, Shi S, Guo Z, Zhang X, Han S, Yang A, et al. Overexpression of YAP and TAZ is an independent predictor of prognosis in colorectal cancer and related to the proliferation and metastasis of colon cancer cells. PLoS One. 2013;8(6):e65539. doi: 10.1371/ journal.pone.0065539.
  23. Liu JY, Li YH, Lin HX, Liao YJ, Mai SJ, Liu ZW, et al. Overexpression of YAP 1 contributes to progressive features and poor prognosis of human urothelial carcinoma of the bladder. BMC Cancer. 2013;13:349. doi: 10.1186/1471-2407-13-349.
  24. Serrano I, McDonald PC, Lock F, Muller WJ, Dedhar S. Inactivation of the Hippo tumour suppressor pathway by integrin-linked kinase. Nat Commun. 2013;4:2976. doi: 10.1038/ncomms3976.
  25. van der Heijden AG, Mengual L, Lozano JJ, Ingelmo- Torres M, Ribal MJ, Fernández PL, et al. A five-gene expression signature to predict progression in T1G3 bladder cancer. Eur J Cancer. 2016;64:127-36. doi: 10.1016/j.ejca.2016.06.003.
  26. Zhu J, Wu J, Pei X, Tan Z, Shi J, Lubman DM. Annexin A10 is a candidate marker associated with the progression of pancreatic precursor lesions to adenocarcinoma. PLoS One. 2017;12(4):e0175039. doi: 10.1371/journal.pone.0175039.
  27. Macaron C, Lopez R, Pai RK, Burke CA. Expression of Annexin A10 in serrated polyps predicts the development of metachronous serrated polyps. Clin Transl Gastroenterol. 2016;7(12):e205. doi: 10.1038/ctg.2016.60.
  28. Sun R, Liu Z, Qiu B, Chen T, Li Z, Zhang X, et al. Annexin10 promotes extrahepatic cholangiocarcinoma metastasis by facilitating EMT via PLA2G4A/PGE2/STAT3 pathway. EBioMedicine. 2019;47:142-55. doi: 10.1016/j.ebiom.2019. 08.062.
  29. Zhang MM, Sun F, Cui B, Zhang LL, Fang Y, Li Y, et al. Tumor-suppressive function of UNC5D in papillary thyroid cancer. Oncotarget. 2017;8(56):96126-38. doi: 10.18632/oncotarget.21759.
  30. Lu D, Dong D, Zhou Y, Lu M, Pang XW, Li Y, et al. The tumor-suppressive function of UNC5D and its repressed expression in renal cell carcinoma. Clin Cancer Res. 2013;19(11):2883-92. doi: 10.1158/1078- 0432.CCR-12-2978.
  31. Zhu Y, Yu M, Chen Y, Wang Y, Wang J, Yang C, et al. Down-regulation of UNC5D in bladder cancer: UNC5D as a possible mediator of cisplatin induced apoptosis in bladder cancer cells. J Urol. 2014;192(2):575-82. doi: 10.1016/j.juro.2014.01.108.
  32. Wang H, Ozaki T, Shamim Hossain M, Nakamura Y, Kamijo T, Xue X, et al. A newly identified dependence receptor UNC5H4 is induced during DNA damagemediated apoptosis and transcriptional target of tumor suppressor p53. Biochem Biophys Res Commun. 2008; 370(4):594-8. doi: 10.1016/j.bbrc.2008.03.152.
  33. Liu P, Lu Y, Liu H, Wen W, Jia D, Wang Y, et al. Genome-wide association and fine mapping of genetic loci predisposing to colon carcinogenesis in mice. Mol Cancer Res. 2012;10(1):66-74. doi: 10.1158/1541- 7786.MCR-10-0540.