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Microarray analysis of cell cycle and apoptosis biomarkers (p16, p21, p27, p53, Bcl-2, Bax, Bcl-xL and Cyclin D1) in thyroid papillary carcinoma, papillary microcarcinoma and lymph node metastasis of thyroid papillary carcinoma

Year 2021, Volume: 8 Issue: 3, 419 - 425, 30.09.2021
https://doi.org/10.34087/cbusbed.837637

Abstract

AObjective: The aim of this study was to identify the role of apoptosis and cell cycle associated gene products in the pathogenesis of thyroid papillary carcinoma (TPC) and its lymph node metastasis.
Materials and Methods: Cases of thyroid papillary carcinoma (n=35), thyroid papillary microcarcinoma (TPMC) (n=22), TPC-lymph node metastasis (TPC-LNM) (n=12), and adenomatous nodule (AN) (n=20) were examined using tissue microarray method (TMA) by immunohistochemistry staining for p16, p21, p27, p53, bcl-2, bax, bcl-xL and cyclin D1.
Results: Bcl-2 staining of the ANs was significantly differed from those of malignant groups. p53, p16, p21 staining percentages were significantly higher in the malignant groups than in the benign lesions. TPC-LNM group had higher p16 and cyclin D1 positivity than the primary tumor groups. The most remarkable difference of p27 staining was between the TPC-LNM and TPC groups.
Conclusion: We concluded that cell cycle regulators, especially bcl-2 family, play important roles in TPC carcinogenesis. The cyclin-dependent kinase inhibitors acting on the cyclin-CDK complex (p16, p21, p27) were more associated with potential for malignancy, progression and poor prognosis. p53 plays an important role in the TPC pathogenesis by interacting with the proteins regulating both apoptosis and the cell cycle.

Supporting Institution

Manisa Celal Bayar University, Scientific Research Projects Coordination Unit

Project Number

2009-134

Thanks

Thank Manisa Celal Bayar University, Scientific Research Projects Coordination Unit (2009-134) who sponsored the study.

References

  • Lloyd, R.V, Osamura, R.Y, Klöppel, G, Rosai, J (editors), WHO classification of tumours of endocrine organs, 4th edn. Lyon, France: IARC, 2017.
  • Thompson, L.D.R, Bishop, J, Malignant neoplams of the thyroid gland. Head and Neck Pathology, 3rd ed. Goldblum JR, series ed., Foundations in Diagnostic Pathology: Expert Consult. Philadelphia: Elsevier Saunders, 2018, 565-632.
  • Goldblum, J.R, Lamps, L.W, McKenney, J.K, Myers, J.L, editors. Rosai and Ackerman's surgical pathology. 11th edition. Elsevier; Philadelphia, PA: 2018.
  • Temiz, P, Akkaş, G, et al. Determination-of apoptosis and cell cycle modulators (p16, p21, p27, p53, BCL-2, Bax, BCL-xL, and cyclin D1) in thyroid follicular carcinoma, follicular adenoma, and adenomatous nodules via a tissue microarray method. Turkish Journal of Medical Sciences, 2015; 45:865-71.
  • Gupta, A, Jain, S, et al. Expression of p63 and Bcl-2 in malignant thyroid tumors and their correlation with other diagnostic immunocytochemical markers, Journal of Clinical and Diagnostic Research, 2016, 10(7), EC04-8.
  • Cvejic, D, Selemetjev, S, et al. Apoptosis and proliferation related molecules (Bcl-2, Bax, p53, PCNA) in papillary microcarcinoma versus papillary carcinoma of the thyroid, Pathology, 2008, 40, 475-480.
  • Aksoy, M, Giles, Y, et al., Expression of bcl-2 in papillary thyroid cancers and its prognostic value. Acta Chirurgica Belgica, 2005, 105, 644-648.
  • Al-Gharrrawi, S.A.R., Alkhafaji, A.H.M.A et al., Immunohistochemical expression of CD68, p53 and Bcl2 in thyroid tumors, Indian Journal of Forensic Medicine & Toxicology, 2020, 14, 1. 
  • Lamba Saini, M, Bouzin, C, et al., An appraisal of proliferation and apoptotic markers in papillary thyroid carcinoma: an automated analysis, PLoS One, 2016, 11 (2), e0148656.
  • Selemetjev, S.A, Savin, S.B et al., Changes in the expression pattern of apoptotic molecules (galectin-3, Bcl-2, Bax, survivin) during progression of thyroid malignancy and their clinical significance, The Wiener klinische Wochenschrift, 2015, 127(9-10), 337-44.
  • Letsas, K.P, Frangou-Lazaridis, M, et al. Transcription factor-mediated proliferation and apoptosis in benign and malignant thyroid lesions, Pathology International, 2005, 55, 694-702.
  • Manetto, V, Lorenzini, R et al., Bcl-2 and Bax expression in thyroid tumours, An immunohistochemical and western blot analysis, Virchows Archieve, 1997, 430, 125–130.
  • Lee, J.S, Jin, S.M et al., Expression of Bcl-2, Bax and p27 in Patients with Papillary Thyroid Cancer with or without Lymph Node Metastasis, Korean Journal of Otorhinolaryngology-Head and Neck Surgery, 2010, 53(3), 153-158.
  • Martínez-Brocca, M.A, Castilla, C, et al., Clinicopathological correlations of Bcl-xL and Bax expression in differentiated thyroid carcinoma, Clinical Endocrinology-Oxford, 2008, 68, 190-197.
  • Cheok, C.F, Verma, C.S, et al., Translating p53 into the clinic, Nature Reviews Clinical Oncology, 2011, 8, 25–37.
  • Nikiforov, Y.E, Nikiforova, M.N, Molecular genetics and diagnosis of thyroid cancer, Nature Reviews Endocrinology, 2011, 7, 569–80.
  • Dwivedi, S.S, Khandeparkar, S.G et al., Study of immunohistochemical markers (ck-19, cd-56, ki-67, p53) in differentiating benign and malignant solitary thyroid nodules with special reference to papillary thyroid carcinomas, Journal of Clinical and Diagnostic Research, 2016, 10(12), EC14-EC19.
  • Balta, A.Z, Filiz, A.I, et al. Prognostic value of oncoprotein expressions in thyroid papillary carcinoma, Medical Oncology, 2012, 29, 734-41.
  • Morita, N, Ikeda, Y, et al., Clinical significance of p53 protein expression in papillary thyroid carcinoma, World Journal of Surgery, 2008, 32, 2617–2622.
  • Horie, S, Maeta, H, et al., Overexpression of p53 protein and MDM2 in papillary carcinomas of the thyroid: Correlations with clinicopathologic features, Pathology International, 2001, 51, 11-5.
  • Hamzany, Y, Soudry, E, et al., Early death from papillary thyroid carcinoma, American Journal of Otolaryngology, 2012, 33, 104-8.
  • Shin, M.K, Kim, J.W, Clinicopathologic and diagnostic significance of p53 protein expression in papillary thyroid carcinoma, Asian Pacific Journal of Cancer Prevention, 2014, 15(5), 2341-4.
  • Lam, A.K, Lo, C.Y, et al., Clinicopathological roles of alterations of tumor suppressor gene p16 in papillary thyroid carcinoma, Annals of Surgical Oncology, 2007, 14, 1772-1779.
  • Boltze, C, Zack, S, et al., Hypermethylation of the CDKN2 / p16INK4A promotor in thyroid carcinogenesis, Pathology-Research and Practice, 2003, 199, 399-404.
  • Barroeta, J.E, Baloch, Z.W, et al., Diagnostic value of differential expression of CK19, Galectin-3, HBME-1, ERK, RET, and p16 in benign and malignant follicular-derived lesions of the thyroid: an immunohistochemical tissue microarray analysis, Endocrine Pathology, 2006, 17, 225-234.
  • Do, S.I, Kim, D.H, et al., Decreased expression of p27 is associated with malignant transformation and extrathyroidal extension in papillary thyroid carcinoma, Tumor Biology, 2016, 37, 3359-64.
  • Melck, A, Masoudi, H, et al., Cell cycle regulators show diagnostic and prognostic utility for differentiated thyroid cancer, Annals of Surgical Oncology, 2007, 14, 3403-3411.
  • Okayasu, I, Osakabe, T, et al., P53 and p21(WAF1) expression in lymphocytic thyroiditis and thyroid tumors, Clinical Immunology and Immunopathology, 1998, 88, 183-191.
  • Pesutić-Pisac, V, Punda, A, et al., Cyclin D1 and p27 expression as prognostic factor in papillary carcinoma of thyroid: association with clinicopathological parameters, Croatian Medical Journal, 2008, 49, 643-649.
  • Lee, S.H, Lee, J.K, et al., Expression of cell-cycle regulators (cyclin D1, cyclin E, p27kip1, p57kip2) in papillary thyroid carcinoma, Otolaryngology Head and Neck Surgery, 2010, 142, 332–337.
  • Barić, A, Marković, V, et al., Cyclin D1, Ret and p27 expression in papillary thyroid microcarcinoma, Acta Clinica Croatica, 2017, 56 (1), 15-20.
  • Zafón, C, Castellví, J, et al., Usefulness of the immunohistochemical analysis of several molecular markers in the characterization of papillary thyroid carcinoma with initial lymph node metastasis, Endocrinología y Nutrición, 2010, 57, 165-9

Tiroid papiller karsinom, papiller mikrokarsinom ve tiroid papiller karsinomun lenf nodu metastazında apoptoz ve hücre siklusu ile ilişkili belirleyicilerin (p16, p2l, p27, p53, bcl-2, bax, bcl-xl ve siklin-D1) doku microarray yöntemiyle saptanması

Year 2021, Volume: 8 Issue: 3, 419 - 425, 30.09.2021
https://doi.org/10.34087/cbusbed.837637

Abstract

Giriş ve Amaç: Bu çalışmanın amacı, tiroid papiller karsinom ve lenf nodu metastazının patogenezinde apoptoz ve hücre döngüsü ile ilişkili gen ürünlerinin rolünü belirlemektir.
Gereç ve Yöntemler: Tiroid papiller karsinom (n = 35), tiroid papiller mikrokarsinom (TPMK) (n = 22), TPK-lenf nodu metastazı (TPK-LNM) (n = 12) ve adenomatöz nodülde (AN) ( n = 20) doku mikroarray yöntemi (TMA) kullanılarak p16, p21, p27, p53, bcl-2, bax, bcl-xL ve siklin D1'in immünohistokimyasal olarak boyanması incelendi.
Bulgular: AN'lerin Bcl-2 boyaması, malign gruplarınkilerden önemli ölçüde farklıydı. p53, p16, p21 boyama yüzdeleri, malign gruplarda benign lezyonlara göre anlamlı olarak daha yüksekti. TPC-LNM grubu, primer tümör gruplarından daha yüksek p16 ve siklin D1 pozitifliğine sahipti. p27 boyanmasındaki en dikkat çekici fark , TPK-LNM ve TPK grupları arasındaydı.
Sonuç: Hücre döngüsü düzenleyicilerinin, özellikle bcl-2 ailesinin, TPC karsinogenezinde önemli roller oynadığı sonucuna vardık. Siklin-CDK kompleksi (p16, p21, p27) üzerinde etkili olan sikline bağımlı kinaz inhibitörleri, malignite, progresyon ve kötü prognoz potansiyeli ile daha çok ilişkiliydi. p53, hem apoptozu hem de hücre döngüsünü düzenleyen proteinlerle etkileşime girerek TPC patogenezinde önemli bir rol oynar.

Project Number

2009-134

References

  • Lloyd, R.V, Osamura, R.Y, Klöppel, G, Rosai, J (editors), WHO classification of tumours of endocrine organs, 4th edn. Lyon, France: IARC, 2017.
  • Thompson, L.D.R, Bishop, J, Malignant neoplams of the thyroid gland. Head and Neck Pathology, 3rd ed. Goldblum JR, series ed., Foundations in Diagnostic Pathology: Expert Consult. Philadelphia: Elsevier Saunders, 2018, 565-632.
  • Goldblum, J.R, Lamps, L.W, McKenney, J.K, Myers, J.L, editors. Rosai and Ackerman's surgical pathology. 11th edition. Elsevier; Philadelphia, PA: 2018.
  • Temiz, P, Akkaş, G, et al. Determination-of apoptosis and cell cycle modulators (p16, p21, p27, p53, BCL-2, Bax, BCL-xL, and cyclin D1) in thyroid follicular carcinoma, follicular adenoma, and adenomatous nodules via a tissue microarray method. Turkish Journal of Medical Sciences, 2015; 45:865-71.
  • Gupta, A, Jain, S, et al. Expression of p63 and Bcl-2 in malignant thyroid tumors and their correlation with other diagnostic immunocytochemical markers, Journal of Clinical and Diagnostic Research, 2016, 10(7), EC04-8.
  • Cvejic, D, Selemetjev, S, et al. Apoptosis and proliferation related molecules (Bcl-2, Bax, p53, PCNA) in papillary microcarcinoma versus papillary carcinoma of the thyroid, Pathology, 2008, 40, 475-480.
  • Aksoy, M, Giles, Y, et al., Expression of bcl-2 in papillary thyroid cancers and its prognostic value. Acta Chirurgica Belgica, 2005, 105, 644-648.
  • Al-Gharrrawi, S.A.R., Alkhafaji, A.H.M.A et al., Immunohistochemical expression of CD68, p53 and Bcl2 in thyroid tumors, Indian Journal of Forensic Medicine & Toxicology, 2020, 14, 1. 
  • Lamba Saini, M, Bouzin, C, et al., An appraisal of proliferation and apoptotic markers in papillary thyroid carcinoma: an automated analysis, PLoS One, 2016, 11 (2), e0148656.
  • Selemetjev, S.A, Savin, S.B et al., Changes in the expression pattern of apoptotic molecules (galectin-3, Bcl-2, Bax, survivin) during progression of thyroid malignancy and their clinical significance, The Wiener klinische Wochenschrift, 2015, 127(9-10), 337-44.
  • Letsas, K.P, Frangou-Lazaridis, M, et al. Transcription factor-mediated proliferation and apoptosis in benign and malignant thyroid lesions, Pathology International, 2005, 55, 694-702.
  • Manetto, V, Lorenzini, R et al., Bcl-2 and Bax expression in thyroid tumours, An immunohistochemical and western blot analysis, Virchows Archieve, 1997, 430, 125–130.
  • Lee, J.S, Jin, S.M et al., Expression of Bcl-2, Bax and p27 in Patients with Papillary Thyroid Cancer with or without Lymph Node Metastasis, Korean Journal of Otorhinolaryngology-Head and Neck Surgery, 2010, 53(3), 153-158.
  • Martínez-Brocca, M.A, Castilla, C, et al., Clinicopathological correlations of Bcl-xL and Bax expression in differentiated thyroid carcinoma, Clinical Endocrinology-Oxford, 2008, 68, 190-197.
  • Cheok, C.F, Verma, C.S, et al., Translating p53 into the clinic, Nature Reviews Clinical Oncology, 2011, 8, 25–37.
  • Nikiforov, Y.E, Nikiforova, M.N, Molecular genetics and diagnosis of thyroid cancer, Nature Reviews Endocrinology, 2011, 7, 569–80.
  • Dwivedi, S.S, Khandeparkar, S.G et al., Study of immunohistochemical markers (ck-19, cd-56, ki-67, p53) in differentiating benign and malignant solitary thyroid nodules with special reference to papillary thyroid carcinomas, Journal of Clinical and Diagnostic Research, 2016, 10(12), EC14-EC19.
  • Balta, A.Z, Filiz, A.I, et al. Prognostic value of oncoprotein expressions in thyroid papillary carcinoma, Medical Oncology, 2012, 29, 734-41.
  • Morita, N, Ikeda, Y, et al., Clinical significance of p53 protein expression in papillary thyroid carcinoma, World Journal of Surgery, 2008, 32, 2617–2622.
  • Horie, S, Maeta, H, et al., Overexpression of p53 protein and MDM2 in papillary carcinomas of the thyroid: Correlations with clinicopathologic features, Pathology International, 2001, 51, 11-5.
  • Hamzany, Y, Soudry, E, et al., Early death from papillary thyroid carcinoma, American Journal of Otolaryngology, 2012, 33, 104-8.
  • Shin, M.K, Kim, J.W, Clinicopathologic and diagnostic significance of p53 protein expression in papillary thyroid carcinoma, Asian Pacific Journal of Cancer Prevention, 2014, 15(5), 2341-4.
  • Lam, A.K, Lo, C.Y, et al., Clinicopathological roles of alterations of tumor suppressor gene p16 in papillary thyroid carcinoma, Annals of Surgical Oncology, 2007, 14, 1772-1779.
  • Boltze, C, Zack, S, et al., Hypermethylation of the CDKN2 / p16INK4A promotor in thyroid carcinogenesis, Pathology-Research and Practice, 2003, 199, 399-404.
  • Barroeta, J.E, Baloch, Z.W, et al., Diagnostic value of differential expression of CK19, Galectin-3, HBME-1, ERK, RET, and p16 in benign and malignant follicular-derived lesions of the thyroid: an immunohistochemical tissue microarray analysis, Endocrine Pathology, 2006, 17, 225-234.
  • Do, S.I, Kim, D.H, et al., Decreased expression of p27 is associated with malignant transformation and extrathyroidal extension in papillary thyroid carcinoma, Tumor Biology, 2016, 37, 3359-64.
  • Melck, A, Masoudi, H, et al., Cell cycle regulators show diagnostic and prognostic utility for differentiated thyroid cancer, Annals of Surgical Oncology, 2007, 14, 3403-3411.
  • Okayasu, I, Osakabe, T, et al., P53 and p21(WAF1) expression in lymphocytic thyroiditis and thyroid tumors, Clinical Immunology and Immunopathology, 1998, 88, 183-191.
  • Pesutić-Pisac, V, Punda, A, et al., Cyclin D1 and p27 expression as prognostic factor in papillary carcinoma of thyroid: association with clinicopathological parameters, Croatian Medical Journal, 2008, 49, 643-649.
  • Lee, S.H, Lee, J.K, et al., Expression of cell-cycle regulators (cyclin D1, cyclin E, p27kip1, p57kip2) in papillary thyroid carcinoma, Otolaryngology Head and Neck Surgery, 2010, 142, 332–337.
  • Barić, A, Marković, V, et al., Cyclin D1, Ret and p27 expression in papillary thyroid microcarcinoma, Acta Clinica Croatica, 2017, 56 (1), 15-20.
  • Zafón, C, Castellví, J, et al., Usefulness of the immunohistochemical analysis of several molecular markers in the characterization of papillary thyroid carcinoma with initial lymph node metastasis, Endocrinología y Nutrición, 2010, 57, 165-9
There are 32 citations in total.

Details

Primary Language English
Subjects Pathology
Journal Section Araştırma Makalesi
Authors

Gizem Akkaş Akgün 0000-0001-9981-6648

Peyker Temiz 0000-0001-6308-0157

Semin Ayhan 0000-0002-8546-0705

Fazilet Uğur Duman This is me 0000-0001-9981-6648

Hasan Aydede 0000-0002-1504-4140

Project Number 2009-134
Publication Date September 30, 2021
Published in Issue Year 2021 Volume: 8 Issue: 3

Cite

APA Akkaş Akgün, G., Temiz, P., Ayhan, S., Uğur Duman, F., et al. (2021). Microarray analysis of cell cycle and apoptosis biomarkers (p16, p21, p27, p53, Bcl-2, Bax, Bcl-xL and Cyclin D1) in thyroid papillary carcinoma, papillary microcarcinoma and lymph node metastasis of thyroid papillary carcinoma. Celal Bayar Üniversitesi Sağlık Bilimleri Enstitüsü Dergisi, 8(3), 419-425. https://doi.org/10.34087/cbusbed.837637
AMA Akkaş Akgün G, Temiz P, Ayhan S, Uğur Duman F, Aydede H. Microarray analysis of cell cycle and apoptosis biomarkers (p16, p21, p27, p53, Bcl-2, Bax, Bcl-xL and Cyclin D1) in thyroid papillary carcinoma, papillary microcarcinoma and lymph node metastasis of thyroid papillary carcinoma. CBU-SBED: Celal Bayar University-Health Sciences Institute Journal. September 2021;8(3):419-425. doi:10.34087/cbusbed.837637
Chicago Akkaş Akgün, Gizem, Peyker Temiz, Semin Ayhan, Fazilet Uğur Duman, and Hasan Aydede. “Microarray Analysis of Cell Cycle and Apoptosis Biomarkers (p16, p21, p27, p53, Bcl-2, Bax, Bcl-XL and Cyclin D1) in Thyroid Papillary Carcinoma, Papillary Microcarcinoma and Lymph Node Metastasis of Thyroid Papillary Carcinoma”. Celal Bayar Üniversitesi Sağlık Bilimleri Enstitüsü Dergisi 8, no. 3 (September 2021): 419-25. https://doi.org/10.34087/cbusbed.837637.
EndNote Akkaş Akgün G, Temiz P, Ayhan S, Uğur Duman F, Aydede H (September 1, 2021) Microarray analysis of cell cycle and apoptosis biomarkers (p16, p21, p27, p53, Bcl-2, Bax, Bcl-xL and Cyclin D1) in thyroid papillary carcinoma, papillary microcarcinoma and lymph node metastasis of thyroid papillary carcinoma. Celal Bayar Üniversitesi Sağlık Bilimleri Enstitüsü Dergisi 8 3 419–425.
IEEE G. Akkaş Akgün, P. Temiz, S. Ayhan, F. Uğur Duman, and H. Aydede, “Microarray analysis of cell cycle and apoptosis biomarkers (p16, p21, p27, p53, Bcl-2, Bax, Bcl-xL and Cyclin D1) in thyroid papillary carcinoma, papillary microcarcinoma and lymph node metastasis of thyroid papillary carcinoma”, CBU-SBED: Celal Bayar University-Health Sciences Institute Journal, vol. 8, no. 3, pp. 419–425, 2021, doi: 10.34087/cbusbed.837637.
ISNAD Akkaş Akgün, Gizem et al. “Microarray Analysis of Cell Cycle and Apoptosis Biomarkers (p16, p21, p27, p53, Bcl-2, Bax, Bcl-XL and Cyclin D1) in Thyroid Papillary Carcinoma, Papillary Microcarcinoma and Lymph Node Metastasis of Thyroid Papillary Carcinoma”. Celal Bayar Üniversitesi Sağlık Bilimleri Enstitüsü Dergisi 8/3 (September 2021), 419-425. https://doi.org/10.34087/cbusbed.837637.
JAMA Akkaş Akgün G, Temiz P, Ayhan S, Uğur Duman F, Aydede H. Microarray analysis of cell cycle and apoptosis biomarkers (p16, p21, p27, p53, Bcl-2, Bax, Bcl-xL and Cyclin D1) in thyroid papillary carcinoma, papillary microcarcinoma and lymph node metastasis of thyroid papillary carcinoma. CBU-SBED: Celal Bayar University-Health Sciences Institute Journal. 2021;8:419–425.
MLA Akkaş Akgün, Gizem et al. “Microarray Analysis of Cell Cycle and Apoptosis Biomarkers (p16, p21, p27, p53, Bcl-2, Bax, Bcl-XL and Cyclin D1) in Thyroid Papillary Carcinoma, Papillary Microcarcinoma and Lymph Node Metastasis of Thyroid Papillary Carcinoma”. Celal Bayar Üniversitesi Sağlık Bilimleri Enstitüsü Dergisi, vol. 8, no. 3, 2021, pp. 419-25, doi:10.34087/cbusbed.837637.
Vancouver Akkaş Akgün G, Temiz P, Ayhan S, Uğur Duman F, Aydede H. Microarray analysis of cell cycle and apoptosis biomarkers (p16, p21, p27, p53, Bcl-2, Bax, Bcl-xL and Cyclin D1) in thyroid papillary carcinoma, papillary microcarcinoma and lymph node metastasis of thyroid papillary carcinoma. CBU-SBED: Celal Bayar University-Health Sciences Institute Journal. 2021;8(3):419-25.