TY  - JOUR
T1  - İnsan Protein Etkileşim Ağı Kullanarak Tiroid Karsinomu İle İlgili Moleküler Hedef ve Biyoişaretçi Adayların Belirlenmesi
TT  - Identification of Thyroid Carcinoma Related Molecular Targets and Signatures Using Human Protein Interaction Network
AU  - Göv, Esra
PY  - 2019
DA  - September
DO  - 10.7240/jeps.536218
JF  - International Journal of Advances in Engineering and Pure Sciences
JO  - JEPS
PB  - Marmara University
WT  - DergiPark
SN  - 2636-8277
SP  - 245
EP  - 254
VL  - 31
IS  - 3
LA  - tr
AB  - Tiroid kanseri görülmesıklığı yüksek olan ve ölümcül bir kanser türüdür. Dolayısıyla tiroidkanserinde etkin rol alan moleküllerin belirlenmesi hastalığın erken tanı vetedavi stratejilerinin oluşturulması için çok önemlidir. Bu çalışmada yüksekboyutlu işlevsel genomiks verilerinin sistem biyolojisi araçları ilebütünleştirilerek analizi sonucu tiroid kanserine özgü moleküler hedefler vebiyoişaretçi adaylar belirlenmiştir. Zenginleştirme analizi sonucunda önemlikanser yolaklarının, metabolik yolakların ve immun sistem ilgili yollarınaktifleştiği belirlenmiştir. İleri istatistiksel analizler ile belirlenen genanlatımı farklılık gösteren genlerin protein etkileşim ağı oluşturulmuş vetiroid kanserine özgü moleküler hedefler ve biyoişaretçi adaylar JUN, LRRK2,BCL2, CCND1, TLE1, MET, ICAM1, DDB2 ve RXRG olarak belirlenmiştir. Bağımsız birveri setinin analizi ile, bu genlerin tümör ve normal dokuları ayırt edebileceğibelirlenmiştir. Bu proteinler arasından JUN, TLE1 ve DBB2’nin yeni molekülerhedef ve biyoişaretçi aday olabileceği bulunmuştur. Belirlenen hedeflerinpapiller tiroid kanserinin teşhis ve tedavi stratejilerinin oluşturulmasındakullanılabileceği öngörülmektedir. Ancak söz konusu adayların eş zamanlı PCRile deneysel çalışmalarının yapılması gerekmektedir.
KW  - Sistem biyotıbbı
KW  - istatiksel analiz
KW  - kanser
KW  - biyobelirteç
N2  - Thyroid cancer is a fataldisease has a high incidence. Therefore, the determination of moleculesinvolved in thyroid cancer is very crucial for early diagnosis and treatmentstrategies of the disease. In this study, high-dimensional functional genomicdata were integrated with system biology tools and the molecular targets andsignatures in thyroid cancer were determined. As a result of enrichmentanalysis, it was determined that important cancer pathways, metabolic pathwaysand immune system related pathways were activated. The protein- proteininteraction network was reconstructed using differential gene expression isdetermined by advanced statistical analysis and the molecular targets and signaturesin thyroid cancer were determined as JUN, LRRK2, BCL2, CCND1, TLE1, MET, ICAM1,DDB2 and RXRG. It was determined that these genes can differentiate tumorsamples and normal thyroid tissues via independent data analysis. Among theseproteins, JUN, TLE1 and DBB2 were found to be novel molecular targets. It ispredicted that these molecular targets can be used in the diagnosis andtreatment strategies of papillary thyroid cancer. However, it is necessary toperform experimental studies with real time-PCR.
CR  - [1]  Carling, T. ve Udelsman, R. (2005). Thyroid tumors. Cancer: principles and practice of oncology., 9, 1457-1472.
CR  - [2] Xing, M. (2013). Molecular pathogenesis and mechanisms of thyroid cancer. Nature Reviews Cancer., 13(3), 184.
CR  - [3] Elisei, R., Ugolini, C., Viola, D., Lupi, C., Biagini, A., Giannini, R., Romei, C., Miccoli, P., Pinchera, A. ve Basolo, F. (2008). BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study. J Clin Endocrinol Metab., 93, 3943–3949.
CR  - [4] Yip, L., Nikiforova, M.N., Carty, S.E., Yim, J.H., Stang, M.T., Tublin, M.J., Lebeau, S.O., Hodak, S.P., Ogilvie, J.B. ve Nikiforov Y.E. (2009). Optimizing surgical treatment of papillary thyroid carcinoma associated with BRAF mutation. Surgery., 146,1215–1223.
CR  - [5] Handkiewicz-Junak, D., Swierniak, M., Rusinek, D., Oczko-Wojciechowska, M., Dom, G., Maenhaut, C., Unger, K., Detours V., Bogdanova, T.,Thomas, G.,Likhtarov, I., Jaksik, R.,Kowalska, M., Chmielik, E., Jarzab, M., ve Swierniak A. (2016). Gene signature of the post-Chernobyl papillary thyroid cancer. European journal of nuclear medicine and molecular imaging., 43(7), 1267-1277.
CR  - [6] Chien, M. N., Yang, P. S., Lee, J. J., Wang, T. Y., Hsu, Y. C. ve Cheng, S. P. (2017). Recurrence-associated genes in papillary thyroid cancer: An analysis of data from The Cancer Genome Atlas. Surgery., 161(6), 1642-1650.
CR  - [7] Vasko, V., Espinosa, A. V., Scouten, W., He, H., Auer, H., Liyanarachchi, S., Larin, A., Savchenko, V., Francis, G. L. de la Chapelle, A., Saji, M. ve  Ringel M.D. (2007). Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion. Proceedings of the National Academy of Sciences., 104(8), 2803-2808.
CR  - [8] Burniat, A., Jin, L., Detours, V., Driessens, N., Goffard, J. C., Santoro, M., Rothstein, J. Dumont, J. E., Miot F. ve Corvilain, B. (2008). Gene expression in RET/PTC3 and E7 transgenic mouse thyroids: RET/PTC3 but not E7 tumors are partial and transient models of human papillary thyroid cancers. Endocrinology., 149(10), 5107-5117.
CR  - [9] McFadden, D. G., Vernon, A., Santiago, P. M., Martinez-McFaline, R., Bhutkar, A., Crowley, D. M., McMahon, M., Sadow P. M. ve Jacks, T. (2014). p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer. Proceedings of the National Academy of Sciences., 111(16), E1600-E1609.
CR  - [10] Zhao, H. ve Li, H. (2018). Network-based meta-analysis in the identification of biomarkers for papillary thyroid cancer. Gene., 661, 160-168.
CR  - [11] Yu, J., Mai, W., Cui, Y. ve Kong, L. (2016). Key genes and pathways predicted in papillary thyroid carcinoma based on bioinformatics analysis. Journal of endocrinological investigation., 39(11), 1285-1293.
CR  - [12] Barrett, T., Troup, D.B., Wilhite, S.E., Ledoux, P., Evangelista, C., Kim, I .F., Tomashevsky, M., Marshall, K.A., Phillippy, K.H., Sherman, P.M., Muertter, R.N., Holko, M., Ayanbule, O., Yefanov, A. ve Soboleva, A. (2011). NCBI GEO: archive for functional genomics data sets-10 years on, Nucleic Acids Res., 39(Database issue): D1005--D1010.
CR  - [13] Handkiewicz-Junak, D., Swierniak, M., Rusinek, D., Oczko-Wojciechowska, M., Dom, G., Maenhaut, C., Unger, K., Detours, V., Bogdanova, T., Thomas, G., Likhtarov, I., Jaksik, R Kowalska, M., Chmielik, E., Jarzab, M., Swierniak, A. ve  Jarzab, B. (2016). Gene signature of the post-Chernobyl papillary thyroid cancer. European journal of nuclear medicine and molecular imaging., 43(7), 1267-1277.
CR  - [14] He, H., Jazdzewski, K., Li, W., Liyanarachchi, S., Nagy, R., Volinia, S., Kloos, R. T. (2005). The role of microRNA genes in papillary thyroid carcinoma. Proceedings of the National Academy of Sciences., 102(52), 19075-19080.
CR  - [15] Vasko, V., Espinosa, A. V., Scouten, W., He, H., Auer, H., Liyanarachchi, S., Larin, A., Savchenko, V., Francis, G. L., Chapelle, A., Saji, M., ve Ringel, M.D. (2007). Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion. Proceedings of the National Academy of Sciences., 104(8), 2803-2808.
CR  - [16] Smyth G.K. (2005). Limma: linear models for microarray data. In: Bioinformatics and Computational Biology Solutions using R and Bioconductor, R. Gentleman, V. Carey, S. Dudoit, R. Irizarry, W. Huber (eds.), Springer, New York, 397-420.
CR  - [17] Huang D.W., Sherman, B.T., Tan, Q., Kir, J., Liu, D., Bryant, D., Guo, Y., Stephens, R., Baseler, M. W., Lane, H. C. ve Lempicki, R.A. (2007). DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists, Nucleic Acids Res., 35(Web Server issue), W169--W175.
CR  - [18] Karagoz, K., Sevimoglu, T., ve Arga, K. Y. (2016). Integration of multiple biological features yields high confidence human protein interactome. Journal of theoretical biology., 403, 85-96.
CR  - [19] Shannon, P., Markiel, A., Ozier, O., Baliga, N.S., Wang, J.T., Ramage, D., Amin, N., Schwikowski, B. ve Ideker, T. (2003). Cytoscape: a software environment for integrated models of biomolecular interaction networks, Genome Res., 13(11), 2498-504.
CR  - [20] Stelzer, G., Rosen, R., Plaschkes, I., Zimmerman, S., Twik, M., Fishilevich, S., Iny Stein, T., Nudel, R., Lieder, I., Mazor, Y., Kaplan, S., Dahary, D., Warshawsky, D., Guan – Golan, Y., Kohn, A., Rappaport, N., Safran, M., ve Lancet D. (2016), The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analysis , Current Protocols in Bioinformatics., 54, 1.30.1.
CR  - [21] Kitahara, C. M. ve Sosa, J. A. (2016). The changing incidence of thyroid cancer. Nature Reviews Endocrinology., 12(11), 646.
CR  - [22] TC Sağlık Bakanlığı, Türkiye Halk Sağlığı Kurumu, Kanser istatistikleri, (2016).
CR  - [23] Liu, E. T. (2010). Foundations for Systems Biomedicine: an Introduction. In Systems Biomedicine Academic Press, Singapur. 1-13
CR  - [24] Calimlioglu, B., Karagoz, K., Sevimoglu, T., Kilic, E., Gov, E. ve Arga, K. Y. (2015). Tissue-specific molecular biomarker signatures of type 2 diabetes: an integrative analysis of transcriptomics and protein–protein interaction data. Omics: a journal of integrative biology., 19(9), 563-573.
CR  - [25] Kori, M., Gov, E. ve Arga, K. Y. (2016). Molecular signatures of ovarian diseases: Insights from network medicine perspective. Systems biology in reproductive medicine., 62(4), 266-282.
CR  - [26] Gov, E., Kori, M. ve Arga, K. Y. (2017). Multiomics analysis of tumor microenvironment reveals Gata2 and miRNA-124-3p as potential novel biomarkers in ovarian cancer. Omics: a journal of integrative biology., 21(10), 603-615.
CR  - [27] Manzella, L., Stella, S., Pennisi, M., Tirrò, E., Massimino, M., Romano, C., Vigneri, P. (2017). New insights in thyroid cancer and p53 family proteins. International journal of molecular sciences., 18(6), 1325.
CR  - [28] Ramírez-Moya, J., Wert-Lamas, L. ve Santisteban, P. (2018). MicroRNA-146b promotes PI3K/AKT pathway hyperactivation and thyroid cancer progression by targeting PTEN. Oncogene., 37(25), 3369.
CR  - [29] Zhao, J., Li, Z., Chen, Y., Zhang, S., Guo, L., Gao, B., Zhang, X. (2019). MicroRNA 766 inhibits papillary thyroid cancer progression by directly targeting insulin receptor substrate 2 and regulating the PI3K/Akt pathway. International journal of oncology., 54(1), 315-325.
CR  - [30] Knauf, J. A., Sartor, M. A., Medvedovic, M., Lundsmith, E., Ryder, M., Salzano, M., Fagin, J. A. (2011). Progression of BRAF-induced thyroid cancer is associated with epithelial–mesenchymal transition requiring concomitant MAP kinase and TGFβ signaling. Oncogene., 30(28), 3153.
CR  - [31] Ashton, T. M., Fokas, E., Kunz-Schughart, L. A., Folkes, L. K., Anbalagan, S., Huether, M., Stratford, M. (2016). The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia. Nature communications., 7, 12308.
CR  - [32] Zhang, Y., Sui, F., Ma, J., Ren, X., Guan, H., Yang, Q., Hou, P. (2016). Positive feedback loops between NrCAM and major signaling pathways contribute to thyroid tumorigenesis. The Journal of Clinical Endocrinology & Metabolism., 102(2), 613-624.
CR  - [33] Liang, W. ve Sun, F. (2018). Identification of key genes of papillary thyroid cancer using integrated bioinformatics analysis. Journal of endocrinological investigation., 41(10), 1237-1245.
CR  - [34] Yamada, T. ve Masuda, M. (2017). Emergence of TNIK inhibitors in cancer therapeutics. Cancer science., 108(5), 818-823.
CR  - [35] Lopez-Bergami, P., Lau, E. ve Ronai, Z. E. (2010). Emerging roles of ATF2 and the dynamic AP1 network in cancer. Nature Reviews Cancer., 10(1), 65.
CR  - [36] Looyenga, B. D., Furge, K. A., Dykema, K. J., Koeman, J., Swiatek, P. J., Giordano, T. J., MacKeigan, J. P. (2011). Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas. Proceedings of the National Academy of Sciences., 108(4), 1439-1444.
CR  - [37] Eun, Y. G., Hong, I. K., Kim, S. K., Park, H. K., Kwon, S., Chung, D. H. ve Kwon, K. H. (2011). A polymorphism (rs1801018, Thr7Thr) of BCL2 is associated with papillary thyroid cancer in Korean population. Clinical and experimental otorhinolaryngology., 4(3), 149.
CR  - [38] Aytekin, T., Aytekin, A., Maralcan, G., Gokalp, M. A., Ozen, D., Borazan, E. ve Yilmaz, L. (2014). A cyclin D1 (CCND1) gene polymorphism contributes to susceptibility to papillary thyroid cancer in the Turkish population. Asian Pac. J. Cancer Prev., 15, 7181-7185.
CR  - [39] Da Yuan, X. Y., Yuan, Z., Zhao, Y. ve Guo, J. (2017). TLE1 function and therapeutic potential in cancer. Oncotarget., 8(9), 15971.
CR  - [40] Salgia, R., Sherman, S., Hong, D. S., Ng, C. S., Frye, J., Janisch, L., Kurzrock, R. (2008). A phase I study of XL184, a RET, VEGFR2, and MET kinase inhibitor, in patients (pts) with advanced malignancies, including pts with medullary thyroid cancer (MTC). Journal of Clinical Oncology., 26(15_suppl), 3522-3522.
CR  - [41] Bentzien, F., Zuzow, M., Heald, N., Gibson, A., Shi, Y., Goon, L., Zhao, L. (2013). In vitro and in vivo activity of cabozantinib (XL184), an inhibitor of RET, MET, and VEGFR2, in a model of medullary thyroid cancer. Thyroid., 23(12), 1569-1577.
CR  - [42] Buitrago, D., Keutgen, X. M., Crowley, M., Filicori, F., Aldailami, H., Hoda, R., Fahey, T. J. (2012). Intercellular adhesion molecule-1 (ICAM-1) is upregulated in aggressive papillary thyroid carcinoma. Annals of surgical oncology., 19(3), 973-980.
CR  - [43] Ennen, M., Klotz, R., Touche, N., Pinel, S., Barbieux, C., Besancenot, V., Domenjoud, L. (2013). DDB2: a novel regulator of NF-κB and breast tumor invasion. Cancer research., 73(16), 5040-5052.
CR  - [44] Han, C., Zhao, R., Liu, X., Srivastava, A., Gong, L., Mao, H., Wang, Q. E. (2014). DDB2 suppresses tumorigenicity by limiting the cancer stem cell population in ovarian cancer. Molecular Cancer Research., 12(5), 784-794.
CR  - [45] Qiao, S., Guo, W., Liao, L., Wang, L., Wang, Z., Zhang, R., Chen, Y. (2015). DDB2 is involved in ubiquitination and degradation of PAQR3 and regulates tumorigenesis of gastric cancer cells. Biochemical Journal., 469(3), 469-480.
CR  - [46] Huang, S., Fantini, D., Merrill, B. J., Bagchi, S., Guzman, G. ve Raychaudhuri, P. (2017). DDB2 is a novel regulator of Wnt signaling in colon cancer. Cancer research., 77(23), 6562-6575.
CR  - [47] Liu, Z., Zhou, G., Nakamura, M., Bai, Y., Li, Y., Ozaki, T., Kakudo, K. (2011). Retinoid X receptor γ up‐regulation is correlated with dedifferentiation of tumor cells and lymph node metastasis in papillary thyroid carcinoma. Pathology international., 61(3), 109-115.
UR  - https://doi.org/10.7240/jeps.536218
L1  - https://dergipark.org.tr/en/download/article-file/796810
ER  -