Mukaddes AVŞAR SARAL, Nurcan ÇIRAK, Gözde TÜRKCAN, Demet A. ÖDEMİŞ, Şeref Buğra TUNÇER, Seda K. ERCİYAS, Özge Ş. ERDOĞAN, Makbule TAMBAŞ, Hülya YAZICI

Metastatik Akciğer Kanserli Hastaların Periferik Kanında Yeni Aday Biyomarker: Yüksek DICER1 Ekspresyon Düzeyi

Amaç: Akciğer kanseri, dünyada kansere bağlı insidans ve mortalite açısından birinci sırada yer almaktadır. Kanserin multifaktoriyel bir hastalık olması nedeniyle kanserle ilişkili mekanizmaların aydınlatılmaya çalışılması oldukça önem taşımaktadır. Kanserle yakından ilgili olan miRNA aktivitesinin çeşitli mekanizmalarla bozulduğu bilinmektedir. Bu mekanizmalardan biri de miRNA işlenmesi sırasında meydana gelen moleküler değişikliklerdir. DICER1, microRNA biyogenezinde önemli bir yere sahiptir. Çalışmamızda, akciğer kanserli hastaların periferik kan lenfositlerinde DICER1 gen ifade düzeyinin sağlıklı kişilerle karşılaştırılarak metastatik akciğer kanseri gelişimindeki etkisinin araştırılması amaçlanmıştır. Materyal ve Metot: Çalışma grubu yeni tanı almış ve daha önce hiç tedavi görmemiş 47 akciğer kanserli hasta ile 45 sağlıklı kişinin periferik kan örneklerinden oluşturuldu. Araştırılan DICER1 hedef geni, HPRT1 referans geni ile eş zamanlı olarak Gerçek-Zamanlı PCR yöntemiyle incelendi. Akciğer kanser hastalarına ait gen ekspresyon düzeyi ile sağlıklı kişilerden oluşan kontrol grubu DICER1 gen ekspresyon sonuçları karşılaştırıldı. Sonuçlar 2-ΔΔCT metodu kullanılarak değerlendirildi. Sonuçlar: Akciğer kanser hastalarının periferik kan lenfositlerinde DICER1 gen ifade düzeyinin (2-ΔΔCt) kontrol grubuna göre 1,756 kat arttığı, bu artmış ekspresyon düzeyinin istatistiksel açıdan anlamlı (p

Anahtar Kelimeler:

Akciğer kanseri, , DICER1, , Metastaz, , Gen ekspresyonu

A New Candidate Biomarker in Peripheral Blood of Patients with Metastatic Lung Cancer: High DICER1 Expression Level

Objective: Lung cancer is in the first place in the world in terms of cancerrelated incidence and mortality. Since cancer is a multifactorial disease, it is very important to try to illuminate the mechanisms associated with cancer. It is known that miRNA activity, which is closely related to carcinogenesis, is impaired with various mechanisms. One of these mechanisms is the molecular changes that occur during miRNA process. DICER1 has an important function in microRNA biogenesis. In our study, it was aimed to investigate the effect of DICER1 gene expression level on metastatic lung cancer development. Material and Method: The study groups consist of peripheral blood samples of 47 patients with metastatic lung cancer who had recently been diagnosed but had never been treated and 45 healthy people. The investigated DICER1 target gene was examined simultaneously with the HPRT1 reference gene by using the Real-Time PCR method. The results of DICER1 gene expression levels of patients and those of healthy individuals were compared. The results were evaluated by using the 2-ΔΔCT method. Results: The expression level of DICER1 gene in the peripheral blood lymphocytes of patients with metastatic lung cancer was increased by 1.756 (2-ΔΔCt) fold compared to the healthy control group and the increased expression level was statistically significant, p

Keywords:

Lung cancer, , DICER1, , Metastasis, , Gene expression,

PDF

___

[1] Alberg, A. J., Ford, J. G., Samet, J. M., & American College of Chest, P. (2007). Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest, 132(3 Suppl), 29S-55S. doi: 10.1378/chest.07-1347
[2] Bade, B. C., & Dela Cruz, C. S. (2020). Lung Cancer 2020: Epidemiology, Etiology, and Prevention. Clin Chest Med, 41(1), 1-24. doi: 10.1016/j.ccm.2019.10.001
[3] Boeri, M., Pastorino, U., & Sozzi, G. (2012). Role of microRNAs in lung cancer: microRNA signatures in cancer prognosis. Cancer J, 18(3), 268-274. doi: 10.1097/PPO.0b013e318258b743
[4] Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 68(6), 394-424. doi: 10.3322/caac.21492
[5] Cagle, P. T., Allen, T. C., & Olsen, R. J. (2013). Lung cancer biomarkers: present status and future developments. Arch Pathol Lab Med, 137(9), 1191-1198. doi: 10.5858/arpa.2013-0319-CR
[6] Chatziandreou, I., Tsioli, P., Sakellariou, S., Mourkioti, I., Giannopoulou, I., Levidou, G., . . . Saetta, A. A. (2015). Comprehensive Molecular Analysis of NSCLC; Clinicopathological Associations. PLoS One, 10(7), e0133859. doi: 10.1371/journal.pone.0133859
[7] Chen, X., Li, W. F., Wu, X., Zhang, H. C., Chen, L., Zhang, P. Y., . . . Tang, K. F. (2017). Dicer regulates non-homologous end joining and is associated with chemosensitivity in colon cancer patients. Carcinogenesis, 38(9), 873-882. doi: 10.1093/carcin/bgx059
[8] Cheng, L., Alexander, R. E., Maclennan, G. T., Cummings, O. W., Montironi, R., Lopez-Beltran, A., . . . Zhang, S. (2012). Molecular pathology of lung cancer: key to personalized medicine. Mod Pathol, 25(3), 347-369. doi: 10.1038/modpathol.2011.215
[9] Chiosea, S., Jelezcova, E., Chandran, U., Acquafondata, M., McHale, T., Sobol, R. W., & Dhir, R. (2006). Up-regulation of dicer, a component of the MicroRNA machinery, in prostate adenocarcinoma. Am J Pathol, 169(5), 1812-1820. doi: 10.2353/ajpath.2006.060480
[10] Chiosea, S., Jelezcova, E., Chandran, U., Luo, J., Mantha, G., Sobol, R. W., & Dacic, S. (2007). Overexpression of Dicer in precursor lesions of lung adenocarcinoma. Cancer Res, 67(5), 2345-2350. doi: 10.1158/0008- 5472.CAN-06-3533
[11] Del Vescovo, V., & Denti, M. A. (2015). microRNA and Lung Cancer. Adv Exp Med Biol, 889, 153-177. doi: 10.1007/978-3-319-23730-5_9
[12] Erson, A. E., & Petty, E. M. (2009). miRNAs and cancer: New research developments and potential clinical applications. Cancer Biol Ther, 8(24), 2317-2322. doi: 10.4161/cbt.8.24.10765
[13] Foulkes, W. D., Priest, J. R., & Duchaine, T. F. (2014). DICER1: mutations, microRNAs and mechanisms. Nat Rev Cancer, 14(10), 662- 672. doi: 10.1038/nrc3802
[14] Gurtner, A., Falcone, E., Garibaldi, F., & Piaggio, G. (2016). Dysregulation of microRNA biogenesis in cancer: the impact of mutant p53 on Drosha complex activity. J Exp Clin Cancer Res, 35, 45. doi: 10.1186/s13046-016-0319-x
[15] Iwakawa, H. O., & Tomari, Y. (2015). The Functions of MicroRNAs: mRNA Decay and Translational Repression. Trends Cell Biol, 25(11), 651-665. doi: 10.1016/j.tcb.2015.07.011
[16] Jakymiw, A., Patel, R. S., Deming, N., Bhattacharyya, I., Shah, P., Lamont, R. J., . . . Chan, E. K. (2010). Overexpression of dicer as a result of reduced let-7 MicroRNA levels contributes to increased cell proliferation of oral cancer cells. Genes Chromosomes Cancer, 49(6), 549-559. doi: 10.1002/gcc.20765
[17] Karube, Y., Tanaka, H., Osada, H., Tomida, S., Tatematsu, Y., Yanagisawa, K., . . . Takahashi, T. (2005). Reduced expression of Dicer associated with poor prognosis in lung cancer patients. Cancer Sci, 96(2), 111-115. doi: 10.1111/j.1349-7006.2005.00015.x
[18] Lee, S. S., Min, H., Ha, J. Y., Kim, B. H., Choi, M. S., & Kim, S. (2019). Dysregulation of the miRNA biogenesis components DICER1, DROSHA, DGCR8 and AGO2 in clear cell renal cell carcinoma in both a Korean cohort and the cancer genome atlas kidney clear cell carcinoma cohort. Oncol Lett, 18(4), 4337-4345. doi: 10.3892/ol.2019.10759
[19] Macfarlane, L. A., & Murphy, P. R. (2010). MicroRNA: Biogenesis, Function and Role in Cancer. Curr Genomics, 11(7), 537-561. doi: 10.2174/138920210793175895
[20] Malhotra, J., Malvezzi, M., Negri, E., La Vecchia, C., & Boffetta, P. (2016). Risk factors for lung cancer worldwide. Eur Respir J, 48(3), 889- 902. doi: 10.1183/13993003.00359-2016
[21] Pampalakis, G., Diamandis, E. P., Katsaros, D., & Sotiropoulou, G. (2010). Down-regulation of dicer expression in ovarian cancer tissues. Clin Biochem, 43(3), 324-327. doi: 10.1016/j.clinbiochem.2009.09.014
[22] Prodromaki, E., Korpetinou, A., Giannopoulou, E., Vlotinou, E., Chatziathanasiadou, M., Papachristou, N. I., . . . Papachristou, D. J.
(2015). Expression of the microRNA regulators Drosha, Dicer and Ago2 in non-small cell lung carcinomas. Cell Oncol (Dordr), 38(4), 307-317. doi: 10.1007/s13402-015-0231-y
[23] Ramalingam, S. S., Owonikoko, T. K., & Khuri, F. R. (2011). Lung cancer: New biological insights and recent therapeutic advances. CA Cancer J Clin, 61(2), 91-112. doi: 10.3322/caac.20102
[24] Rupaimoole, R., & Slack, F. J. (2017). MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov, 16(3), 203-222. doi: 10.1038/nrd.2016.246
[25] To, S. K. Y., Mak, A. S. C., Eva Fung, Y. M., Che, C. M., Li, S. S., Deng, W., . . . Wong, A. S. T. (2017). beta-catenin downregulates Dicer to promote ovarian cancer metastasis. Oncogene, 36(43), 5927-5938. doi: 10.1038/onc.2017.185
[26] Torre, L. A., Siegel, R. L., & Jemal, A. (2016). Lung Cancer Statistics. Adv Exp Med Biol, 893, 1-19. doi: 10.1007/978-3-319-24223-1_1
[27] Villalobos, P., & Wistuba, II. (2017). Lung Cancer Biomarkers. Hematol Oncol Clin North Am, 31(1), 13-29. doi: 10.1016/j.hoc.2016.08.006
[28] Wakelee, H. A., Chang, E. T., Gomez, S. L., Keegan, T. H., Feskanich, D., Clarke, C. A., . . . West, D. W. (2007). Lung cancer incidence in never smokers. J Clin Oncol, 25(5), 472-478. doi: 10.1200/JCO.2006.07.2983
[29] Zhang, L., Huang, J., Yang, N., Greshock, J., Megraw, M. S., Giannakakis, A., . . . Coukos, G. (2006). microRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci U S A, 103(24), 9136-9141. doi: 10.1073/pnas.0508889103