Meme Kanseri Hastalarında hTERT Gen Ekspresyonunun Klinikopatolojik Önemi

Year 2022, , 22 - 27, 14.01.2022

Ebubekir Dirican , Burak Kankaya Zeynep Tatar

https://doi.org/10.33631/sabd.1055209

Abstract

Amaç: Bu çalışma, meme kanserinde insan telomeraz ters transkriptaz (hTERT) genin mRNA ekspresyonunun klinik önemini incelemeyi ve klinikopatolojik rolünü araştırmayı amaçlamıştır. hTERT geni hücre proliferasyonu, apoptoz ve hücre invazyonu gibi olaylarda rol almaktadır. Yüksek hTERT mRNA ekspresyonunun meme kanseri, mide, akciğer, glioblastoma, baş ve boyun gibi solid tümörlerde kötü prognoz ile ilişkili olduğu bildirilmektedir.
Gereç ve Yöntemler: 59 meme kanser ve sağlıklı kan örneklerinin RNA izolasyonları gerçekleştirildi. hTERT geni mRNA ekspresyonu Gerçek Zamanlı Polimeraz Zincir Reaksiyonu (RT-PZR) yöntemi ile analiz edildi. mRNA ekspresyon sonuçları 2-∆∆ct metoduyla kanserli ve sağlıklı örneklerde değerlendirildi. Klinik veriler toplandı ve bu verilerin hTERT gen ekspresyonu ile ilişkisi istatiksel olarak değerlendirildi.
Bulgular: Meme kanser hastalarında hTERT geni mRNA ekspresyonu sağlıklı örneklere kıyasla anlamlı derecede yüksekti (p=0,0211). Düşük hTERT geni ekspresyonu östrojen reseptör (ÖR) (+) ve insan epidermal büyüme faktör reseptörü 2 (HER 2) (+) olan hastalarda anlamlı derecede ilişkiliydi (sırasıyla p=0,0464; p=0,0080). hTERT geni ekspresyonu histolojik derece (grade) 3 hastalarda derece 2’ye kıyasla yüksek anlamlı bulundu (p=0,0389). Bununla birlikte hTERT ekspresyonun bazal benzeri histolojik tipte luminal A ve luminal B’ye kıyasla anlamlı derecede yüksek olduğu gösterildi (sırasıyla p=0,0160; p=0,0008).
Sonuç: Çalışmamızın bulguları, meme kanser hastalarında hTERT gen ekspresyonunun sağlıklı örneklere göre anlamlı olarak daha yüksek olduğunu gösterdi. Anormal hTERT gen ekspresyonu kanserojenez veya teşhiste önemli bir rol oynayabilir.

Keywords

Meme kanseri, hTERT, ÖR, PZR, bazal benzeri, luminal

Clinicopathological Significance of hTERT gene expression in Breast Cancer Patients

Abstract

Aim: This study aimed to examine the clinical significance of the mRNA expression of the human telomerase reverse transcriptase (hTERT) gene in breast cancer (BCa) and to investigate its clinicopathological role. The hTERT gene is involved in events such as cell proliferation, apoptosis and cell invasion. It has been reported that high hTERT mRNA expression is associated with poor prognosis in solid tumors such as BCa, stomach, lung, glioblastoma, head and neck.
Material and Methods: RNA isolations of 59 BCa and healthy blood samples were performed. hTERT gene mRNA expression was analyzed by Real-Time-Polymerase Chain Reaction (RT-PCR) method. mRNA expression results were evaluated in cancer and healthy samples by the 2-∆∆ct method. Clinical data were collected and the relationship of these data with hTERT gene expression was evaluated statistically.
Results: hTERT gene mRNA expression in BCa patients was significantly higher than in healty samples (p=0,0211). Low hTERT gene expression was significantly associated with estrogen receptor (ER) (+) and human epidermal growth factor receptor 2 (HER 2) (+) patients (p=0.0464; p=0.0080, respectively). hTERT gene expression was found to be higher in histological grade 3 patients compared to grade 2 (p=0.0389). Moreover, hTERT expression was shown to be significantly higher in basal-like histological type compared to luminal A and luminal B (p=0.0160; p=0.0008, respectively).
Conclusion: The findings of our study showed that hTERT gene expression was significantly higher in BCa patients than in healthy samples. Abnormal hTERT gene expression may play an important role in carcinogenesis or diagnosis.

Keywords

Breast cancer, hTERT, PCR, basal like, luminal

References

• Zhang J, Tian Q, Zhang M, Wang H, Wu L, Yang J. Immune-related biomarkers in triple-negative breast cancer. Breast Cancer [Internet]. 2021 Apr 9; Available from: https://link.springer.com/10.1007/s12282-021-01247-8
• Elsers D, Temerik DF, Attia AM, Hadia A, Hussien MT. Prognostic role of ALK-1 and h-TERT expression in glioblastoma multiforme: correlation with ALK gene alterations. J Pathol Transl Med [Internet]. 2021 May 11; Available from: http://www.ncbi.nlm.nih.gov/pubmed/33966367
• Bieche I, Nogues C, Paradis V, Olivi M, Bedossa P, Lidereau R, et al. Quantitation of hTERT gene expression in sporadic breast tumors with a real-time reverse transcription-polymerase chain reaction assay. Clin Cancer Res. 2000; 6(2): 452-9.
• Zhang J, Tian Q, Zhang M, Wang H, Wu L, Yang J. Immune-related biomarkers in triple-negative breast cancer. 1994; 266(5193): 2011-5.
• Buseman CM, Wright WE, Shay JW. Is telomerase a viable target in cancer? Mutat Res. 2012; 730(1-2): 90-7.
• Wright WE, Piatyszek MA, Rainey WE, Byrd W, Shay JW. Telomerase activity in human germline and embryonic tissues and cells. Dev Genet. 1996; 18(2): 173-9.
• Low KC, Tergaonkar V. Telomerase: central regulator of all of the hallmarks of cancer. Trends Biochem Sci. 2013; 38(9): 426-34.
• Wang K, Wang R-L, Liu J-J, Zhou J, Li X, Hu W-W, et al. The prognostic significance of hTERT overexpression in cancers: A systematic review and meta-analysis. Medicine (Baltimore). 2018; 97(35): e11794.
• Kirkpatrick KL, Mokbel K. The significance of human telomerase reverse transcriptase (hTERT) in cancer. Eur J Surg Oncol. 2001; 27(8): 754-60.
• Yoon AJ, Santella RM, Wang S, Kutler DI, Carvajal RD, Philipone E, et al. MicroRNA-based cancer mortality risk scoring system and htert expression in early-stage oral squamous cell carcinoma. J Oncol. 2021; 2021: 8292453.
• Castiglia P, Sanna V, Azara A, De Miglio MR, Murgia L, Pira G, et al. Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms in breast cancer: a Sardinian preliminary case-control study. Int J Med Sci. 2019; 16(8): 1089-95.
• Bagheri R, Sanaat Z, Zarghami N. Synergistic Effect of Free and Nano-encapsulated Chrysin-Curcumin on Inhibition of hTERT Gene Expression in SW480 Colorectal Cancer Cell Line. Drug Res (Stuttg). 2018; 68(06): 335-43.
• Jafri MA, Ansari SA, Alqahtani MH, Shay JW. Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Med. 2016;8(1):69. A
• Wright WE, Piatyszek MA, Rainey WE, Byrd W, Shay JW. Telomerase activity in human germline and embryonic tissues and cells. Dev Genet. 1996; 18(2): 173-9.
• Takakura M, Kyo S, Kanaya T, Hirano H, Takeda J, Yutsudo M, et al. Cloning of human telomerase catalytic subunit (hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer Res. 1999; 59(3): 551-7.
• Elkak A, Mokbel R, Wilson C, Jiang WG, Newbold RF, Mokbel K. hTERT mRNA expression is associated with a poor clinical outcome in human breast cancer. Anticancer Res. 2006; 26(6C): 4901-4.
• Kirkpatrick KL, Mokbel K. The significance of human telomerase reverse transcriptase (hTERT) in cancer. Eur J Surg Oncol. 2001; 27(8): 754-60.
• Çalışkan Can E, Atalay MC, Miser Salihoğlu E, Yalçıntaş Arslan Ü, Şimşek HB, Yardım Akaydın S. Normal and tumour tissue mRNA expressions of telomerase complex genes in several types of cancer. Balkan Med J. 2017; 34(3): 269-74.
• Hines WC, Fajardo AM, Joste NE, Bisoffi M, Griffith JK. Quantitative and spatial measurements of telomerase reverse transcriptase expression within normal and malignant human breast tissues. Mol Cancer Res. 2005; 3(9): 503-9.
• Farajzadeh R, Pilehvar-Soltanahmadi Y, Dadashpour M, Javidfar S, Lotfi-Attari J, Sadeghzadeh H, et al. Nano-encapsulated metformin-curcumin in PLGA/PEG inhibits synergistically growth and hTERT gene expression in human breast cancer cells. Artif cells, nanomedicine, Biotechnol. 2018; 46(5): 917-25.
• Yu P, Shen X, Yang W, Zhang Y, Liu C, Huang T. ZEB1 stimulates breast cancer growth by up-regulating hTERT expression. Biochem Biophys Res Commun. 2018; 495(4): 2505-11.
• Kazemi Noureini S, Fatemi L, Wink M. Telomere shortening in breast cancer cells (MCF7) under treatment with low doses of the benzylisoquinoline alkaloid chelidonine. Lustig AJ, editor. PLoS One. 2018; 13(10): e0204901.
• Zhang W, Veisaga ML, Barbieri MA. Role of RIN1 on telomerase activity driven by EGF-Ras mediated signaling in breast cancer. Exp Cell Res. 2020; 396(2): 112318.
• Mathiyazhagan J, Kodiveri Muthukaliannan G. Combined Zingiber officinale and Terminalia chebula Induces Apoptosis and Modulates mTOR and hTERT Gene Expressions in MCF-7 Cell Line. Nutr Cancer. 2020; 1-10.
• Romaniuk-Drapała A, Totoń E, Konieczna N, Machnik M, Barczak W, Kowal D, et al. hTERT downregulation attenuates resistance to DOX, impairs FAK-mediated adhesion, and leads to autophagy induction in breast cancer cells. Cells. 2021; 10(4): 867.