Meme kanseri hastalarında iki potansiyel eksen: hsa_circ_0001546/hsa-miR-532-5p/ZFHX3 ve hsa_circ_0025244/hsa-miR-210-5p/BTG2

Yıl 2025, Cilt: 50 Sayı: 3, 782 - 795, 30.09.2025

Fahrünnisa Abanoz , İlknur Suer , Murat Kaya , Asmaa Abuaisha , Selman Emiroğlu , Şükrü Öztürk

https://doi.org/10.17826/cumj.1679241

Öz

Amaç: Bu çalışmanın amacı, meme doku örneklerinde hsa_circ_0025244 ve hsa_circ_0001546’nın ekspresyon profillerini araştırmak ve bu sirküler RNA’lar için potansiyel regülatör aksisler önermektir.
Gereç ve Yöntem: Hsa_circ_0025244 ve hsa_circ_0001546’nın ekspresyon düzeyi, kantitatif polimeraz zincir reaksiyonu ile 55 tümör dokusu örneğinde (30 Luminal B ve 25 Luminal A) ve 55 bitişik normal doku örneğinde tespit edildi. Bunu takiben, potansiyel sünger mikroRNA'ları ve hedef genleri belirlemek amacıyla in silico veri tabanları ve PubMed literatür araştırması yapıldı. Son olarak, meme kanserinde daha çok araştırılmak üzere potansiyel regülatör aksisler önerildi.
Bulgular: Hem hsa_circ_0025244 hem de hsa_circ_0001546 normal dokulara kıyasla tüm tümör dokuda ve Luminal B tümör dokuda aşağı yönde regüle edildi. Bununla birlikte, sadece hsa_circ_0025244'ün normal dokulara kıyasla Luminal A tümörde aşağı regüle edildiği tespit edildi. İn silico veri tabanları ve PubMed araştırmalarımıza göre, en güçlü hedef mikroRNA/gen ilişkisinin hsa_circ_0025244 için hsa-miR-210-5p/BTG2 ve hsa_circ_0001546 için hsa-miR-532-5p/ZFHX3 olduğu belirlendi.
Sonuç: Bu çalışma, meme kanserinde ilk defa araştırılan hem hsa_circ_0025244 hem de hsa_circ_0001546’nın normal doku örneklerine kıyasla meme kanseri doku örneklerinde ekspresyonunun azaldığını göstermektedir.

Anahtar Kelimeler

Meme Kanseri , circRNA , miRNA , hsa_circ_0001546 , hsa_circ_0025244

Proje Numarası

Project No: 40807 and ADEP Project No: 39483

Two potential regulatory axes in breast cancer patients: hsa_circ_0001546/hsa-miR-532-5p/ZFHX3 and hsa_circ_0025244/hsa-miR-210-5p/BTG2

Öz

Purpose: This study aims to investigate the expression profiles of hsa_circ_0025244 and hsa_circ_0001546 in breast tissue samples and to propose potential regulatory axes for these circular RNAs.
Materials and Methods: The expression levels of hsa_circ_0025244 and hsa_circ_0001546 were determined in 55 tumor tissue samples (30 Luminal B and 25 Luminal A) and 55 adjacent normal tissue samples using quantitative polymerase chain reaction. Subsequently, in silico databases and PubMed literature searches were employed to identify potential sponge microRNAs and target genes. Finally, potential regulatory axes were proposed for further investigation in breast cancer.
Results: Both hsa_circ_0025244 and hsa_circ_0001546 were downregulated in total tumor tissues and Luminal B tumor tissues compared to normal tissues. However, only hsa_circ_0025244 was downregulated in Luminal A tumors compared to normal tissues. According to in silico tools and PubMed searches, the strongest target microRNA/gene association was determined to be hsa-miR-210-5p/BTG2 for hsa_circ_0025244 and hsa-miR-532-5p/ZFHX3 for hsa_circ_0001546.
Conclusion: This study demonstrates that, hsa_circ_0025244 and hsa_circ_0001546, investigated for the first time in breast cancer, were found to exhibit decreased expression in breast cancer compared to normal tissue samples.

Anahtar Kelimeler

Breast Cancer , circRNA , miRNA , hsa_circ_0001546 , hsa_circ_0025244

Etik Beyan

Ethical approval was received from the Istanbul University Ethics Committee.

Destekleyen Kurum

Financial support was provided by the Istanbul University-Scientific Research Projects Coordination Unit (Project No: 40807 and ADEP Project No: 39483).

Proje Numarası

Project No: 40807 and ADEP Project No: 39483

Teşekkür

We would like to thank Istanbul University Scientific Research Projects Coordination Unit (Project No: 40807 and ADEP Project No: 39483) for their support.

Kaynakça

• Cooper GM. The Cell: A Molecular Approach, 2nd edition. Sunderland (MA), Sinauer Associates. 2000.
• Absolute numbers, Incidence, Females, age [0-74], in 2022, World. https://gco.iarc.fr/today/en/dataviz/pie?mode=cancer&group_populations=1&sexes=2&populations=900&age_end=14 (accessed Jul 2024).
• Absolute numbers, Incidence, Females, age [0-74], in 2022 Türkiye. https://gco.iarc.fr/today/en/dataviz/pie?mode=cancer&group_populations=1&sexes=2&populations=792&age_end=14 (accessed Jul 2024).
• Age-Standardized Rate (World) per 100 000, Incidence and Mortality, Both sexes, age [0-74], in 2022, Türkiye, (Top 15 cancer sites). https://gco.iarc.fr/today/en/dataviz/bars?types=0_1&mode=cancer&group_populations=1&sort_by=value1&sexes=2&populations=792&age_end=14 (accessed Jul 2024).
• Age-Standardized Rate (World) per 100 000, Incidence and Mortality, Both sexes, age [0-74], in 2022, World, (Top 15 cancer sites). https://gco.iarc.fr/today/en/dataviz/bars?types=0_1&mode=cancer&group_populations=1&sort_by=value1&sexes=2&populations=900&age_end=14 (accessed Jul 2024).
• Meme Kanseri. https://www.kanser.org/saglik/toplum/kanser-turleri-alt-kategori/meme-kanseri (accessed Dec 2023).
• Orrantia-Borunda E, Anchondo-Nuñez P, Acuña-Aguilar LE, Gómez-Valles FO, Ramírez-Valdespino CA. Breast Cancer [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK583808/ (accessed Dec 2023). (Ed Mayrovitz HN). Brisbane (AU), Exon Publications. 2022.
• Alfonse M, Aref MM, M.Salem A-B. An Ontology-based system for cancer diseases knowledge management. International Journal of Information Engineering and Electronic Business. 2014;6:55-63.
• Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281-97.
• Bhaskaran M, Mohan M. MicroRNAs: history, biogenesis, and their evolving role in animal development and disease. Vet Pathol. 2014;51:759-74.
• Esmaeilzadeh Aghjeh M, Suer I, Dirim AB, Kaya M, Ozturk S. Advances in focal segmental glomerulosclerosis research: genetic causes to non-coding RNAs. Mol Biol Rep. 2025;52:384.
• Wang, Y, Huang S. Cancer and noncoding RNAs. Academic Press, Boston, 2018.
• Radanova M, Mihaylova G, Nazifova-Tasinova N, Levkova M, Tasinov O, Ivanova D et al. Oncogenic functions and clinical significance of circular RNAs in colorectal cancer. Cancers (Basel) 2021;13:3395.
• Zhang B, Pan X, Cobb GP, Anderson TA. microRNAs as oncogenes and tumor suppressors. Dev Biol. 2007;302:1-12.
• Capik O, Sanli F, Kurt A, Ceylan O, Suer I, Kaya M et al. CASC11 promotes aggressiveness of prostate cancer cells through miR-145/IGF1R axis. Prostate Cancer Prostatic Dis. 2021;24:891-902.
• Huang M, He YR, Liang LC, Huang Q, Zhu ZQ. Circular RNA hsa_circ_0000745 may serve as a diagnostic marker for gastric cancer. World J Gastroenterol. 2017;23:6330-38.
• Qiu X, Zhang Q, Deng Q, Li Q. Circular RNA hsa_circ_0012673 promotes breast cancer progression via miR-576-3p/SOX4 axis. Mol Biotechnol. 2023;65:61-71.
• Xu X, Zhang J, Tian Y, Gao Y, Dong X, Chen W et al. CircRNA inhibits DNA damage repair by interacting with host gene. Mol Cancer. 2020;19:128.
• Ding X, Ding E, Yin H, Mei P, Chen H, Han L et al. Serum hsa-circ-0025244 as a biomarker in Chinese occupational mercury-exposed population and mediate apoptosis through JNK/p38 MAPK signaling pathway. J Trace Elem Med Biol. 2022;74:127057.
• Liu T, Lu Q, Liu J, Xie S, Feng B, Zhu W et al. Circular RNA FAM114A2 suppresses progression of bladder cancer via regulating ∆NP63 by sponging miR-762. Cell Death Dis. 2020;11:47.
• Tsui NB, Ng EK, Lo YM. Molecular analysis of circulating RNA in plasma. Methods Mol Biol. 2006;336:123-34.
• Lai M, Li D, Liu M, Zhang R, Wang L, Peng W et al. CircFAM114A2 inhibits the progression of hepatocellular carcinoma via miR-630/HHIP axis. Cancer Med. 2023;12:12553-12568.
• Lv J, Zhou Z, Wang J, Yang X, Yu H, Han J et al. CircFAM114A2 promotes cisplatin sensitivity via miR-222-3p/P27 and miR-146a-5p/P21 cascades in urothelial carcinoma. Front Oncol. 2021;11:659166.
• Wu Q, Wang H, Liu L, Zhu K, Yu W, Guo J. Hsa_circ_0001546 acts as a miRNA-421 sponge to inhibit the chemoresistance of gastric cancer cells via ATM/Chk2/p53-dependent pathway. Biochem Biophys Res Commun. 2020;521:303-309.
• Chai B, Wu Y, Yang H, Fan B, Cao S, Zhang X et al. Tau aggregation-dependent lipid peroxide accumulation driven by the hsa_circ_0001546/14-3-3/CAMK2D/Tau complex inhibits epithelial ovarian cancer peritoneal metastasis. Adv Sci (Weinh). 2024;11:e2310134.
• Huang G, Sun D, Hu X, Wang Q. CircFAM114A2 suppresses cell proliferation, migration, and invasion of colorectal cancer through sponging miR-647 to upregulate DAB2IP expression. Biochem Genet. 2024;63:3414-3427.
• Kaya M, Abuaisha A, Süer İ, Alptekin MS, Abanoz F, Emiroğlu S et al. Overexpression of CDC25A, AURKB, and TOP2A genes could be an important clue for luminal A breast cancer. Eur J Breast Health. 2024;20:284-91.
• Erdogan C, Suer I, Kaya M, Ozturk S, Aydin N, Kurt Z. Bioinformatics analysis of the potentially functional circRNA-miRNA-mRNA network in breast cancer. PLoS One. 2024;19:e0301995.
• Huang X, Song C, Zhang J, Zhu L, Tang H. Circular RNAs in breast cancer diagnosis, treatment and prognosis. Oncol Res. 2023;32:241-49.
• Kaya M, Abuaisha A, Suer I, Emiroglu S, Abanoz F, Palanduz S et al. Turmeric inhibits MDA-MB-231 cancer cell proliferation, altering miR-638-5p and its potential targets. Eur J Breast Health. 2024;20:102-9.
• Jordan-Alejandre E, Campos-Parra AD, Castro-López DL, Silva-Cázares MB. Potential miRNA use as a biomarker: from breast cancer diagnosis to metastasis. Cells. 2023;12:525.
• Li X, Dai A, Tran R, Wang J. Identifying miRNA biomarkers for breast cancer and ovarian cancer: a text mining perspective. Breast Cancer Res Treat. 2023;201:5-14.
• Petri BJ, Klinge CM. Regulation of breast cancer metastasis signaling by miRNAs. Cancer Metastasis Rev. 2020;39:837-86.
• Venkatesh J, Wasson MD, Brown JM, Fernando W, Marcato P. LncRNA-miRNA axes in breast cancer: novel points of interaction for strategic attack. Cancer Lett. 2021;509:81-8.
• Xu J, Wu KJ, Jia QJ, Ding XF. Roles of miRNA and lncRNA in triple-negative breast cancer. J Zhejiang Univ Sci B. 2020;21:673-89.
• Yang M, Zhang Y, Li M, Liu X, Darvishi M. The various role of microRNAs in breast cancer angiogenesis, with a special focus on novel miRNA-based delivery strategies. Cancer Cell Int. 2023;23:24. Erratum in: Cancer Cell Int. 2023;23:55.
• Cao L, Wang M, Dong Y, Xu B, Chen J, Ding Y et al. Circular RNA circRNF20 promotes breast cancer tumorigenesis and Warburg effect through miR-487a/HIF-1α/HK2. Cell Death Dis. 2020;11:145.
• Fu B, Liu W, Zhu C, Li P, Wang L, Pan L et al. Circular RNA circBCBM1 promotes breast cancer brain metastasis by modulating miR-125a/BRD4 axis. Int J Biol Sci. 2021;17:3104-17.
• Ghazimoradi MH, Babashah S. The role of circRNA/miRNA/mRNA axis in breast cancer drug resistance. Front Oncol. 2022;12:966083.
• Liu Z, Zhou Y, Liang G, Ling Y, Tan W, Tan L et al. Circular RNA hsa_circ_001783 regulates breast cancer progression via sponging miR-200c-3p. Cell Death Dis. 2019;10:55.
• Xu L, Lyu M, Yang S, Zhang J, Yu D. CircRNA expression profiles of breast cancer and construction of a circRNA-miRNA-mRNA network. Sci Rep. 2022;12:17765.
• Zhang M, Bai X, Zeng X, Liu J, Liu F, Zhang Z. circRNA-miRNA-mRNA in breast cancer. Clin Chim Acta. 2021;523:120-30.
• Bar I, Theate I, Haussy S, Beniuga G, Carrasco J, Canon JL et al. MiR-210 is overexpressed in tumor-infiltrating plasma cells in triple-negative breast cancer. J Histochem Cytochem. 2020;68:25-32.
• Liu W, Jiang D, Gong F, Huang Y, Luo Y, Rong Y et al. miR-210-5p promotes epithelial-mesenchymal transition by inhibiting PIK3R5 thereby activating oncogenic autophagy in osteosarcoma cells. Cell Death Dis. 2020;11:93.
• He G, Pang R, Han J, Jia J, Ding Z, Bi W et al. TINCR inhibits the proliferation and invasion of laryngeal squamous cell carcinoma by regulating miR-210/BTG2. BMC Cancer. 2021;21:753.
• BTG2 BTG anti-proliferation factor 2 [ Homo sapiens (human) ]. https://www.ncbi.nlm.nih.gov/gene/7832 (accessed Nov 2024).
• Wang R, Wang R, Tian J, Wang J, Tang H, Wu T et al. BTG2 as a tumor target for the treatment of luminal A breast cancer. Exp Ther Med. 2022;23:339.
• Huang L, Tang X, Shi X, Su L. miR-532-5p promotes breast cancer proliferation and migration by targeting RERG. Exp Ther Med. 2020;19:400-8.
• ZFHX3 zinc finger homeobox 3 [ Homo sapiens (human) ]. https://www.ncbi.nlm.nih.gov/gene/463 (accessed Aug 2024).
• Dayoub A, Fokin AI, Lomakina ME, James J, Plays M, Jacquin T et al. Inactivation of PTEN and ZFHX3 in mammary epithelial cells alters patterns of collective cell migration. Int J Mol Sci. 2022;24:313.
• Song K, Farzaneh M. Signaling pathways governing breast cancer stem cells behavior. Stem Cell Res Ther. 2021;12:245.
• Swanton C, Bernard E, Abbosh C, André F, Auwerx J, Balmain A et al. Embracing cancer complexity: hallmarks of systemic disease. Cell. 2024;187:1589-616.
• Toden S, Zumwalt TJ, Goel A. Non-coding RNAs and potential therapeutic targeting in cancer. Biochim Biophys Acta Rev Cancer. 2021;1875:188491.
• Yang J, Meng X, Pan J, Jiang N, Zhou C, Wu Z et al. CRISPR/Cas9-mediated noncoding RNA editing in human cancers. RNA Biol. 2018;15:35-43.