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The effect of miR-640 on metastatic genes in breast cancer

Yıl 2026, Cilt: 65 Sayı: 1, 1 - 10, 09.03.2026

İsmail Mert Alkaç , Çığır Biray Avcı

https://doi.org/10.19161/etd.1771783
https://izlik.org/JA85MA83PB

Öz

Aim: Despite the implementation of numerous treatment protocols for breast cancer, which remains a leading cause of cancer-related mortality among women, metastasis continues to pose a major challenge during therapy. This results in prolonged treatment durations, poor prognosis, and the need to manage newly emerging cancer types due to the development of secondary tumors. This study aimed to investigate the anti-metastatic effects of miR-640 previously shown to influence tumorigenesis, angiogenesis, inflammatory responses, and metastasis in various cancers, including breast cancer—by examining its potential to downregulate metastasis-associated genes.
Materials and Methods: To assess the anti-metastatic potential of miR-640, functional assays—including wound healing, Annexin V, analyses—were conducted following lipofectamine-mediated transfection in MCF7 and MDA-MB-231 breast cancer cell lines. Additionally, expression levels of metastasis-associated genes (WNT7A, TMSB4X, NFIB, ZEB2, IL11, AURKA, CAV1, SLC7A11, PDK1, and PTK6) identified as potential targets of miR-640, were analyzed.
Results: Successful transfection was achieved in both cell lines, with a significant increase in miR-640 expression (~25-fold in MCF7, ~5-fold in MDA-MB-231). Statistically significant effects of miR-640 were observed in wound healing and Annexin V assays following transfection. Additionally, gene expression analyses revealed significant reductions in the expression of metastasis-related genes WNT7A, TMSB4X, NFIB, IL11, AURKA, CAV1, SLC7A11, PDK1, PTK6 in the MCF7 cell line, and in WNT7A, NFIB and ZEB2 genes in the MDA-MB-231 cell line.
Conclusion: This study is the first to demonstrate that miR-640 exerts an anti-metastatic effect in breast cancer by suppressing metastatic formation through the downregulation of metastasis-related genes. The findings show that cell migration is significantly inhibited in the transfected cell lines and suggest that miR-640 may serve as a potential therapeutic molecule

Anahtar Kelimeler

Metastasis breast cancer gene regulation miR-640.

Destekleyen Kurum

This study was supported by the TUSEB (Presidency of Turkish Health Institutes) A GROUP EMERGENCY Research and Development PROJECT SUPPORT PROGRAM No. 35685.

Proje Numarası

35685

Teşekkür

This study was supported by the TUSEB (Presidency of Turkish Health Institutes) A GROUP EMERGENCY Research and Development PROJECT SUPPORT PROGRAM No. 35685.

Kaynakça

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  • Awolaran, O., Brooks, S. A., & Lavender, V. (2016). Breast cancer osteomimicry and its role in bone specific metastasis; an integrative, systematic review of preclinical evidence. Breast (Edinburgh, Scotland), 30, 156–171. doi:10.1016/J.BREAST.2016.09.017
  • Brasó-Maristany, F., Paré, L., Chic, N., Martínez-Sáez, O., Pascual, T., Mallafré-Larrosa, M., … Prat, A. (2022). Gene expression profiles of breast cancer metastasis according to organ site. Molecular Oncology, 16(1), 69. doi:10.1002/1878-0261.13021
  • Castanon, I., Von Stetina, S., Kass, J., & Baylies, M. K. (2001). Dimerization partners determine the activity of the Twist bHLH protein during Drosophila mesoderm development. Development, 128(16), 3145–3159. doi:10.1242/DEV.128.16.3145
  • Cha, S., Lee, E., & Won, H. H. (2021). Comprehensive characterization of distinct genetic alterations in metastatic breast cancer across various metastatic sites. Npj Breast Cancer 2021 7:1, 7(1), 1–11. doi:10.1038/s41523-021-00303-y
  • Chhichholiya, Y., Ruthuparna, M., Velagaleti, H., & Munshi, A. (2023). Brain metastasis in breast cancer: focus on genes and signaling pathways involved, blood–brain barrier and treatment strategies. Clinical and Translational Oncology 2023 25:5, 25(5), 1218–1241. doi:10.1007/S12094-022-03050-Z
  • Coleman, R. E., Smith, P., & Rubens, R. D. (1998). Clinical course and prognostic factors following bone recurrence from breast cancer. British Journal of Cancer 1998 77:2, 77(2), 336–340. doi:10.1038/bjc.1998.52
  • Friedel, G., Pastorino, U., Ginsberg, R. J., Goldstraw, P., Johnston, M., Pass, H., … Toomes, H. (2002). Results of lung metastasectomy from breast cancer: prognostic criteria on the basis of 467 cases of the international registry of lung metastases. European Journal of Cardio-Thoracic Surgery, 22(3), 335–344. doi:10.1016/S1010-7940(02)00331-7
  • Gennari, A., Conte, P. F., Rosso, R., Orlandini, C., & Bruzzi, P. (2005). Survival of metastatic breast carcinoma patients over a 20-year period. Cancer, 104(8), 1742–1750. doi:10.1002/CNCR.21359
  • Grigaitis, P., Starkuviene, V., Rost, U., Serva, A., Pucholt, P., & Kummer, U. (2020). miRNA target identification and prediction as a function of time in gene expression data. RNA Biology, 17(7), 990. doi:10.1080/15476286.2020.1748921
  • Harel, S., Sanchez-Gonzalez, V., Echavarria, R., Mayaki, D., & Hussain, S. N. (2020). Roles of miR-640 and Zinc Finger Protein 91 (ZFP91) in Angiopoietin-1-Induced In Vitro Angiogenesis. Cells 2020, Vol. 9, Page 1602, 9(7), 1602. doi:10.3390/CELLS9071602
  • Hosonaga, M., Saya, H., & Arima, Y. (2020). Molecular and cellular mechanisms underlying brain metastasis of breast cancer. Cancer and Metastasis Reviews, 39(3), 711–720. doi:10.1007/S10555-020-09881-Y/FIGURES/1
  • Huber, K. E., Carey, L. A., & Wazer, D. E. (2009). Breast Cancer Molecular Subtypes in Patients With Locally Advanced Disease: Impact on Prognosis, Patterns of Recurrence, and Response to Therapy. Seminars in Radiation Oncology, 19(4), 204–210. doi:10.1016/J.SEMRADONC.2009.05.004
  • Ihle, M. A., Trautmann, M., Kuenstlinger, H., Huss, S., Heydt, C., Fassunke, J., … Merkelbach-Bruse, S. (2015). miRNA‐221 and miRNA‐222 induce apoptosis via the KIT/AKT signalling pathway in gastrointestinal stromal tumours. Molecular Oncology, 9(7), 1421. doi:10.1016/J.MOLONC.2015.03.013
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miR-640'ın meme kanserinde metastatik genler üzerindeki etkisi

Yıl 2026, Cilt: 65 Sayı: 1, 1 - 10, 09.03.2026

İsmail Mert Alkaç , Çığır Biray Avcı

https://doi.org/10.19161/etd.1771783
https://izlik.org/JA85MA83PB

Öz

Amaç: Kadınlarda kansere bağlı ölümlerin başlıca nedeni olmaya devam eden meme kanseri için çok sayıda tedavi protokolü uygulanmasına rağmen, metastaz tedavi sırasında önemli bir sorun olmaya devam etmektedir. Bu durum, tedavi süresinin uzamasına, kötü prognoza ve ikincil tümörlerin gelişmesi nedeniyle yeni ortaya çıkan kanser türlerinin yönetilmesi ihtiyacına yol açmaktadır. Bu çalışma, daha önce meme kanseri dahil çeşitli kanserlerde tümör oluşumu, anjiyogenez, inflamatuar yanıtlar ve metastazı etkilediği gösterilen miR-640'ın metastazla ilişkili genleri aşağı regüle etme potansiyelini inceleyerek, anti-metastatik etkilerini araştırmayı amaçlamıştır.
Gereç ve Yöntem: miR-640'ın anti-metastatik potansiyelini değerlendirmek için, MCF7 ve MDA-MB-231 meme kanseri hücre hatlarında lipofektamin aracılı transfeksiyonun ardından yara iyileşmesi, Annexin V ve hücre döngüsü analizleri dahil olmak üzere fonksiyonel testler gerçekleştirilmiştir.
Ek olarak, miR-640'ın potansiyel hedefleri olarak tanımlanan metastazla ilişkili genlerin
(WNT7A, TMSB4X, NFIB, ZEB2, IL11, AURKA, CAV1, SLC7A11, PDK1 ve PTK6) ekspresyon düzeyleri analiz edildi.
Bulgular: Her iki hücre hattında da başarılı transfeksiyon gerçekleştirildi ve miR-640 ekspresyonunda önemli bir artış gözlendi (MCF7'de ~25 kat, MDA-MB-231'de ~5 kat). Transfeksiyonun ardından yara iyileşmesi ve Annexin V testlerinde miR-640'ın istatistiksel olarak anlamlı etkileri gözlendi. Ek olarak, gen ekspresyon analizleri, MCF7 hücre hattında metastazla ilişkili genler WNT7A, TMSB4X, NFIB, IL11, AURKA, CAV1, SLC7A11, PDK1, PTK6'nın ve MDA-MB-231 hücre hattında WNT7A, NFIB ve ZEB2 genlerinin ekspresyonunda önemli azalmalar olduğunu ortaya koydu.
Sonuç: Bu çalışma, miR-640'ın metastazla ilişkili genlerin aşağı regülasyonu yoluyla metastaz oluşumunu baskılayarak meme kanserinde anti-metastatik etki gösterdiğini ortaya koyan ilk çalışmadır. Bulgular, transfekte edilmiş hücre hatlarında hücre göçünün önemli ölçüde inhibe edildiğini göstermektedir ve miR-640'ın potansiyel bir terapötik molekül olarak hizmet edebileceğini düşündürmektedir.

Anahtar Kelimeler

Metastaz meme kanseri gen düzenleme miR-640

Destekleyen Kurum

Bu çalışma, 35685 numaralı TUSEB (Türkiye Sağlık Enstitüleri Başkanlığı) A GRUBU ACİL AR-GE PROJE DESTEK PROGRAMI tarafından desteklenmiştir.

Proje Numarası

35685

Kaynakça

  • Avgustinova, A., Iravani, M., Robertson, D., Fearns, A., Gao, Q., Klingbeil, P., … Isacke, C. M. (2016). Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness. Nature Communications 2016 7:1, 7(1), 1–14. doi:10.1038/ncomms10305
  • Awolaran, O., Brooks, S. A., & Lavender, V. (2016). Breast cancer osteomimicry and its role in bone specific metastasis; an integrative, systematic review of preclinical evidence. Breast (Edinburgh, Scotland), 30, 156–171. doi:10.1016/J.BREAST.2016.09.017
  • Brasó-Maristany, F., Paré, L., Chic, N., Martínez-Sáez, O., Pascual, T., Mallafré-Larrosa, M., … Prat, A. (2022). Gene expression profiles of breast cancer metastasis according to organ site. Molecular Oncology, 16(1), 69. doi:10.1002/1878-0261.13021
  • Castanon, I., Von Stetina, S., Kass, J., & Baylies, M. K. (2001). Dimerization partners determine the activity of the Twist bHLH protein during Drosophila mesoderm development. Development, 128(16), 3145–3159. doi:10.1242/DEV.128.16.3145
  • Cha, S., Lee, E., & Won, H. H. (2021). Comprehensive characterization of distinct genetic alterations in metastatic breast cancer across various metastatic sites. Npj Breast Cancer 2021 7:1, 7(1), 1–11. doi:10.1038/s41523-021-00303-y
  • Chhichholiya, Y., Ruthuparna, M., Velagaleti, H., & Munshi, A. (2023). Brain metastasis in breast cancer: focus on genes and signaling pathways involved, blood–brain barrier and treatment strategies. Clinical and Translational Oncology 2023 25:5, 25(5), 1218–1241. doi:10.1007/S12094-022-03050-Z
  • Coleman, R. E., Smith, P., & Rubens, R. D. (1998). Clinical course and prognostic factors following bone recurrence from breast cancer. British Journal of Cancer 1998 77:2, 77(2), 336–340. doi:10.1038/bjc.1998.52
  • Friedel, G., Pastorino, U., Ginsberg, R. J., Goldstraw, P., Johnston, M., Pass, H., … Toomes, H. (2002). Results of lung metastasectomy from breast cancer: prognostic criteria on the basis of 467 cases of the international registry of lung metastases. European Journal of Cardio-Thoracic Surgery, 22(3), 335–344. doi:10.1016/S1010-7940(02)00331-7
  • Gennari, A., Conte, P. F., Rosso, R., Orlandini, C., & Bruzzi, P. (2005). Survival of metastatic breast carcinoma patients over a 20-year period. Cancer, 104(8), 1742–1750. doi:10.1002/CNCR.21359
  • Grigaitis, P., Starkuviene, V., Rost, U., Serva, A., Pucholt, P., & Kummer, U. (2020). miRNA target identification and prediction as a function of time in gene expression data. RNA Biology, 17(7), 990. doi:10.1080/15476286.2020.1748921
  • Harel, S., Sanchez-Gonzalez, V., Echavarria, R., Mayaki, D., & Hussain, S. N. (2020). Roles of miR-640 and Zinc Finger Protein 91 (ZFP91) in Angiopoietin-1-Induced In Vitro Angiogenesis. Cells 2020, Vol. 9, Page 1602, 9(7), 1602. doi:10.3390/CELLS9071602
  • Hosonaga, M., Saya, H., & Arima, Y. (2020). Molecular and cellular mechanisms underlying brain metastasis of breast cancer. Cancer and Metastasis Reviews, 39(3), 711–720. doi:10.1007/S10555-020-09881-Y/FIGURES/1
  • Huber, K. E., Carey, L. A., & Wazer, D. E. (2009). Breast Cancer Molecular Subtypes in Patients With Locally Advanced Disease: Impact on Prognosis, Patterns of Recurrence, and Response to Therapy. Seminars in Radiation Oncology, 19(4), 204–210. doi:10.1016/J.SEMRADONC.2009.05.004
  • Ihle, M. A., Trautmann, M., Kuenstlinger, H., Huss, S., Heydt, C., Fassunke, J., … Merkelbach-Bruse, S. (2015). miRNA‐221 and miRNA‐222 induce apoptosis via the KIT/AKT signalling pathway in gastrointestinal stromal tumours. Molecular Oncology, 9(7), 1421. doi:10.1016/J.MOLONC.2015.03.013
  • Jafari, H., Mahami-Oskouei, M., Spotin, A., Baradaran, B., Shanehbandi, D., Baghbanzadeh, A., & Alizadeh, Z. (2024). MicroRNA-1 Inhibits the Growth of Breast Cancer Cells MDA-MB-231 and MCF-7 Treated with Hydatid Cyst Fluid. Journal of Tropical Medicine, 2024, 7474039. doi:10.1155/2024/7474039
  • Jin, L., Han, B., Siegel, E., Cui, Y., Giuliano, A., & Cui, X. (2018). Breast cancer lung metastasis: Molecular biology and therapeutic implications. Https://Doi.Org/10.1080/15384047.2018.1456599, 19(10), 858–868. doi:10.1080/15384047.2018.1456599
  • Lee, J. Y., Park, K., Lee, E., Ahn, T. J., Jung, H. H., Lim, S. H., … Park, Y. H. (2016). Gene Expression Profiling of Breast Cancer Brain Metastasis. Scientific Reports 2016 6:1, 6(1), 1–10. doi:10.1038/srep28623
  • Li, S., Lu, Z., Sun, R., Guo, S., Gao, F., Cao, B., & Aa, J. (2022). The Role of SLC7A11 in Cancer: Friend or Foe? Cancers 2022, Vol. 14, Page 3059, 14(13), 3059. doi:10.3390/CANCERS14133059
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  • LUO, C., LU, Z., CHEN, Y., CHEN, X., LIU, N., CHEN, J., & DONG, S. (2021). MicroRNA-640 promotes cell proliferation and adhesion in glioblastoma by targeting Slit guidance ligand 1. Oncology Letters, 21(2). doi:10.3892/OL.2020.12422
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  • Paul, M. R., Pan, T. C., Pant, D. K., Shih, N. N. C., Chen, Y., Harvey, K. L., … Chodosh, L. A. (2020). Genomic landscape of metastatic breast cancer identifies preferentially dysregulated pathways and targets. The Journal of Clinical Investigation, 130(8), 4252–4265. doi:10.1172/JCI129941
  • Pei, L., Lv, X., Jia, G., Tan, X., Li, M., & Zhang, A. (2021). Silencing circular RNA circ_0054537 and upregulating microRNA-640 suppress malignant progression of renal cell carcinoma via regulating neuronal pentraxin-2 (NPTX2). Bioengineered, 12(1), 8279–8295. doi:10.1080/21655979.2021.1984002/SUPPL_FILE/KBIE_A_1984002_SM7065.ZIP
  • Petri, B. J., & Klinge, C. M. (2020). Regulation of breast cancer metastasis signaling by miRNAs. Cancer Metastasis Reviews, 39(3), 837. doi:10.1007/S10555-020-09905-7
  • Rasoolnezhad, M., Safaralizadeh, R., Hosseinpourfeizi, M. A., Banan-Khojasteh, S. M., & Baradaran, B. (2021). MiRNA-138–5p: A strong tumor suppressor targeting PD-L-1 inhibits proliferation and motility of breast cancer cells and induces apoptosis. European Journal of Pharmacology, 896. doi:10.1016/j.ejphar.2021.173933
  • Samaeekia, R., Adorno-Cruz, V., Bockhorn, J., Chang, Y. F., Huang, S., Prat, A., … Liu, H. (2017). miR-206 inhibits stemness and metastasis of breast cancer by targeting MKL1/IL11 pathway. Clinical Cancer Research, 23(4), 1091–1103. doi:10.1158/1078-0432.CCR-16-0943,
  • Savci-Heijink, C. D., Halfwerk, H., Koster, J., & van de Vijver, M. J. (2016). A novel gene expression signature for bone metastasis in breast carcinomas. Breast Cancer Research and Treatment, 156(2), 249–259. doi:10.1007/S10549-016-3741-Z
  • Schulten, H. J., Bangash, M., Karim, S., Dallol, A., Hussein, D., Merdad, A., … Al-Qahtani, M. H. (2017). Comprehensive molecular biomarker identification in breast cancer brain metastases. Journal of Translational Medicine, 15(1). doi:10.1186/S12967-017-1370-X
  • SR, S., RL, C., T, R., L, M., L, M.-B., & HW, L. (2016). EGFR and HER2 signaling in breast cancer brain metastasis. Frontiers in Bioscience (Elite Edition), 8(2), 245–263. doi:10.2741/E765
  • Tang, C., Wang, X., Ji, C., Zheng, W., Yu, Y., Deng, X., … Fang, L. (2021). The Role of miR-640: A Potential Suppressor in Breast Cancer via Wnt7b/β-catenin Signaling Pathway. Frontiers in Oncology, 11, 1142. doi:10.3389/FONC.2021.645682/BIBTEX
  • Venkatadri, R., Muni, T., Iyer, A. K. V., Yakisich, J. S., & Azad, N. (2016). Role of apoptosis-related miRNAs in resveratrol-induced breast cancer cell death. Cell Death & Disease 2016 7:2, 7(2), e2104–e2104. doi:10.1038/cddis.2016.6
  • Wang, J., Tsouko, E., Jonsson, P., Bergh, J., Hartman, J., Aydogdu, E., & Williams, C. (2014). miR-206 inhibits cell migration through direct targeting of the actin-binding protein Coronin 1C in triple-negative breast cancer. Molecular Oncology, 8(8), 1690–1702. doi:10.1016/J.MOLONC.2014.07.006
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  • Weier, H.-U. G., & Mao, J.-H. (2013). Meta-analysis of Aurora Kinase A (AURKA) Expression Data Reveals a Significant Correlation Between Increased AURKA Expression and Distant Metastases in Human ER-positive Breast Cancers. Journal of Data Mining in Genomics & Proteomics, 4(1), 127. doi:10.4172/2153-0602.1000127
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  • Yates, L. R., Knappskog, S., Wedge, D., Farmery, J. H. R., Gonzalez, S., Martincorena, I., … Campbell, P. J. (2017). Genomic Evolution of Breast Cancer Metastasis and Relapse. Cancer Cell, 32(2), 169-184.e7. doi:10.1016/J.CCELL.2017.07.005
  • Yazici, H., Akin, B., Yazici, H., & Akin, B. (2019). Molecular Genetics of Metastatic Breast Cancer. Tumor Progression and Metastasis. doi:10.5772/INTECHOPEN.86674
  • Yeeravalli, R., & Das, A. (2021). Molecular mediators of breast cancer metastasis. Hematology/Oncology and Stem Cell Therapy, 14(4), 275–289. doi:10.1016/J.HEMONC.2021.02.002
  • Yoo, B., Ross, A., Pantazopoulos, P., & Medarova, Z. (2021). MiRNA10b-directed nanotherapy effectively targets brain metastases from breast cancer. Scientific Reports 2021 11:1, 11(1), 1–7. doi:10.1038/s41598-021-82528-2
  • Zadeh, M. M., Motamed, N., Ranji, N., Majidi, M., & Falahi, F. (2016). Silibinin-Induced Apoptosis and Downregulation of MicroRNA-21 and MicroRNA-155 in MCF-7 Human Breast Cancer Cells. Journal of Breast Cancer, 19(1), 45–52. doi:10.4048/JBC.2016.19.1.45
  • Zhang, H. Y., Liang, F., Zhang, J. W., Wang, F., Wang, L., & Kang, X. G. (2017). Effects of long noncoding RNA-ROR on tamoxifen resistance of breast cancer cells by regulating microRNA-205. Cancer Chemotherapy and Pharmacology, 79(2), 327–337. doi:10.1007/S00280-016-3208-2/FIGURES/8
  • Zilli, F., Ramos, P. M., Auf Der Maur, P., Jehanno, C., Sethi, A., Coissieux, M.-M., … Bentires-Alj, M. (2021). The NFIB-ERO1A axis promotes breast cancer metastatic colonization of disseminated tumour cells. EMBO Molecular Medicine, 13(4), e13162. doi:10.15252/EMMM.202013162
Toplam 51 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Kanser Tedavisi (Kemoterapi ve Radyoterapi hariç), Kemoterapi, Moleküler Hedefler, Onkoloji ve Karsinogenez (Diğer)
Bölüm Araştırma Makalesi
Yazarlar

İsmail Mert Alkaç 0000-0003-0847-7738

Çığır Biray Avcı 0000-0001-8251-4520

Proje Numarası 35685
Gönderilme Tarihi 25 Ağustos 2025
Kabul Tarihi 10 Eylül 2025
Yayımlanma Tarihi 9 Mart 2026
DOI https://doi.org/10.19161/etd.1771783
IZ https://izlik.org/JA85MA83PB
Yayımlandığı Sayı Yıl 2026 Cilt: 65 Sayı: 1

Kaynak Göster

Vancouver 1.İsmail Mert Alkaç, Çığır Biray Avcı. The effect of miR-640 on metastatic genes in breast cancer. ETD. 01 Mart 2026;65(1):1-10. doi:10.19161/etd.1771783

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