Differential Expression of Cancer-Related miRNAs in Response to Chemotherapeutics and the Regulatory Axis of miR-595/E2F7 in Colorectal Cancer Cells

Year 2025, Volume: 14 Issue: 3, 305 - 313, 31.12.2025

Ali Sedeeq Noaman Ercan Çaçan

https://doi.org/10.54187/jnrs.1752003

Abstract

MicroRNAs (miRNAs) are critical post-transcriptional regulators of gene expression and play key roles in cancer progression and chemoresistance. In this study, we investigated the expression profiles of selected cancer-associated miRNAs in response to two chemotherapeutic agents, docetaxel and lapatinib, in colorectal cancer cell lines. We also explored the potential regulatory interaction between miR-595 and the oncogene E2F7. Colorectal cancer cells (HT-29 and HCT-116) were treated with the IC₅₀ concentrations of docetaxel and lapatinib. RT-qPCR analysis revealed that docetaxel treatment significantly upregulated miR-718, miR-206, miR-1199, and miR-595 in HT-29 cells. In contrast, only miR-206 was upregulated, while the other genes were downregulated in HCT-116 cells. Lapatinib moderately increased the expression of the selected miRNAs in HT-29 cells but consistently downregulated all four miRNAs in HCT-116 cells. Bioinformatic analysis using TargetScan identified E2F7 as a potential target of miR-595. E2F7 expression was found to be elevated in colorectal cancer and further increased in docetaxel-treated HT-29 cells, suggesting a role in drug resistance. Overexpression of miR-595 resulted in the downregulation of E2F7, supporting a regulatory interaction. These findings suggest that miR-595 negatively regulates E2F7 and may contribute to modulating chemoresistance in colorectal cancer. Targeting the miR-595/E2F7 axis may offer a novel therapeutic strategy to enhance the efficacy of chemotherapy in colorectal cancer treatment.

Keywords

miRNAs , E2F7 , chemoresistance , colorectal cancer

Ethical Statement

This study did not require ethical approval.

References

• F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA: Cancer Journal Clinicians 68 (6) (2018) 394–424.
• E. Cacan, Z. C. Ozmen, Regulation of Fas in response to bortezomib and epirubicin in colorectal cancer cells, J Chemother 32 (4) (2020) 193–201.
• B. Kucuk, E. Yilmaz, E. Cacan, Expression profiles of Natural Killer Group 2D Ligands (NGK2DLs) in colorectal carcinoma and changes in response to chemotherapeutic agents, Molecular Biology Reports 48 (5) (2021) 3999–4008.
• E. R. Fearon, B. Vogelstein, A genetic model for colorectal tumorigenesis, Cell 61 (5) (1990) 759–767.
• C. Berkel, E. Cacan, Transcriptomic analysis reveals tumor stage- or grade-dependent expression of miRNAs in serous ovarian cancer, Human Cell 34 (3) (2021) 862–877.
• Z. A. Syeda, S. S. S. Langden, C. Munkhzul, M. Lee, S. J. Song, Regulatory mechanism of microRNA expression in cancer, International Journal of Molecular Sciences 21 (5) (2020) 1723.
• M. Hill, N. Tran, miRNA interplay: mechanisms and consequences in cancer, Disease Models&Mechanisms 14 (4) (2021) dmm047662.
• R. Garzon, G. A. Calin, C. M. Croce, MicroRNAs in cancer, Annual Revıew of Medıcıne 60 (2009) 167–179.
• N. Valeri, P. Gasparini, C. Braconi, A. Paone, F. Lovat, M. Fabbri, K. M. Sumani, H. Alder, D. Amadori, T. Patel, G. J. Nuovo, R. Fishel, C. M. Croce, MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2), Proceedings of the National Academy of Sciences USA 107 (49) (2010) 21098–21103.
• H. Siemens, R. Jackstadt, S. Hünten, M. Kaller, A. Menssen, U. Götz, H. Hermeking, miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions, Cell Cycle 10 (24) (2011) 4256–4271.
• Komal, D. Kumar, S. R. Khan, P. Kaur, K. Majumdar, N. Chakraborty, A. Singh, Advancements in colon cancer therapy: A review on docetaxel and the role of nanotechnology in enhancing efficacy, Current Drug Safety 21 (1) (2026) 23–33.
• M. A. Youshanlui, H. Nasiri, Z. Valedkarimi, M. Sadeghi, M. Akbari, K. M. Asghari, F. Jamali, D. Abdi, B. Mehramouz, F. R. Bonab, B. Baradaran, Impact of doxorubicin and docetaxel on immune checkpoint expression in colorectal cancer: Insights into chemotherapy resistance mechanisms, Biochemical Genetics 63 (3) (2025) 2263–2275.
• A. Sartore-Bianchi, L. Trusolino, C. Martino, K. Bencardino, S. Lonardi, F. Bergamo, V. Zagonel, F. Leone, I. Depetris, E. Martinelli, T. Troiani, F. Ciardiello, P. Racca, A. Bertotti, G. Siravegna, V. Torri, A. Amatu, S. Ghezzi, G. Marrapese, L. Palmeri, ..., S. Siena, Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): A proof-of-concept, multicentre, open-label, phase 2 trial, The Lancet Oncology 17 (6) (2016) 738–746.
• M. Diepenbruck, S. Tiede, M. Saxena, R. Ivanek, R. K. R. Kalathur, F. Lüönd, N. Meyer-Schaller, G. Christofori, miR-1199-5p and Zeb1 function in a double-negative feedback loop potentially coordinating EMT and tumour metastasis, Nature Communications 8 (1) (2017) 1168.
• Y. Hao, S. Zhang, S. Sun, J. Zhu, Y. Xiao, MİR-595 targeting regulation of SOX7 expression promoted cell proliferation of human glioblastoma, Biomedicine&Pharmacotherapy 80 (2016) 121–126.
• H. Wang, F. Jiang, W. Liu, W. Tian, miR-595 suppresses cell proliferation and metastasis in hepatocellular carcinoma by inhibiting NF-κB signalling pathway, Pathology-Research and Practice 216 (4) (2020) 152899.
• S. Tian, M. Zhang, X. Chen, Y. Liu, G. Lou, MicroRNA-595 sensitizes ovarian cancer cells to cisplatin by targeting ABCB1, Oncotarget 7 (52) (2016) 87091–87099.
• Z.-D. Wang, F.-Y. Qu, Y.-Y. Chen, Z.-S. Ran, H.-Y. Liu, H.-D. Zhang, Involvement of microRNA-718, a new regulator of EGR3, in regulation of malignant phenotype of HCC cells, Journal of Zhejiang University-SCIENCE B 18 (1) (2017) 27–36.
• Q. Bai, L. Li, F. Chen, J. Zhu, L. Cao, Y. Yang, F. Zhong, Suppression of circular RNA Hsa_circ_0109320 attenuates non-small cell lung cancer progression via MiR-595/E2F7 axis, Medical Science Monitor 26 (2020) e921200.
• R. Leng, L. Zha, L. Tang, MiR-718 represses VEGF and inhibits ovarian cancer cell progression, FEBS Letters 588 (12) (2014) 2078–2086.
• S. Wang, H. Sun, X. Zhan, Q. Wang, MicroRNA 718 serves a tumor suppressive role in non small cell lung cancer by directly targeting CCNB1, International Journal of Molecular Medicine 45 (1) (2020) 33–44.
• S. Liu, Y. Tian, C. Zhu, X. Yang, Q. Sun, High miR-718 suppresses phosphatase and tensin homolog (PTEN) expression and correlates to unfavorable prognosis in gastric cancer, Medical Science Monitor 24 (2018) 5840–5850.
• R. Fu, P. Yang, S. Amin, Z. Li, A novel miR-206/hnRNPA1/PKM2 axis reshapes the Warburg effect to suppress colon cancer growth, Biochemical and Biophysical Research Communications 531 (4) (2020) 465–471.
• Y. Wang, Q. Tai, J. Zhang, J. Kang, F. Gao, F. Zhong, L. Cai, F. Fang, Y. Gao, MiRNA-206 inhibits hepatocellular carcinoma cell proliferation and migration but promotes apoptosis by modulating cMET expression, Acta Biochimica et Biophysica Sinica 51 (3) (2019) 243–253.
• F. Tosi, A. Sartore-Bianchi, S. Lonardi, A. Amatu, F. Leone, S. Ghezzi, C. Martino, K. Bencardino, E. Bonazzina, F. Bergamo, E. Fenocchio, E. Martinelli, T. Troiani, G. Siravegna, G. Mauri, V. Torri, G. Marrapese, E. Valtorta, A. Cassingena, G. Cappello, …, S. Siena, Long-term clinical outcome of trastuzumab and lapatinib for HER2-positive metastatic colorectal cancer, Clinical Colorectal Cancer and Other Gastrointinal Malignancies 19 (4) (2020) 256–262.E2.
• M. Baretti, E. Karunasena, M. Zahurak, R. Walker, Y. Zhao, T. R. Pisanic, T.-H. Wang, T. F. Greten, A. G. Duffy, E. Gootjes, G. Meijer, H. M. W. Verheul, N. Ahuja, J. G. Herman, N. S. Azad, A phase 2 trial of gemcitabine and docetaxel in patients with metastatic colorectal adenocarcinoma with methylated checkpoint with forkhead and ring finger domain promoter and/or microsatellite instability phenotype, Clinical and Translaional Sicience 14 (3) (2021) 954–963.
• E. Cacan, A. M. Spring, A. Kumari, S. F. Greer, C. Garnett-Benson, Combination treatment with sublethal ionizing radiation and the proteasome inhibitor, bortezomib, enhances death-receptor mediated apoptosis and anti-tumor immune attack, International Journal of Molecular Sciences 16 (12) (2015) 30405–30421.
• F. Y. Caldiran, E. Cacan, RGS10 suppression by DNA methylation is associated with low survival rates in colorectal carcinoma, Pathology-Research and Practice 236 (2022) 154007.
• M. A. Jordan, L. Wilson, Microtubules as a target for anticancer drugs, Nature Reviews Cancer 4 (4) (2004) 253–265.
• F. Ciardiello, G. Tortora, EGFR antagonists in cancer treatment, The New England Journal of Medicine 358 (11) (2008) 1160–1174.
• Y. Hao, S. Zhang, S. Sun, J. Zhu, Y. Xiao, MİR-595 targeting regulation of SOX7 expression promoted cell proliferation of human glioblastoma, Biomedicine & Pharmacotherapy 80 (2016) 121–126.
• H. C. Zheng, The molecular mechanisms of chemoresistance in cancers, Oncotarget 8 (35) (2017) 59950–59964.
• J. Li, C. Ran, E. Li, F. Gordon, G. Comstock, H. Siddiqui, W. Cleghorn, H.-Z. Chen, K. Kornacker, C.-G. Liu, S. K. Pandit, M. Khanizadeh, M. Weinstein, G. Leone, A. de Bruin, Synergistic function of E2F7 and E2F8 is essential for cell survival and embryonic development, Developmental Cell 14 (1) (2008) 62–75.
• L. N. Kent, G. Leone, The broken cycle: E2F dysfunction in cancer, Nature Reviews Cancer 19 (6) (2019) 326–338.
• K.-Q. Chen, H.-B. Lei, X. Liu, S.-Z. Wang, The roles of E2F7 in cancer: Current knowledge and prospects, Heliyon 10 (14) (2024) e34362.