Khamaneh Amir Mahdi, Mohajeri Nasrin, Naghili Behrooz, Zarghami Nosratollah
Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
J Appl Genet. 2025 Sep;66(3):601-610. doi: 10.1007/s13353-024-00909-5. Epub 2024 Oct 7.
Luminal A and B subtypes of breast tumors have fluctuated in proliferation rates, which arise from cell cycle dysregulation in cancer. Besides, microRNAs can regulate various cell processes through integration with mRNA. miRNAs that target the cell cycle are significant because of their prediction capability of prognosis. The objective of this study is to discover the integration between miRNA-mRNA and miRNA-miRNA related to cyclin-dependent kinase. Thirty-four pairs of human primary breast cancer and tumor margin samples from luminal breast cancer patients were investigated to assess the expression levels of CCND1, E2F1, miR-124, miR-503, miR-449a, and miR-449b. Afterward, the expression levels of mRNAs and miRNAs were investigated by real-time PCR. Statistical analysis was conducted to compare the expression levels between breast cancer and corresponding normal tissues. The protein expressions of E2F1 and CCND1 were verified by western blotting. Further, the correlation between mRNAs and miRNAs was calculated. E2F1 was significantly increased in both luminal A and B patients, while CCND1 was upregulated only in luminal B. Significant differences in all miRNAs were detected in both luminal A and B biopsy specimens (p < 0.0001). The correlation analysis revealed a positive strong correlation between miR-124 and E2F1 in luminal A patient. Moreover, the correlation test confirmed the ability of miR-449a to increase the CCND1 gene in luminal B subtypes. Also, miRNA correlation exhibited the miRNA-miRNA interaction in luminal breast cancer. This study demonstrated the novel miRNA-mRNA and miRNA-miRNA interactions, providing new insights into the molecular integration in luminal A and B patients. The authors propose that this research could contribute to introducing valuable biomarkers for luminal cancerous cells.
乳腺肿瘤的管腔A型和B型亚型的增殖率有所波动，这源于癌症中的细胞周期失调。此外，微小RNA（miRNA）可通过与信使核糖核酸（mRNA）结合来调节各种细胞过程。靶向细胞周期的miRNA因其对预后的预测能力而具有重要意义。本研究的目的是发现与细胞周期蛋白依赖性激酶相关的miRNA-mRNA和miRNA-miRNA之间的整合情况。研究了34对来自管腔型乳腺癌患者的人原发性乳腺癌及肿瘤边缘样本，以评估细胞周期蛋白D1（CCND1）、E2F转录因子1（E2F1）、miR-124、miR-503、miR-449a和miR-449b的表达水平。随后，通过实时聚合酶链反应（PCR）研究mRNA和miRNA的表达水平。进行统计分析以比较乳腺癌组织与相应正常组织之间的表达水平。通过蛋白质免疫印迹法验证E2F1和CCND1的蛋白表达。此外，计算mRNA与miRNA之间的相关性。E2F1在管腔A型和B型患者中均显著增加，而CCND1仅在管腔B型中上调。在管腔A型和B型活检标本中均检测到所有miRNA存在显著差异（p < 0.0001）。相关性分析显示，管腔A型患者中miR-124与E2F1之间存在强正相关。此外，相关性测试证实了miR-449a在管腔B型亚型中增加CCND1基因的能力。而且，miRNA相关性显示了管腔型乳腺癌中的miRNA-miRNA相互作用。本研究证明了新型的miRNA-mRNA和miRNA-miRNA相互作用，为管腔A型和B型患者的分子整合提供了新的见解。作者提出，这项研究可能有助于引入针对管腔癌细胞的有价值的生物标志物。
