Shrestha Archana, Lahooti Behnaz, Hossian A K M Nawshad, Madadi Mahboubeh, Mikelis Constantinos M, Mattheolabakis George
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA.
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
Int J Mol Sci. 2024 Apr 17;25(8):4432. doi: 10.3390/ijms25084432.
The mainstays of lung cancer pathogenesis are cell cycle progression dysregulation, impaired apoptosis, and unregulated cell proliferation. While individual microRNA (miR) targeting or delivering is a promising approach that has been extensively studied, combination of miR targeting can enhance therapeutic efficacy and overcome limitations present in individual miR regulations. We previously reported on the use of a miR-143 and miR-506 combination via transient transfections against lung cancer. In this study, we evaluated the effect of miR-143 and miR-506 under stable deregulations in A549 lung cancer cells. We used lentiviral transductions to either up- or downregulate the two miRs individually or in combination. The cells were sorted and analyzed for miR deregulation via qPCR. We determined the miR deregulations' effects on the cell cycle, cell proliferation, cancer cell morphology, and cell motility. Compared to the individual miR deregulations, the combined miR upregulation demonstrated a miR-expression-dependent G2 cell cycle arrest and a significant increase in the cell doubling time, whereas the miR-143/506 dual downregulation demonstrated increased cellular motility. Furthermore, the individual miR-143 and miR-506 up- and downregulations exhibited cellular responses lacking an apparent miR-expression-dependent response in the respective analyses. Our work here indicates that, unlike the individual miR upregulations, the combinatorial miR treatment remained advantageous, even under prolonged miR upregulation. Finally, our findings demonstrate potential advantages of miR combinations vs. individual miR treatments.
肺癌发病机制的主要因素是细胞周期进程失调、凋亡受损和细胞增殖失控。虽然单个微小RNA（miR）靶向或递送是一种很有前景的方法且已得到广泛研究，但miR靶向联合使用可提高治疗效果并克服单个miR调控中存在的局限性。我们之前报道过通过瞬时转染使用miR-143和miR-506联合治疗肺癌。在本研究中，我们评估了在A549肺癌细胞中稳定失调情况下miR-143和miR-506的作用。我们使用慢病毒转导单独或联合上调或下调这两种miR。通过qPCR对细胞进行分选并分析miR失调情况。我们确定了miR失调对细胞周期、细胞增殖、癌细胞形态和细胞运动性的影响。与单个miR失调相比，联合上调miR表现出miR表达依赖性的G2期细胞周期阻滞以及细胞倍增时间显著增加，而miR-143/506双下调则表现出细胞运动性增加。此外，在各自的分析中，单个miR-143和miR-506的上调和下调表现出缺乏明显miR表达依赖性反应的细胞反应。我们在此的工作表明，与单个miR上调不同，即使在长时间miR上调的情况下，联合miR治疗仍然具有优势。最后，我们的研究结果证明了miR联合治疗相对于单个miR治疗的潜在优势。
