Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
Life Sci. 2022 Oct 15;307:120884. doi: 10.1016/j.lfs.2022.120884. Epub 2022 Aug 13.
The potential of all-trans retinoic acid (ATRA) in regulating some microRNAs (miRNAs) involved in multiple cancer-related pathways, including resistance to chemotherapeutics, may be a valuable idea for overcoming the CDDP resistance of GC cells.
Treatment of gastric AGS and MKN-45 cells with CDDP enriched the CDDP surviving cells (CDDP-SCs). The abilities of chemoresistance to CDDP drug, migration, either apoptosis or cell cycle distribution, spheroid body formation and changes at miRNA and protein levels were evaluated in vitro by MTT assay, colony formation assay, flow cytometry, tumor spheres culture, qRT-PCR and western blot assay in CDDP-SCs and ATRA-treated CDDP-SCs cells, respectively.
CDDP-based chemotherapy significantly reduced microRNA-30a (miR-30a) levels in GC cells. We also observed elevated autophagy activity in cancer cells that possess stem cell-like properties with overexpressed specific stem cell markers. Our extended study suggested that the reduction of miR-30a by CDDP treatment, is the possible underlying mechanism of enhanced autophagic activity, as demonstrated by enhancing autophagy-related protein beclin 1 and LC3-II/LC-I ratio. The addition of ATRA in the culture medium of GC cells increased the expression of miR-30a, and disturbed characteristic CSC-like properties. Additional studies revealed that the increased expression of miR-30a declined the expression level of its target gene, beclin 1, and beclin 1-mediated autophagy. This leads to promoted CDDP-induced GC cell apoptosis and G2/M cell cycle arrest.
Overall, miR-30a/autophagy signaling has a critical role in regulating the chemoresistance of GC cells that ATRA could modulate.
全反式维甲酸（ATRA）在调节多种癌症相关途径中涉及的一些 microRNAs（miRNAs）的潜力，包括对化疗药物的耐药性，可能是克服 GC 细胞对顺铂耐药性的一个有价值的想法。
用顺铂处理胃 AGS 和 MKN-45 细胞，使顺铂存活细胞（CDDP-SCs）富集。通过 MTT 测定、集落形成测定、流式细胞术、肿瘤球体培养、qRT-PCR 和 Western blot 测定，分别评估 CDDP-SCs 和 ATRA 处理的 CDDP-SCs 细胞中对 CDDP 药物的化疗耐药性、迁移、凋亡或细胞周期分布、球体形成能力以及 miRNA 和蛋白水平的变化。
基于顺铂的化疗显著降低了 GC 细胞中的 microRNA-30a（miR-30a）水平。我们还观察到具有干细胞样特性的癌细胞中自噬活性升高，这些癌细胞表达高水平的特定干细胞标记物。我们的扩展研究表明，CDDP 处理降低 miR-30a 是增强自噬活性的可能潜在机制，这表现在自噬相关蛋白 beclin 1 和 LC3-II/LC-I 比值增加。在 GC 细胞的培养基中添加 ATRA 增加了 miR-30a 的表达，并扰乱了特征性 CSC 样特性。进一步的研究表明，miR-30a 的表达增加降低了其靶基因 beclin 1 的表达水平，以及 beclin 1 介导的自噬。这导致促进 CDDP 诱导的 GC 细胞凋亡和 G2/M 细胞周期停滞。
总的来说，miR-30a/自噬信号在调节 ATRA 可调节的 GC 细胞化疗耐药性方面起着关键作用。
