Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P. R. China.
Bioengineered. 2021 Dec;12(1):5334-5347. doi: 10.1080/21655979.2021.1938497.
Development of chemoresistance remains a major challenge in treating patients suffering from esophageal squamous cell carcinoma (ESCC), despite treatment advances. MicroRNAs (miRNAs) have been shown to play critical roles in the regulation of ESCC cell chemoresistance. Here, we aimed to investigate the role of miR-624 in ESCC and its molecular mechanism in mediating the resistance of ESCC cells to two common chemotherapeutic drugs, cisplatin (CIS) and paclitaxel (PT). Expression patterns of miR-624, arrestin domain-containing 3 (ARRDC3), Yes-associated protein (YAP), and hypoxia-inducible factor-1α (HIF1α) in ESCC tissues and cell lines were identified using RT-qPCR and Western blot analysis. The binding affinities with the miR-624/ARRDC3/YAP/HIF1α axis were characterized. The chemotherapy-sensitive cell line KYSE150 and chemotherapy-resistant cell line KYSE410 were transfected with an overexpression plasmid or shRNA to study the effect of miR-624/ARRDC3/YAP/HIF1α axis on ESCC cell resistance to CIS and PT. Their effects on resistance to PT were assessed in tumor-bearing nude mice. High expression of miR-624, YAP and HIF1α, and low expression of ARRDC3 were observed in ESCC tissues and cell lines. miR-624 presented with higher expression in KYSE410 than in KYSE150 cells. miR-624 downregulated ARRDC3 to increase YAP and HIF1α expression so as to enhance ESCC cell resistance to CIS and PT and . Taken together, these data indicate an important role for miR-624 in promoting the chemoresistance of ESCC cells, highlighting a potential strategy to overcome drug resistance in ESCC treatment. miR-624 targets ARRDC3 to inhibit its expression, and consequently upregulates YAP expression by inhibiting degradation of YAP. By this mechanism, HIF1α expression is upregulated and the HIF1α signaling pathway is activated. ESCC cell chemotherapy resistance is eventually increased.
尽管在治疗方面取得了进展，但化疗耐药性的发展仍是治疗食管鳞状细胞癌（ESCC）患者的主要挑战。microRNAs（miRNAs）已被证明在调节 ESCC 细胞化疗耐药性方面发挥着关键作用。在这里，我们旨在研究 miR-624 在 ESCC 中的作用及其在介导 ESCC 细胞对两种常用化疗药物顺铂（CIS）和紫杉醇（PT）耐药性中的分子机制。使用 RT-qPCR 和 Western blot 分析鉴定了 miR-624、含 arrestin 结构域的 3（ARRDC3）、Yes 相关蛋白（YAP）和缺氧诱导因子-1α（HIF1α）在 ESCC 组织和细胞系中的表达模式。通过转染过表达质粒或 shRNA 研究 miR-624/ARRDC3/YAP/HIF1α 轴对 ESCC 细胞对 CIS 和 PT 耐药性的影响，鉴定了与 miR-624/ARRDC3/YAP/HIF1α 轴的结合亲和力。在荷瘤裸鼠中评估了 miR-624/ARRDC3/YAP/HIF1α 轴对 PT 耐药性的影响。
在 ESCC 组织和细胞系中观察到 miR-624、YAP 和 HIF1α 高表达，ARRDC3 低表达。与 KYSE150 细胞相比，KYSE410 细胞中 miR-624 表达更高。miR-624 通过下调 ARRDC3 增加 YAP 和 HIF1α 的表达，从而增强 ESCC 细胞对 CIS 和 PT 的耐药性。
总之，这些数据表明 miR-624 在促进 ESCC 细胞化疗耐药性方面发挥着重要作用，为克服 ESCC 治疗中的药物耐药性提供了一种潜在策略。miR-624 靶向 ARRDC3 抑制其表达，通过抑制 YAP 的降解来上调 YAP 的表达。通过这种机制，HIF1α 的表达上调，HIF1α 信号通路被激活，最终增加 ESCC 细胞的化疗耐药性。
