Zhang Zhigao, Zhang Fucheng, Xue Chuan, Song Xiaoling, Wang Yaojun
Department of Gastroenterology, Sunshine Union Hospital, No. 9000, Yingqian Street, Gaoxin District, Weifang City, 261000, Shandong Province, China.
Department of Gastroenterology I, Shandong Second Provincial General Hospital, Jinan City, 250021, Shandong Province, China.
Hereditas. 2025 Jun 3;162(1):96. doi: 10.1186/s41065-025-00461-0.
Esophageal cancer (EC) is the ninth most common cancer worldwide that kills about 300,000 people each year. Esophageal squamous cell carcinoma (ESCC) is the main type of EC. Long non-coding RNAs (lncRNAs) have been proven to be severely dysregulated in EC, but the functions of more lncRNAs still need to be explored.
To explore the new molecular mechanism of ESCC development, the online biology databases (GEO, lncRNASNP2, Starbase, TargetScan) were employed to investigate the novel pathways implicated. To assess the expression levels of FLG-AS1, miR-23a-3p, and associated genes, we utilized RT-qPCR. The expression of HOXD10 was evaluated through western blotting analysis. To elucidate the regulatory interactions among FLG-AS1, miR-23a-3p, and HOXD10, a combination of dual luciferase assays, silencing techniques, and overexpression studies were conducted. The migratory and invasive capabilities of the cells were examined using a transwell apparatus. Cell viability was measured employing the CCK-8 assay, while apoptosis was detected through Annexin V/PI double staining methodology. Concentrations of glucose and lactic acid were determined utilizing appropriate biochemical kits.
FLG-AS1 and HOXD10 exhibited low expression levels in ESCC cells, whereas miR-23a-3p was found to be highly expressed. FLG-AS1 was observed to reduce the free level of miR-23a-3p by directly binding to it, and in turn, miR-23a-3p inhibited the expression of HOXD10 by targeting its mRNA. The overexpression of FLG-AS1 and HOXD10 resulted in the attenuation of anaerobic glycolysis, as well as a decrease in the migratory and invasive capabilities of ESCC cells, effectively reversing their resistance to cisplatin. Conversely, the upregulation of miR-23a-3p yielded opposing effects. Furthermore, ESCC patients exhibiting elevated levels of FLG-AS1 and HOXD10, alongside reduced expression of miR-23a-3p, demonstrated a significantly higher 5-year survival rate post-surgery.
FLG-AS1 effectively inhibits the progression of ESCC and counters cisplatin resistance through the modulation of the miR-23a-3p/HOXD10 axis. This is a new mechanism affecting ESCC and will provide new ideas for the targeted therapy of ESCC.
食管癌（EC）是全球第九大常见癌症，每年导致约30万人死亡。食管鳞状细胞癌（ESCC）是EC的主要类型。长链非编码RNA（lncRNAs）已被证实在EC中严重失调，但更多lncRNAs的功能仍有待探索。
为探究ESCC发生发展的新分子机制，利用在线生物学数据库（GEO、lncRNASNP2、Starbase、TargetScan）研究其中涉及的新途径。为评估FLG-AS1、miR-23a-3p及相关基因的表达水平，我们采用了RT-qPCR。通过蛋白质免疫印迹分析评估HOXD10的表达。为阐明FLG-AS1、miR-23a-3p和HOXD10之间的调控相互作用，进行了双荧光素酶报告基因检测、沉默技术和过表达研究的组合实验。使用Transwell小室检测细胞的迁移和侵袭能力。采用CCK-8法检测细胞活力，通过Annexin V/PI双染法检测细胞凋亡。使用合适的生化试剂盒测定葡萄糖和乳酸浓度。
FLG-AS1和HOXD10在ESCC细胞中表达水平较低，而miR-23a-3p高表达。观察发现FLG-AS1通过直接结合降低miR-23a-3p的游离水平，反过来，miR-23a-3p通过靶向HOXD10的mRNA抑制其表达。FLG-AS1和HOXD10的过表达导致厌氧糖酵解减弱，以及ESCC细胞的迁移和侵袭能力降低，有效逆转了它们对顺铂的耐药性。相反，miR-23a-3p的上调产生相反的效果。此外，FLG-AS1和HOXD10水平升高且miR-23a-3p表达降低的ESCC患者术后5年生存率显著更高。
FLG-AS1通过调节miR-23a-3p/HOXD10轴有效抑制ESCC的进展并对抗顺铂耐药性。这是一种影响ESCC的新机制，将为ESCC的靶向治疗提供新思路。
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