Fan Changru, Yuan Qiulan, Liu Guifeng, Zhang Yuliang, Yan Maojun, Sun Qingxu, Zhu Chaoyu
Department of Abdominal Surgery, Linyi Cancer Hospital, No. 6 Lingyuan East Road, Linyi, 276001 Shandong China.
Cancer Cell Int. 2020 Sep 29;20:473. doi: 10.1186/s12935-020-01549-5. eCollection 2020.
Colorectal cancer (CRC) is one of the most general malignant tumors. Accumulating evidence implied that long non-coding RNA Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) participated in the tumorigenesis of CRC. However, the effect of MALAT1 in drug-resistance needed to be further illustrated.
Levels of MALAT1, microRNA (miR)-324-3p, and a disintegrin and metalloprotease metallopeptidase domain 17 (ADAM17) were detected using quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assay. Cell Counting Kit 8 (CCK-8) was used to assess the half maximal inhibitory concentration (IC50) of oxaliplatin (Ox). Meanwhile, cell proliferation, migration and apoptosis were detected by CCK-8, transwell assay, and flow cytometry, respectively. The interaction between miR-324-3p and MALAT1 or ADAM17 was clarified by dual-luciferase reporter assay. Also, the effect of MALAT1 on tumor growth was detected in xenograft tumor mice treated with Ox.
Significant up regulation of MALAT1 and ADAM17, and decrease of miR-324-3p were observed in Ox-resistant CRC tissues and cells. MALAT1 deficiency enhanced the sensitivity of Ox-resistant CRC cells response to Ox, while miR-324-3p repression or ADAM17 acceleration could overturn this effect. Moreover, MALAT1 silencing repressed tumor growth in Ox-treated nude mice. Mechanically, MALAT1 exerted promotion effect on the resistance response to Ox via miR-324-3p/ADAM17 axis in Ox-resistant CRC cells.
MALAT1 modulated the sensitivity of Ox through ADAM17 in Ox-resistant CRC cells by sponging miR-324-3p, thus MALAT1 might serve as a novel insight for the therapy of CRC.
结直肠癌（CRC）是最常见的恶性肿瘤之一。越来越多的证据表明，长链非编码RNA转移相关肺腺癌转录本1（MALAT1）参与了结直肠癌的肿瘤发生。然而，MALAT1在耐药性方面的作用仍需进一步阐明。
采用定量实时聚合酶链反应（qRT-PCR）或蛋白质免疫印迹法检测MALAT1、微小RNA（miR）-324-3p和去整合素金属蛋白酶17（ADAM17）的水平。使用细胞计数试剂盒8（CCK-8）评估奥沙利铂（Ox）的半数抑制浓度（IC50）。同时，分别通过CCK-8、Transwell实验和流式细胞术检测细胞增殖、迁移和凋亡情况。通过双荧光素酶报告基因实验阐明miR-324-3p与MALAT1或ADAM17之间的相互作用。此外，在用Ox处理的异种移植瘤小鼠中检测MALAT1对肿瘤生长的影响。
在耐奥沙利铂的结直肠癌组织和细胞中，观察到MALAT1和ADAM17显著上调，miR-324-3p下调。MALAT1缺失增强了耐奥沙利铂的结直肠癌细胞对奥沙利铂的敏感性，而miR-324-3p抑制或ADAM17过表达可逆转这种作用。此外，MALAT1沉默抑制了奥沙利铂处理的裸鼠肿瘤生长。机制上，MALAT1通过miR-324-3p/ADAM17轴对耐奥沙利铂的结直肠癌细胞的耐药反应起促进作用。
在耐奥沙利铂的结直肠癌细胞中，MALAT1通过吸附miR-324-3p，经由ADAM17调节对奥沙利铂的敏感性，因此MALAT1可能为结直肠癌的治疗提供新的思路。
