Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing 211166, PR China.
Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing 211166, PR China.
Toxicol Lett. 2014 Jun 5;227(2):75-83. doi: 10.1016/j.toxlet.2014.03.016. Epub 2014 Mar 27.
Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related mortality worldwide. Current standard practices for treatment of HCC are less than satisfactory because of metastasis and recurrence. In addition to treating acute promyelocytic leukemia (APL), arsenic trioxide (As2O3) also suppresses other solid tumors, such as HCC. However, the effects of As2O3 on the migration/invasion potential of liver cancer cells and the molecular mechanisms underlying in remain unclear. Here we found that As2O3 attenuated the migration/invasion potential of HCC cell lines by blocking matrix metalloproteinases (MMPs) activities and inducing a mesenchymal to epithelial transition (MET). Indeed, As2O3 elevated the expression of microRNA-491 (miR-491) via demethylation. On one hand, as a target miRNA of MMP9, miR-491 decreased the MMP9 expression. On the other hand, miR-491 blocked the activation of nuclear factor κB (NF-κB), which transcriptionally inactivated MMP2 and induced a MET (as determined by the increased expression of E-cadherin and decreased expressions of snail, slug, and vimentin). Knockdown of miR-491 abolished the As2O3-induced MMPs inactivation, MET, and the migration/invasion potential of HCC cell lines. By understanding a novel mechanism how As2O3 inhibits the migration/invasion potential of liver cancer cells, our study may help to identify potential therapeutic targets for liver cancer.
肝细胞癌（HCC）是全球癌症相关死亡的第三大主要原因。由于转移和复发，目前 HCC 的治疗标准实践效果并不理想。三氧化二砷（As2O3）除了治疗急性早幼粒细胞白血病（APL）外，还能抑制其他实体肿瘤，如 HCC。然而，As2O3 对肝癌细胞迁移/侵袭潜力的影响及其潜在的分子机制尚不清楚。在这里，我们发现 As2O3 通过阻断基质金属蛋白酶（MMPs）的活性并诱导间质-上皮转化（MET）来减弱 HCC 细胞系的迁移/侵袭潜力。事实上，As2O3 通过去甲基化来提高 microRNA-491（miR-491）的表达。一方面，miR-491 作为 MMP9 的靶 miRNA，降低了 MMP9 的表达。另一方面，miR-491 阻断了核因子 κB（NF-κB）的激活，NF-κB 转录失活 MMP2 并诱导 MET（通过增加 E-钙粘蛋白的表达和降低 snail、slug 和波形蛋白的表达来确定）。miR-491 的敲低消除了 As2O3 诱导的 MMPs 失活、MET 和 HCC 细胞系的迁移/侵袭潜力。通过了解 As2O3 抑制肝癌细胞迁移/侵袭潜力的新机制，我们的研究可能有助于确定肝癌的潜在治疗靶点。
