Long noncoding RNAs (lncRNA) have been found to play critical roles in tumorigenesis and the development of various cancers, including hepatocellular carcinoma (HCC). Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) has been identified as an oncogene and prognostic biomarker in HCC. Here, we demonstrated that MALAT1 expression was obviously high in sorafenib-resistant HCC cells. Furthermore, knockdown of MALAT1 increased sorafenib sensitivity in nonresponsive HCC cells, whereas forced expression of MALAT1 conferred sorafenib resistance to responsive HCC cells in vitro. In addition, loss/gain-of-function assays revealed that MALAT1 promoted cell proliferation, migration, and epithelial–mesenchymal transition in HCC cells. Mechanistically, MALAT1 regulated Aurora-A expression by sponging miR-140-5p, thus promoting sorafenib resistance in HCC cells. Moreover, MALAT1 inhibition enhanced the antitumor efficacy of sorafenib in vivo. Clinically, we found that MALAT1 expression was negatively correlated with miR-140-5p expression but positively correlated with Aurora-A expression in patients with HCC and that upregulated MALAT1 was closely correlated with poor survival outcomes in patients with HCC. These findings indicated that MALAT1 may be a novel target for prognosis prediction and therapeutic strategies in patients with HCC treated with sorafenib.

中文翻译：

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长链非编码 RNA MALAT1 通过靶向肝细胞癌中的 miR-140-5p/Aurora-A 信号促进索拉非尼耐药

已发现长链非编码 RNA (lncRNA) 在肿瘤发生和各种癌症的发展中发挥关键作用，包括肝细胞癌 (HCC)。与肺腺癌转录本-1 (MALAT1) 相关的转移已被确定为 HCC 的癌基因和预后生物标志物。在这里，我们证明了 MALAT1 表达在索拉非尼耐药的 HCC 细胞中明显高。此外，MALAT1 的敲低增加了无反应性 HCC 细胞中索拉非尼的敏感性，而 MALAT1 的强制表达赋予了索拉非尼对体外反应性 HCC 细胞的抗性。此外，功能丧失/获得试验表明 MALAT1 促进了 HCC 细胞的细胞增殖、迁移和上皮间质转化。从机制上讲，MALAT1 通过海绵 miR-140-5p 调节 Aurora-A 表达，从而促进 HCC 细胞对索拉非尼的耐药性。此外，MALAT1 抑制增强了索拉非尼的体内抗肿瘤功效。临床上，我们发现 MALAT1 表达与 miR-140-5p 表达呈负相关，但与 HCC 患者的 Aurora-A 表达呈正相关，并且 MALAT1 上调与 HCC 患者的不良生存结果密切相关。这些发现表明 MALAT1 可能是索拉非尼治疗的 HCC 患者预后预测和治疗策略的新靶点。我们发现 MALAT1 表达与 miR-140-5p 表达呈负相关，但与 HCC 患者中的 Aurora-A 表达呈正相关，并且 MALAT1 上调与 HCC 患者的不良生存结果密切相关。这些发现表明 MALAT1 可能是索拉非尼治疗的 HCC 患者预后预测和治疗策略的新靶点。我们发现 MALAT1 表达与 miR-140-5p 表达呈负相关，但与 HCC 患者中的 Aurora-A 表达呈正相关，并且 MALAT1 上调与 HCC 患者的不良生存结果密切相关。这些发现表明 MALAT1 可能是索拉非尼治疗的 HCC 患者预后预测和治疗策略的新靶点。