Department of General Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nangjing, P.R. China.
Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.
Mol Cancer Ther. 2020 May;19(5):1197-1209. doi: 10.1158/1535-7163.MCT-19-0203. Epub 2020 Mar 27.
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 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 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.
长链非编码 RNA（lncRNA）已被发现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）。转移相关肺腺癌转录物 1（MALAT1）已被确定为 HCC 中的癌基因和预后生物标志物。在这里，我们证明 MALAT1 在索拉非尼耐药 HCC 细胞中表达明显升高。此外，MALAT1 的敲低增加了非应答性 HCC 细胞对索拉非尼的敏感性，而 MALAT1 的强制表达赋予了应答性 HCC 细胞对索拉非尼的耐药性。此外，失活/功能获得试验表明，MALAT1 通过海绵 miR-140-5p 促进 HCC 细胞的增殖、迁移和上皮间质转化。在机制上，MALAT1 通过海绵 miR-140-5p 调节 Aurora-A 的表达，从而促进 HCC 细胞对索拉非尼的耐药性。此外，MALAT1 的抑制增强了索拉非尼在 HCC 患者中的抗肿瘤疗效。临床上，我们发现 HCC 患者中 MALAT1 的表达与 miR-140-5p 的表达呈负相关，而与 Aurora-A 的表达呈正相关，上调的 MALAT1 与 HCC 患者的不良生存结局密切相关。这些发现表明，MALAT1 可能是索拉非尼治疗 HCC 患者预后预测和治疗策略的新靶点。
