Long non-coding RNAs (LncRNAs) have recently emerged as vital regulators in the development and progression of hepatocellular carcinoma (HCC), providing new opportunities as novel therapeutic targets. Here we identified the lncRNA NIFK-AS1 as being highly expressed in HCC tissues and cells and showed this up-regulation resulted from METTL3-dependent m⁶A methylation. Functionally, knockdown of NIFK-AS1 inhibited the proliferation, colony formation, migration, and invasion of HCC cells. Moreover, these effects were elicited though AKT1 and we uncovered a ceRNA network involving an NIFK-AS1/miR-637/AKT1 axis with downstream effects on HCC progression involving regulation of MMP-7 and MMP-9 expression. From the clinical perspective, we showed that knockdown of NIFK-AS1 sensitized HCC cells to sorafenib through the up-regulation of the drug transporters OATP1B1 and OATP1B3. Clinical investigations showed HCC patients with low NIFK-AS1 expression benefited from sorafenib therapy and this phenomenon was reproduced in patient-derived tumor xenograft models (PDX) comparing HCC with low and high expression of NIFK-AS1. Taken together, these results suggest an essential role for NIFK-AS1 in HCC progression and promote NIFK-AS1 as a new therapeutic target and predictor of sorafenib benefit in HCC patients.

长链非编码 RNA (LncRNA) 最近已成为肝细胞癌 (HCC) 发展和进展的重要调节因子，为新的治疗靶点提供了新的机会。在这里，我们确定 lncRNA NIFK-AS1 在 HCC 组织和细胞中高度表达，并表明这种上调是由 METTL3 依赖性 m ^6引起的甲基化。在功能上，NIFK-AS1 的敲低抑制了 HCC 细胞的增殖、集落形成、迁移和侵袭。此外，这些影响是通过 AKT1 引起的，我们发现了一个涉及 NIFK-AS1/miR-637/AKT1 轴的 ceRNA 网络，该网络对 HCC 进展有下游影响，涉及 MMP-7 和 MMP-9 表达的调节。从临床角度来看，我们发现 NIFK-AS1 的敲低通过上调药物转运蛋白 OATP1B1 和 OATP1B3 使 HCC 细胞对索拉非尼敏感。临床研究表明，NIFK-AS1 低表达的 HCC 患者受益于索拉非尼治疗，这种现象在患者衍生的肿瘤异种移植模型 (PDX) 中重现，比较了 NIFK-AS1 低表达和高表达的 HCC。综合起来，