Silencing of long noncoding RNA LEF1‐AS1 prevents the progression of hepatocellular carcinoma via the crosstalk with microRNA‐136‐5p/WNK1

Abstract Long noncoding RNAs (lncRNAs) have been recognized as cancer‐associated biological molecules, favoring hepatocellular carcinoma (HCC) progression. This study was conducted to elucidate the effects lncRNA lymphoid enhancer‐binding Factor 1 antisense RNA (LEF1‐AS1) on the pathological development of HCC, along with the crosstalk involving microRNA‐136‐5p (miR‐136‐5p) and with‐no‐K (lysine) kinase 1 (WNK1). The study recruited primary HCC tissues and their corresponding nonneoplastic liver tissues. The gain‐ and loss‐of‐function studies were performed in HCC cells HuH‐7 and tumor xenografts in nude mice. The dual luciferase reporter gene assay system, RNA pull‐down, and radioimmunoprecipitation assays were applied to detect their interactions among lncRNA LEF1‐AS1, miR‐136‐5p, and WNK1. 5‐Ethynyl‐2′‐deoxyuridine staining, scratch test, Transwell assays, and in vitro tube formation assays were conducted to examine HCC cell proliferation, migration, and invasion and HUVEC angiogenesis. HCC tissues and cells contained high lncRNA LEF1‐AS1 expression. LncRNA LEF1‐AS1 upregulation triggered markedly increased HCC cell proliferation, migration, and invasion and human umbilical vein endothelial cell angiogenesis. In vivo silencing lncRNA LEF1‐AS1 resulted in reduced tumor cell vitality and matrix metalloproteinase‐9 and the vascular endothelial growth factor expression. Additionally, the role of lncRNA LEF1‐AS1 was found to be largely dependent on WNK1. Association of lncRNA LEF1‐AS1 with WNK1 blocked the inhibitory effect of miR‐136‐5p on WNK1, which was confirmed by in vivo experiments. Altogether, our results revealed an important role of lncRNA LEF1‐AS1 in regulating the HCC progression by regulating WNK1, providing a potential biomarker for the therapeutic modalities regarding HCC.