Abstract
BackgroundLong non-coding RNAs (lncRNAs) are crucial in the invasion, angiogenesis, progression, and metastasis of hepatocellular carcinoma (HCC). The lncRNA MYLK-AS1 promotes the growth and invasion of HCC through the EGFR/HER2-ERK1/2 signaling pathway. However, the clinical significance of MYLK-AS1 in HCC still needs to be further determined.MethodsBioinformatic analysis was performed to determine the potential relationship among MYLK-AS1, miRNAs and mRNAs. A total of 156 samples of normal liver and paired HCC tissues from HCC patients were used to evaluate MYLK-AS1 expression by qRT-PCR. Human HCC cell lines were used to evaluate the colony formation, cell proliferation, migration, invasion, cell cycle and apoptosis after transfection of lentiviral short-hairpin RNAs (shRNAs) targeting MYLK-AS1 or MYLK-AS1 vectors. The competitive endogenous RNA (ceRNA) mechanism was clarified using fluorescence in situ hybridization (FISH), Western blotting, qPCR, RNA binding protein immunoprecipitation (RIP), and dual luciferase reporter analysis.ResultsMYLK-AS1 up-regulation was detected in the HCC tumor tissues and cell lines associated with the enhancement of the angiogenesis and tumor progression. The down-regulation of MYLK-AS1 reversed the effects on angiogenesis, proliferation, invasion and metastasis in the HCC cells and in vivo. MYLK-AS1 acted as ceRNA, capable of regulating the angiogenesis in HCC, while the microRNA miR-424-5p was the direct target of MYLK-AS1. Promoting the angiogenesis and the tumor proliferation, the complex MYLK-AS1/miR-424-5p activated the VEGFR-2 signaling through E2F7, whereas the specific targeting of E2F transcription factor 7 (E2F7) by miR-424-5p, was indicated by the mechanism studies.ConclusionsMYLK-AS1 and E2F7 are closely related to some malignant clinicopathological features and prognosis of HCC, thus the MYLK-AS1/ miR-424-5p/E2F7 signaling pathway might represent a promising treatment strategy to combat HCC.
Highlights
Long non-coding RNAs are crucial in the invasion, angiogenesis, progression, and metastasis of hepatocellular carcinoma (HCC)
The cancer genome atlas (TCGA) data analysis A total of 1081 Long non-coding RNAs (lncRNAs) (1027/95.0% upregulated and 54/ 5.0% downregulated), 127 miRNAs (124/97.6% upregulated and 3/2.4% downregulated), and 1983 DEmRNAs (1776/89.6% upregulated and 207/10.4% downregulated), were identified on 50 adjacent non-tumor samples and 374 HCC samples obtained from TCGA after filtering with logFC > 2 and P < 0.01 (Fig. 1a-f)
Some mRNAs in the competitive endogenous RNA (ceRNA) network were previously known as linked with cancer including the E2F Transcription Factor 7 (E2F7), Solute Carrier Family 7 Member 11 (SLC7A11), Kinesin Family Member 23 (KIF23), Chromobox 2 (CBX2), Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2), and Cell Division Cycle 25A (CDC25A)
Summary
Long non-coding RNAs (lncRNAs) are crucial in the invasion, angiogenesis, progression, and metastasis of hepatocellular carcinoma (HCC). The lncRNA MYLK-AS1 promotes the growth and invasion of HCC through the EGFR/HER2-ERK1/2 signaling pathway. The clinical significance of MYLK-AS1 in HCC still needs to be further determined. MYLKAS1 is located on chromosome 3 and is a long noncoding RNA with a length of 814 bp It was originally reported in the Mammalian Gene Collection project of the National Institutes of Health, with the purpose of identifying putative alternative promoters for human genes, but no detailed study is yet available [5, 6]. MYLK-AS1 promotes the growth and invasion of HCC through the EGFR/HER2-ERK1/2 signaling pathway [8]. The specific biological function of MYLK-AS1 is still unclear, and the clinical significance of MYLK-AS1 in HCC still needs to be further determined
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