BackgroundInsulin-like growth factor-1 receptor (IGF-1R) is a well-studied oncogenic factor that promotes cell proliferation and energy metabolism and is overexpressed in numerous cancers including hepatocellular carcinoma (HCC). Aerobic glycolysis is a hallmark of cancer, and drugs targeting its regulators, including IGF-1R, are being developed. However, the mechanisms of IGF-1R inhibition and the physiological significance of the IGF-1R inhibitors in cancer cells are unclear.Materials and methodsCell proliferation was evaluated by cell counting Kit-8 and colony formation assay. Western blot and real-time PCR were accordingly used to detect the relevant proteins, miRNA and gene expression. Luciferase reporter assays were used to illustrate the interaction between miR-342-3p and IGF-1R. The effect of miR-342-3p on glycolysis was determined by glucose uptake, ATP concentration, lactate generation, extracellular acidification rate and oxygen consumption rate assays. In vivo, subcutaneous tumor formation assay and PET were performed in nude mice.ResultsIn this study, we demonstrate that by directly targeting the 3′-UTR (3′-untranslated regions) of IGF-1R, microRNA-342-3p (miR-342-3p) suppresses IGF-1R-mediated PI3K/AKT/GLUT1 signaling pathway both in vitro and in vivo. Through suppression of IGF-1R, miR-342-3p dampens glycolysis by decreasing glucose uptake, lactate generation, ATP production, and extracellular acidification rate (ECAR), and increasing oxygen consumption rate (OCR) in hepatoma cells. Importantly, glycolysis regulated by miR-342-3p is critical for its regulating HCC growth both in vitro and in vivo.ConclusionOur findings provide clues regarding the role of miR-342-3p as a tumor suppressor in liver cancer mainly through the inhibition of IGF-1R. Targeting IGF-1R by miR-342-3p could be a potential therapeutic strategy in liver cancer.
Background and Aims Oxaliplatin (OXA) is one of the most common chemotherapeutics in advanced hepatocellular carcinoma (HCC), the resistance of which poses a big challenge. Long noncoding RNAs (lncRNAs) play vital roles in chemoresistance. Therefore, elucidating the underlying mechanisms and identifying predictive lncRNAs for OXA resistance is needed urgently. Methods RNA sequencing (RNA‐seq) and fluorescence in situ hybridization (FISH) were used to investigate the OXA‐resistant (OXA‐R) lncRNAs. Survival analysis was performed to determine the clinical significance of homo sapiens long intergenic non‐protein‐coding RNA 1134 (LINC01134) and p62 expression. Luciferase, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and chromatin isolation by RNA purification (ChIRP) assays were used to explore the mechanisms by which LINC01134 regulates p62 expression. The effects of LINC01134/SP1/p62 axis on OXA resistance were evaluated using cell viability, apoptosis, and mitochondrial function and morphology analysis. Xenografts were used to estimate the in vivo regulation of OXA resistance by LINC01134/SP1/p62 axis. ChIP, cell viability, and xenograft assays were used to identify the demethylase for LINC01134 up‐regulation in OXA resistance. Results LINC01134 was identified as one of the most up‐regulated lncRNAs in OXA‐R cells. Higher LINC01134 expression predicted poorer OXA therapeutic efficacy. LINC01134 activates anti‐oxidative pathway through p62 by recruiting transcription factor SP1 to the p62 promoter. The LINC01134/SP1/p62 axis regulates OXA resistance by altering cell viability, apoptosis, and mitochondrial homeostasis both in vitro and in vivo. Furthermore, the demethylase, lysine specific demethylase 1 (LSD1) was responsible for LINC01134 up‐regulation in OXA‐R cells. In patients with HCC, LINC01134 expression was positively correlated with p62 and LSD1 expressions, whereas SP1 expression positively correlated with p62 expression. Conclusions LSD1/LINC01134/SP1/p62 axis is critical for OXA resistance in HCC. Evaluating LINC01134 expression in HCC will be effective in predicting OXA efficacy. In treatment‐naive patients, targeting the LINC01134/SP1/p62 axis may be a promising strategy to overcome OXA chemoresistance.
Decreased expression of PPARgamma may play an important role in the development of hepatocellular inflammation, necrosis and fibrosis of rats with FLD. Thus, activating PPARgamma by its ligand can be anticipated to provide a therapy target for FLD.
The present study aimed to identify novel diagnostic differentially expressed microRNAs (miRNAs/miRs) in order to understand the molecular mechanisms underlying hepatocellular carcinoma. The expression data of miRNA and mRNA were downloaded for differential expression analysis. Optimal diagnostic differentially expressed miRNA biomarkers were identified via a random forest algorithm. Classification models were established to distinguish patients with hepatocellular carcinoma and normal individuals. A regulatory network between optimal diagnostic differentially expressed miRNA and differentially expressed mRNAs was then constructed. The GSE63046 dataset and in vitro experiments were used to validate the expression of the optimal diagnostic differentially expressed miRNAs identified. In addition, diagnostic and prognostic analyses of optimal diagnostic differentially expressed miRNAs were performed. In total, 14 differentially expressed miRNAs (all upregulated) and 2,982 differentially expressed mRNAs (1,989 upregulated and 993 downregulated) were identified. hsa-miR-10b-5p, hsa-miR-10b-3p, hsa-miR-224-5p, hsa-miR-183-5p and hsa-miR-182-5p were considered as the optimal diagnostic biomarkers for hepatocellular carcinoma. The mRNAs targeted by these five miRNAs included secreted frizzled related protein 1 (SFRP1), endothelin receptor type B (EDNRB), nuclear receptor subfamily 4 group A member 3 (NR4A3), four and a half LIM domains 2 (FHL2), NK3 homeobox 1 (NKX3-1), interleukin 6 signal transducer (IL6ST) and forkhead box O1 (FOXO1). 'Bile acid biosynthesis and cholesterol' was the most enriched signaling pathways of these target mRNAs. The expression validation of the five miRNAs was consistent with the present bioinformatics analysis. Notably, hsa-miR-10b-5p and hsa-miR-10b-3p had a significant prognosis value for patients with hepatocellular carcinoma. In conclusion, the five differentially expressed miRNAs may be considered as diagnostic biomarkers for patients with hepatocellular carcinoma. In addition, the differential expression levels of the targets of these five mRNAs, including SFRP1, EDNRB, NR4A3, FHL2, NKX3-1, IL6ST and FOXO1, may be involved in hepatocellular carcinoma tumorigenesis.
Sorafenib resistance is a major challenge in the therapy for advanced hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of HCC resistance to sorafenib remain unclear. Activator of thyroid and retinoid receptor (ACTR, also known as SRC‐3), overexpressed in HCC patients, plays an important oncogenic role in HCC; however, the link between ACTR and sorafenib resistance in HCC is unknown. Our study demonstrated that ACTR was one of the most upregulated genes in sorafenib‐resistant HCC xenografts. ACTR increases sorafenib resistance through regulation of the Warburg effect. ACTR promotes glycolysis through upregulation of glucose uptake, ATP and lactate production, and reduction of the extracellular acidification and the oxygen consumption rates. Glycolysis regulated by ACTR is vital for the susceptibility of HCC to sorafenib in vitro and in vivo. Mechanistically, ACTR knockout or knockdown decreases the expression of glycolytic enzymes. In HCC patients, ACTR expression is positively correlated with glycolytic gene expression and is associated with poorer outcome. Furthermore, ACTR interacts with the central regulator of the Warburg effect, c‐Myc, and promotes its recruitment to glycolytic gene promoters. Our findings provide new clues regarding the role of ACTR as a prospective sensitizing target for sorafenib therapy in HCC.
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