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Long non-coding RNA TUG1 regulates multiple glycolytic enzymes in hepatocellular carcinoma cells via sponging microRNA-122-5p

ABSTRACT: Hepatocellular carcinoma (HCC) remains the third leading cause of cancer deaths; however, its therapeutic options are limited. Understanding the molecular mechanisms of HCC could shed light on new therapies. Emerging studies indicate the important role of long-noncoding RNAs (lncRNAs) in the pathogenesis of HCC. One of the early discovered lncRNAs, taurine-upregulated gene 1 (TUG1), has been up-regulated in HCC tissues, but its impact on HCC cells’ transcriptomics remains unexplored. We established TUG1-knockdown HCC cells and performed RNA-seq analysis. KEGG analysis revealed the significant enrichment of downregulated genes involved in glycolysis. Accordingly, TUG1-depleted HCC cells showed impairments in glucose uptake, ATP synthesis, and lactate production. Clinical HCC tissue data revealed positive gene expression correlations between TUG1 and glycolysis genes identified by RNA-seq. To identify a molecular function of TUG1 in glycolysis, we explored the competing endogenous (ceRNA) model and identified five microRNAs (miRNAs) with the highest number of TUG1 binding sites using bioinformatic tools. Amongst these miRNAs, microRNA-122-5p (miR-122-5p) displayed an inverse relationship for gene expression with most TUG1-regulated glycolysis genes, including PKM, ALDOA, ENO2, and PFKM. Dual luciferase assays confirmed the direct interaction between TUG1 and miR-122-5p and between miR-122-5p and the 3’ untranslated regions (3’UTR) of PKM and ALDOA. We further showed that inhibition of miR-122-5p alleviated the suppression of glycolysis induced by TUG1 depletion. Together, our RNA-seq analysis of TUG1-depleted HCC cells in combination with clinical data reveals the crucial function of TUG1 in promoting glycolysis via sponging miR-122-5p, which is a negative regulator of multiple glycolytic enzymes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273253 | GEO | 2025/07/29

REPOSITORIES: GEO

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Project description:Meis1 is a transcription factor involved in a broad range of functions including development and proliferation and has been previously shown to harness cell cycle progression. This study aimed to investigate the regulation of Meis1 by long non-coding RNAs (lncRNAs) and their sponged microRNAs (miRNAs) and hence the impact of this regulatory axis on cell proliferation. Using in-silico analysis, miR-499-5p was predicted to target Meis1 and Malat1 was predicted and previously proven to sponge miR-499-5p. We showed that forcing the expression of miR-499-5p downregulates Meis1 expression in C166 cell line by directly binding to its 3’UTR. In addition, Malat1 knockdown significantly increases miR-499-5p expression, subsequently suppressing Meis1 mRNA and protein expression levels. Furthermore, the impact of manipulating the Malat1/miR-499-5p/Meis1 axis on cellular proliferation was assessed using the BrdU incorporation assay. We demonstrated that upon knockdown of Malat1, mimicking with miR-499-5p, or knockdown of Meis1, cell proliferation was induced. Gene Ontology, KEGG and Reactome enrichment analyses were performed on proteins detected by mass spectrometry following manipulation of the Malat1/miR-499-5p/Meis1 axis. The data revealed a multitude of differentially expressed proteins (DEPs) significantly enriched in processes related to cell cycle, cell division and proliferation. These DEPs were also involved in key signaling pathways, such as Wnt and mTOR, known to play critical roles in cell proliferation and cell cycle. Finally, since Malat1 and miR-499-5p are conserved in humans and mice, we examined the expression pattern of both non-coding RNAs (ncRNAs) in the hearts of neonatal, postnatal, and adult mice, representing models of proliferative and non-proliferative tissues. We demonstrated a paradoxical expression pattern, where Malat1 is underexpressed while miR-499-5p is overexpressed in proliferative neonatal cardiomyocytes. Collectively, our findings confirm that Malat1 sponges miR-499-5p which directly regulates Meis1, and that Malat1/miR-499-5p/Meis1 axis has a pivotal influence on cellular proliferation.

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Long non-coding RNA TUG1 regulates multiple glycolytic enzymes in hepatocellular carcinoma cells via sponging microRNA-122-5p

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