Abstract
BackgroundIncreasing evidence suggests that taurine upregulated gene 1 (TUG1) is crucial for tumor progression; however, its role in hepatocellular carcinoma (HCC) and the underlying mechanisms are not well characterized.MethodsThe expression levels of TUG1, miR-524-5p, and sine oculis homeobox homolog 1 (SIX1) were determined using quantitative real-time PCR. The regulatory relationships were confirmed by dual-luciferase reporter assay. Cell proliferation and invasion were assessed using Cell Counting Kit 8 and transwell assays. Glucose uptake, cellular levels of lactate, lactate dehydrogenase (LDH), and adenosine triphosphate (ATP) were detected using commercially available kits. Silencing of TUG1 or SIX1 was performed by lentivirus transduction. Protein levels were measured by immunoblotting.ResultsCancer-associated fibroblasts (CAFs)-secreted exosomes promoted migration, invasion, and glycolysis in HepG2 cells by releasing TUG1. The promotive effects of CAFs-secreted exosomes were attenuated by silencing of TUG1. TUG1 and SIX1 are targets of miR-524-5p. SIX1 knockdown inhibited the promotive effects of miR-524-5p inhibitor. Silencing of TUG1 suppressed tumor growth and lung metastasis and therefore increased survival of xenograft model mice. We also found that TUG1 and SIX1 were increased in HCC patients with metastasis while miR-524-5p was decreased in HCC patients with metastasis.ConclusionsCAFs-derived exosomal TUG1 promoted migration, invasion, and glycolysis in HCC cells via the miR-524-5p/SIX1 axis. These findings may help establish the foundation for the development of therapeutics strategies and clinical management for HCC in future.
Highlights
Increasing evidence suggests that taurine upregulated gene 1 (TUG1) is crucial for tumor progression; its role in hepatocellular carcinoma (HCC) and the underlying mechanisms are not well characterized
Cancer-associated fibroblasts (CAFs) promoted migration, invasion, and glycolysis in HepG2 cells In order to study the role of CAFs in cell migration, invasion and glycolysis, CAFs and Adjacent non-tumor fibroblasts (NFs) were isolated from tumor tissues and adjacent non-tumor tissues and co-cultured with HepG2 cells
Glycolysis is related to multiple reactions such as glucose uptake, converting pyruvate to lactate by lactate dehydrogenase (LDH), and adenosine triphosphate (ATP) production [30]
Summary
Increasing evidence suggests that taurine upregulated gene 1 (TUG1) is crucial for tumor progression; its role in hepatocellular carcinoma (HCC) and the underlying mechanisms are not well characterized. Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related deaths worldwide [1]. The incidence rates of HCC are high in Asia and Africa [2]. Alcohol consumption, diabetes, and nonalcoholic steatohepatitis are the main risk factors for the development of HCC [4, 5]. Development of improved therapeutics for HCC is imperative. Exosomes can be produced by different types of cells [7]. Recent studies have shown that exosomes contribute to cancer progression by transferring different types of substances [10, 11]
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