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HIF-1α promotes the migration and invasion of cancer-associated fibroblasts by miR-210.

ABSTRACT: Metastasis is the major cause of death in colorectal cancer (CRC) patients. Inhibition of metastasis will prolong the survival of patients with CRC. Cancer cells bring their own soil, cancer-associated fibroblasts (CAFs), to metastasize together, promoting the survival and colonization of circulating cancer cells. However, the mechanism by which CAFs metastasize remains unclear. In this study, CAFs were derived from adipose mesenchymal stem cells (MSCs) after co-culture with CRC cell lines. Transwell assays showed that CAFs have stronger migration and invasion abilities than MSCs. In a nude mouse subcutaneous xenograft model, CAFs metastasized from the primary tumour to the lung and promoted the formation of CRC metastases. The expression of HIF-1α was upregulated when MSCs differentiated into CAFs. Inhibition of HIF-1α expression inhibited the migration and invasion of CAFs. Western blot and ChIP assays were used to identify the genes regulated by HIF-1α. HIF-1α regulated the migration and invasion of CAFs by upregulating miR-210 transcription. Bioinformatics analysis and luciferase reporter assays revealed that miR-210 specifically targeted the 3'UTR of VMP1 and regulated its expression. Downregulation of VMP1 enhanced the migration and invasion of CAFs. In vivo, inhibition of miR-210 expression in CAFs reduced the metastasis of CAFs and tumour cells. Therefore, the HIF-1α/miR-210/VMP1 pathway might regulate the migration and invasion of CAFs in CRC. Inhibition of CAF metastasis might reduce CRC metastasis.

SUBMITTER: Yang Y

PROVIDER: S-EPMC8460292 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Carcinoma associated fibroblasts small extracellular vesicles with low miR-7641 promotes breast cancer stemness and glycolysis by HIF-1α.

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HIF-1α Stabilization Increases miR-210 Eliciting First Trimester Extravillous Trophoblast Mitochondrial Dysfunction.

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| S-EPMC6487019 | biostudies-literature

A positive feedback loop promotes HIF-1α stability through miR-210-mediated suppression of RUNX3 in paraquat-induced EMT.

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miR-212 regulated by HIF-1α promotes the progression of pancreatic cancer.

Project description:MicroRNA-212 (miR-212) is dysregulated in numerous tissues and cancer types and serves a role in the progression of human cancer. However, the function and mechanism of miR-212 in the development of pancreatic ductal adenocarcinoma (PDAC) remain unknown, particularly in a hypoxic microenvironment. In the present study, miR-212 expression was observed to be significantly upregulated in PDAC tissues compared with normal tissues. Clinical data analysis indicated that miR-212 was positively associated with a large tumor size, Tumor-Node-Metastasis stage, lymph node metastasis and vessel invasion, and influenced the overall survival time. Notably, there was a positive association between the expression of hypoxia-inducible factor-1α (HIF-1α) and miR-212 in vivo and in vitro in hypoxic conditions. Mechanistically, HIF-1α bound directly to a hypoxia response element in the miR-212 promoter region and activated miR-212 expression in PDAC cells. Collectively, these results demonstrated that HIF-1α positively regulated miR-212 expression and resulted in PDAC progression.

| S-EPMC6396010 | biostudies-literature

Exosomal lncRNA TUG1 from cancer-associated fibroblasts promotes liver cancer cell migration, invasion, and glycolysis by regulating the miR-524-5p/SIX1 axis.

Project description: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.

| S-EPMC8903597 | biostudies-literature

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| S-EPMC6484400 | biostudies-literature

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