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

ABSTRACT: Fibroblasts play an important role in cancer development and progression. Small extracellular vesicles (sEVs) are one type of extracellular vesicles, which mediate the interaction between cancer-associated fibroblasts and cancer cells by transferring their contents. However, the roles of sEVs from cancer-associated fibroblasts on breast cancer stem cell properties are largely unraveled. The purpose of this study was to explore the roles of sEVs from cancer-associated fibroblasts on breast cancer progression. The miRNA array data showed a different miRNA profile between CAFs sEVs and normal fibroblasts sEVs. By verification using real-time RT-PCR, the data analysis indicated that miR-7641 levels were lower in sEVs from CAFs compared with NFs. The cellular functions were assayed and the results indicated that CAFs derived sEVs with low miR-7641 levels suppressed breast cancer cell survival, glycolysis, and stem cell properties via the HIF-1α pathway. Collectively, these findings indicated that sEVs from CAFs promoted breast cancer stem cell properties and glycolysis via miR-7641/HIF-1α, which was a possible new way for targeting breast cancer.

SUBMITTER: Liu Y

PROVIDER: S-EPMC8266840 | biostudies-literature | 2021 Jul

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.

Liu Yonglei Y Hua Fanli F Zhan Yanxia Y Yang Yanfei Y Xie Jianfang J Cheng Yunfeng Y Li Feng F

Cell death discovery 20210708 1

Fibroblasts play an important role in cancer development and progression. Small extracellular vesicles (sEVs) are one type of extracellular vesicles, which mediate the interaction between cancer-associated fibroblasts and cancer cells by transferring their contents. However, the roles of sEVs from cancer-associated fibroblasts on breast cancer stem cell properties are largely unraveled. The purpose of this study was to explore the roles of sEVs from cancer-associated fibroblasts on breast cancer ...[more]

PMID: 34238918

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Project description:BackgroundAlbuminuria is a hallmark of diabetic kidney disease (DKD) that promotes its progression, leading to renal fibrosis. Renal macrophage function is complex and influenced by macrophage metabolic status. However, the metabolic state of diabetic renal macrophages and the impact of albuminuria on the macrophage metabolic state are poorly understood.MethodsExtracellular vesicles (EVs) from tubular epithelial cells (HK-2) were evaluated using transmission electron microscopy, nanoparticle tracking analysis and western blotting. Glycolytic enzyme expression in macrophages co-cultured with HSA-treated HK-2 cell-derived EVs was detected using RT-qPCR and western blotting. The potential role of EV-associated HIF-1α in the mediation of glycolysis was explored in HIF-1α siRNA pre-transfected macrophages co-cultured with HSA-treated HK-2 cell-derived EVs, and the extent of HIF-1α hydroxylation was measured using western blotting. Additionally, we injected db/db mice with EVs via the caudal vein twice a week for 4 weeks. Renal macrophages were isolated using CD11b microbeads, and immunohistofluorescence was applied to confirm the levels of glycolytic enzymes and HIF-1α in these macrophages.ResultsGlycolysis was activated in diabetic renal macrophages after co-culture with HSA-treated HK-2 cells. Moreover, HSA-treated HK-2 cell-derived EVs promoted macrophage glycolysis both in vivo and in vitro. Inhibition of glycolysis activation in macrophages using the glycolysis inhibitor 2-DG decreased the expression of both inflammatory and fibrotic genes. Mechanistically, EVs from HSA-stimulated HK-2 cells were found to accelerate macrophage glycolysis by stabilizing HIF-1α. We also found that several miRNAs and lncRNAs, which have been reported to stabilize HIF-1α expression, were increased in HSA-treated HK-2 cell-derived EVs.ConclusionOur study suggested that albuminuria induced renal macrophage glycolysis through tubular epithelial cell-derived EVs by stabilizing HIF-1α, indicating that regulation of macrophage glycolysis may offer a new treatment strategy for DKD patients, especially those with macroalbuminuria.

Project description:ObjectivesReprogramming of cellular metabolism is profoundly implicated in tumorigenesis and can be exploited to cancer treatment. Cancer cells are known for their propensity to use glucose-dependent glycolytic pathway instead of mitochondrial oxidative phosphorylation for energy generation even in the presence of oxygen, a phenomenon known as Warburg effect. The type II beta regulatory subunit of protein kinase A (PKA), PRKAR2B, is highly expressed in castration-resistant prostate cancer (CRPC) and contributes to tumour growth and metastasis. However, whether PRKAR2B regulates glucose metabolism in prostate cancer remains largely unknown.Materials and methodsLoss-of-function and gain-of-function studies were used to investigate the regulatory role of PRKAR2B in aerobic glycolysis. Real-time qPCR, Western blotting, luciferase reporter assay and chromatin immunoprecipitation were employed to determine the underlying mechanisms.ResultsPRKAR2B was sufficient to enhance the Warburg effect as demonstrated by glucose consumption, lactate production and extracellular acidification rate. Mechanistically, loss-of-function and gain-of-function studies showed that PRKAR2B was critically involved in the tumour growth of prostate cancer. PRKAR2B was able to increase the expression level of hypoxia-inducible factor 1α (HIF-1α), which is a key mediator of the Warburg effect. Moreover, we uncovered that HIF-1α is a key transcription factor responsible for inducing PRKAR2B expression in prostate cancer. Importantly, inhibition of glycolysis by the glycolytic inhibitor 2-deoxy-d-glucose (2-DG) or replacement of glucose in the culture medium with galactose (which has a much lower rate than glucose entry into glycolysis) largely compromised PRKAR2B-mediated tumour-promoting effect. Similar phenomenon was noticed by genetic silencing of HIF-1α.ConclusionsOur study identified that PRKAR2B-HIF-1α loop enhances the Warburg effect to enable growth advantage in prostate cancer.

Dataset Information

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

Publications

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

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