MicroRNA-6084 orchestrates angiogenesis and liver metastasis in colorectal cancer via extracellular vesicles
Ontology highlight
ABSTRACT:
ORGANISM(S): synthetic construct Homo sapiens
PROVIDER: GSE297674 | GEO | 2025/06/02
REPOSITORIES: GEO
Similar Datasets
Project description:Background: The cancer-related mortality of primary liver cancer ranks third globally, and hepatocellular carcinoma (HCC) is predominant, posing a serious threat to patients' health. Understanding HCC's pathogenesis and target molecules is crucial for early diagnosis and prognosis. Extracellular vesicles (EVs) and their carried miRNAs impact tumor progression. This study aims to investigate miR-183-5p in HCC cell-derived EVs on angiogenesis, progression, and metastasis, and provide diagnostic and therapeutic evidence. Methods: q-PCR was used to evaluate the expression of miR-183-5p in HCC tissue and plasma EV samples. Contrast-enhanced ultrasound and The Cancer Genome Atlas evaluated its correlation with angiogenesis and prognosis. In vitro, cell counting kit-8 (CCK-8), colony formation, transwell, tube formation, and permeability assays examined the effect of HCC cell-derived EVs on human umbilical vein endothelial cells (HUVECs). Subcutaneous tumor and lung metastasis models in nude mice verified it in vivo effects. RNA sequencing and databases predicted downstream genes and pathways, and dual luciferase and western blotting assays verified binding and activation. Conditioned medium from treated HUVECs was used on HCC cells, and chemokine levels measured. The CCL20/CCR6 axis effect was studied in vitro and in vivo by knocking down CCR6. Results: This study revealed the abnormal upregulation of miR-183-5p in both tissues and plasma EVs from patients with HCC, and its association with unfavorable prognosis. In vivo experiments, the promoting effects of miR-183-5p in HCC cell-derived EVs on the progression, metastasis and angiogenesis were verified by employing subcutaneous tumor formation models and lung metastasis models in nude mice. We demonstrated that miR-183-5p in HCC cell-derived EVs induced HUVECs proliferation, migration, angiogenesis and permeability by downregulating SIK1 expression and activating the PI3K/AKT signaling pathway in vitro. Moreover, stimulated HUVECs could secrete the chemokine CCL20 and induce HCC progression and metastasis through the CCL20/CCR6 signal pathway in vitro and in vivo. Conclusion: The findings indicated that miR-183-5p delivered by EVs from HCC cells is crucial in mediating the communication between HUVECs and HCC cells by modulating the SIK1/PI3K/AKT and CCL20/CCR6 signaling pathways, and EVs-miR-183-5p might be a potential therapeutic target for HCC patients.
2025-03-25 | GSE289187 | GEO
Project description:Colon and liver have an inseparable relationship since embryological development. More than half of colorectal cancer patients developed liver metastases accompanied with poor prognosis. Recent evidence suggests that distant metastatic organs are “educated” by primary tumor-derived extracellular vesicles. Here we found that the liver-specific pro-metastatic effect of colorectal cancer (CRC)-derived small extracellular vesicles (sEVs). In vivo experiments showed that the injected fluorescence-labeled CRC-derived sEVs were accumulated and taken up by macrophages in the mouse liver. MicroRNA sequencing revealed the highest expression of microRNA (miR)-21-5p in CRC-derived sEVs. In vitro co-culture experiments showed that the sEVs polarized macrophages toward an interleukin-6(IL-6)-secreting type of macrophages. Further mouse experiments and microarray studies indicated that the CRC-sEVs increased macrophage invasion and induced an inflammatory microenvironment in the liver, which promoted liver metastasis of orthotropic- transplanted CRC cells. Most importantly, the TCGA data analysis and clinical sample examinations demonstrated that miR-21-5p expressions were sharply raised in the CRC tissues. We apply Tethered Cationic Lipoplex Nanoparticles (tCLN) technology in detecting CRC patients’ sEVs miR-21 in plasma and found strong correlation between sEVs-miR-21 and CRC liver metastasis. The serum IL-6 level was much higher in CRC patients with liver metastasis, and the liver metastasis relevance of MiR-21, macrophages, and IL-6 in CRC patients. Thus, we propose the role of CRC-derived sEVs in the formation of an inflammatory pre-metastatic niche in liver for CRC metastasis through macrophage polarization via a miR-21/TLRs pro-inflammation pathway.
2019-07-01 | GSE100435 | GEO
Project description:Malignant germ-cell-tumours (GCTs) are characterised by microRNA (miRNA/miR-) dysregulation, with universal over-expression of miR-371~373 and miR-302/367 clusters regardless of patient age, tumour site, or subtype (seminoma/yolk-sac-tumour/embryonal carcinoma). These miRNAs are released into the bloodstream, presumed within extracellular-vesicles (EVs) and represent promising biomarkers. Here, we comprehensively examined the role of EVs, and their miRNA cargo, on (fibroblast/endothelial/macrophage) cells representative of the testicular GCT (TGCT) tumour microenvironment (TME). Small RNA next-generation-sequencing was performed on 34 samples, comprising representative malignant GCT cell lines/EVs and controls (testis fibroblast [Hs1.Tes] cell-line/EVs and testis/ovary samples). TME cells received TGCT co-culture, TGCT-derived EVs, and a miRNA overexpression system (miR-371a-OE) to assess functional relevance. TGCT cells secreted EVs into culture media. MiR-371~373 and miR-302/367 cluster miRNAs were overexpressed in all TGCT cells/subtypes compared with control cells and were highly abundant in TGCT-derived EVs, with miR-371a-3p/miR-371a-5p the most abundant. TGCT co-culture resulted in increased levels of miRNAs from the miR-371~373 and miR-302/367 clusters in TME (fibroblast) cells. Next, fluorescent labelling demonstrated TGCT-derived EVs were internalised by all TME (fibroblast/endothelial/macrophage) cells. TME (fibroblast/endothelial) cell treatment with EVs derived from different TGCT subtypes resulted in increased miR-371~373 and miR-302/367 miRNA levels, and other generic (eg, miR-205-5p/miR-148-3p) and subtype-specific (seminoma, eg, miR-203a-3p; yolk-sac-tumour, eg, miR-375-3p) miRNAs. MiR-371a-OE in TME cells resulted in increased collagen contraction (fibroblasts) and angiogenesis (endothelial cells), via direct mRNA downregulation and alteration of relevant pathways. TGCT cells communicate with nontumour stromal TME cells through release of EVs enriched in oncogenic miRNAs, potentially contributing to tumour progression.
2023-09-30 | E-MTAB-13322 | biostudies-arrayexpress
Project description:Background: circRNAs, a recently identified new member of non-coding RNAs, have been proved to play an essential role in the development and progression of various cancers. However, the functions and mechanisms of circRNAs in colorectal liver metastasis have not been fully elucidated. Methods: We performed circRNA microarray to screen differentially expressed novel circRNAs in the pathology of colorectal liver metastasis. Quantitative real-time PCR was used to detect the circ102049 expression in colorectal cancer (CRC) samples. Then CRC cells were transfected with a circ102049 over-expression vector or siRNAs, and the effects of circ102049 on biological functions in CRC cells were accessed in vitro. Mechanistically, the bioinformatics analysis, fluorescence in situ hybridization, RIP assay, RNA pull down assay and luciferase reporter assay were conducted to confirm the relationships among circ102049, miR-761, miR-192-3p and FRAS1. Moreover, the mechanism of circ102049 how to recruit and distribute DGCR8 protein in cytoplasm was elucidated. Results: The results showed that circ102049 was highly expressed in primary CRC tumors with liver metastasis and closely correlated with the CRC patients' prognosis. Circ102049 might act as a novel metastasis-related non-coding RNA, and significantly promote the adhesion, migration and invasion abilities of CRC cells. Mechanistically, we verified that circ102049 promoted the CRC development and progression via a miR-761/miR-192-3p-FRAS1-dependent mechanism. Notably, due to the distribution of DGCR8 protein, circ102049 might also reduce the mature products of miR-761 and miR-192-3p in cytoplasm indirectly. In addition, the role of circ102049 in promoting colorectal liver metastasis was also confirmed in vivo. Conclusions: Our findings provided new clues that circ102049 might be a potential prognostic factor in CRC, and the circ102049-miR-761/miR-192-3p-FRAS1 axis could be further explored as a therapeutic target for anti-metastatic therapy in CRC patients with liver metastases. Keywords: Hsa_circ_102049, miR-761, miR-192-3p, FRAS1, Colorectal liver metastasis
2021-02-08 | GSE147597 | GEO
Project description:Background: circRNAs, a recently identified new member of non-coding RNAs, have been proved to play an essential role in the development and progression of various cancers. However, the functions and mechanisms of circRNAs in colorectal liver metastasis have not been fully elucidated. Methods: We performed circRNA microarray to screen differentially expressed novel circRNAs in the pathology of colorectal liver metastasis. Quantitative real-time PCR was used to detect the circ102049 expression in colorectal cancer (CRC) samples. Then CRC cells were transfected with a circ102049 over-expression vector or siRNAs, and the effects of circ102049 on biological functions in CRC cells were accessed in vitro. Mechanistically, the bioinformatics analysis, fluorescence in situ hybridization, RIP assay, RNA pull down assay and luciferase reporter assay were conducted to confirm the relationships among circ102049, miR-761, miR-192-3p and FRAS1. Moreover, the mechanism of circ102049 how to recruit and distribute DGCR8 protein in cytoplasm was elucidated. Results: The results showed that circ102049 was highly expressed in primary CRC tumors with liver metastasis and closely correlated with the CRC patients' prognosis. Circ102049 might act as a novel metastasis-related non-coding RNA, and significantly promote the adhesion, migration and invasion abilities of CRC cells. Mechanistically, we verified that circ102049 promoted the CRC development and progression via a miR-761/miR-192-3p-FRAS1-dependent mechanism. Notably, due to the distribution of DGCR8 protein, circ102049 might also reduce the mature products of miR-761 and miR-192-3p in cytoplasm indirectly. In addition, the role of circ102049 in promoting colorectal liver metastasis was also confirmed in vivo. Conclusions: Our findings provided new clues that circ102049 might be a potential prognostic factor in CRC, and the circ102049-miR-761/miR-192-3p-FRAS1 axis could be further explored as a therapeutic target for anti-metastatic therapy in CRC patients with liver metastases. Keywords: Hsa_circ_102049, miR-761, miR-192-3p, FRAS1, Colorectal liver metastasis
2021-02-08 | GSE147603 | GEO
Project description:Background: circRNAs, a recently identified new member of non-coding RNAs, have been proved to play an essential role in the development and progression of various cancers. However, the functions and mechanisms of circRNAs in colorectal liver metastasis have not been fully elucidated. Methods: We performed circRNA microarray to screen differentially expressed novel circRNAs in the pathology of colorectal liver metastasis. Quantitative real-time PCR was used to detect the circ102049 expression in colorectal cancer (CRC) samples. Then CRC cells were transfected with a circ102049 over-expression vector or siRNAs, and the effects of circ102049 on biological functions in CRC cells were accessed in vitro. Mechanistically, the bioinformatics analysis, fluorescence in situ hybridization, RIP assay, RNA pull down assay and luciferase reporter assay were conducted to confirm the relationships among circ102049, miR-761, miR-192-3p and FRAS1. Moreover, the mechanism of circ102049 how to recruit and distribute DGCR8 protein in cytoplasm was elucidated. Results: The results showed that circ102049 was highly expressed in primary CRC tumors with liver metastasis and closely correlated with the CRC patients' prognosis. Circ102049 might act as a novel metastasis-related non-coding RNA, and significantly promote the adhesion, migration and invasion abilities of CRC cells. Mechanistically, we verified that circ102049 promoted the CRC development and progression via a miR-761/miR-192-3p-FRAS1-dependent mechanism. Notably, due to the distribution of DGCR8 protein, circ102049 might also reduce the mature products of miR-761 and miR-192-3p in cytoplasm indirectly. In addition, the role of circ102049 in promoting colorectal liver metastasis was also confirmed in vivo. Conclusions: Our findings provided new clues that circ102049 might be a potential prognostic factor in CRC, and the circ102049-miR-761/miR-192-3p-FRAS1 axis could be further explored as a therapeutic target for anti-metastatic therapy in CRC patients with liver metastases. Keywords: Hsa_circ_102049, miR-761, miR-192-3p, FRAS1, Colorectal liver metastasis
2021-02-08 | GSE147602 | GEO
Project description:Ischemia and hypoxia caused by vascular injury aggravate nerve injury. The extracellular vesicles from skin precursor-derived Schwann cells (SKP-SC-EVs) have proven to be beneficial to the regeneration of peripheral nerve injury, but whether SKP-SC-EVs can repair injured peripheral nerves by promoting angiogenesis remains unclear. Here, we found that SKP-SC-EVs enhanced the angiogenesis, which were verified by the transparency of tissue engineered nerve graft (TENG) and ultrasonic blood flow imaging. In vitro we verified that SKP-SC-EVs promote the proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs), which were traditionally used for the evaluating angiogenesis capacity. Furthermore, the expression pattern of microRNA (miRNA) in SKP-SC-EVs was profiled and functional experiments were screened. Notably, miR-30a-5p was selected because of the remarkably pro-angiogenic ability in vivo and in vitro, which was similar to the effects of SKP-SC-EVs. Luciferase reporter assay and functional experiments revealed miR-30a-5p contained in SKP-SC-EVs promoted angiogenesis by targeting ANGPT2 and LIF in the insufficient of VEGFa. Taken together, miR-30a-5p enriched in SKP-SC-EVs may be a key regulator of angiogenesis for the cell-free treatment for peripheral nerve injury.
2025-02-12 | GSE245328 | GEO
Project description:Using the orthotopic breast cancer xenograft model of basal-like breast cancer MDA-MB-231 line, we have found that the expression of miRNAs encoded by MIR17HG was significantly decreased in cells isolated from spontaneous lung metastases compared to cells from primary tumors grown in orthotopic sites. We investigated the role of a MIR17HG family member, miR-18a, in primary tumor growth and pulmonary metastasis from the orthotopic site. We demonstrated that enforced expression of exogenous miR-18a, significantly limited continuous growth of primary tumors in mammary gland fat pads and reduced spontaneous lung metastasis. Further investigation on the mechanism of miR-18a action led to the finding that the expression of HIF1A, a key regulator of tumor metastasis, was regulated by miR-18a. Enforced miR-18a expression significantly decreased HIF1A expression at both mRNA and protein levels, resulting in altered transcriptional response and decreased survival of cells in response to Cobalt(II) chloride (CoCl2), a hypoxia-mimicking agent. Conversely, miR-18a knockdown significantly increased HIF1A expression levels and enhanced cell survival in response to CoCl2. Analysis of expression data of human breast tumor tissues showed that miR-18a expression is inversely correlated with HIF1A expression in basal-like breast tumors, supporting a role of miR-18a in restricting HIF1A expression in this subtype of breast cancer. In addition, we demonstrated that hypoxia inhibits miR-18a expression, likely through MYC inactivation. Furthermore, gene expression and functional analysis revealed that miR-18a also plays a role in regulating cell adhesion, migration and invasion. Taken together, this study provides evidence for a novel role of miR-18a to inhibit breast cancer metastasis. Our results suggest that miR-18a downregulation might provide tumor cells survival/growth advantage under hypoxic pressure in basal-like breast cancer. A lung metastatic subline, designated as MB231RN-LM, was derived from MDA-MB-231 breast cancer cells through in vivo selection. The MB231RN-LM cells were stably transfected with has-miR-18a or control vector and treated with 200uM Cobalt(II) chloride (CoCl2, a hypoxia-mimicking agent) for 4 hr. A total of 8 samples were subjected to microarray analysis, with two biological repeats for each experiment condition.
2013-07-31 | E-GEOD-45362 | biostudies-arrayexpress
Project description:Cancer cells secrete extracellular vesicles (EV) encapsulating bioactive cargoes to facilitate inter-organ communication in vivo and are emerging as critical mediators of tumor progression and metastasis, a condition which is often accompanied by a dysregulated cholesterol metabolism. Whether EVs are involved in the control of cholesterol homeostasis during tumor metastasis is still undefined and warrant further investigation. Here, we find that breast cancer-derived exosomal miR-9-5p induces the expression of HMGCR and CH25H, two enzymes involved in cholesterol synthesis and the conversion of 25-hydroxycholesterol from cholesterol by targeting INSIG1, INSIG2 and ATF3 genes in the liver. Notably, in vivo miR-9-5p antagomir treatment and genetic CH25H ablation prevents tumor metastasis in a mouse model of breast cancer. Thus, our findings reveal the regulatory mechanism of tumor-derived miR-9-5p in liver metastasis by linking oxysterol metabolism and Kupffer cell polarization, shedding light on future applications for cancer diagnosis and treatment.
2024-08-31 | GSE222708 | GEO
Project description:WNT2 is important for placenta vascularization and acts as a pro-angiogenic factor for liver and other endothelial cells (ECs). WNT2 induction has been shown in many carcinomas and is associated with tumor progression. In colorectal cancer (CRC) WNT2 is selectively elevated in cancer associated fibroblasts (CAFs), leading to increased invasion and metastasis. However, if there is a role for WNT2 in colon cancer angiogenesis has not been addressed so far. Here, we demonstrate that WNT2 enhances EC migration and invasion, while it induces ß catenin dependent signaling in only a small subset of HUVECs. We show that siRNA-mediated knockdown of WNT2 in CAFs reduced the growth of vessel-like structures significantly in a co-culture assay, while the overexpression of WNT2 in skin fibroblasts otherwise being devoid of WNT2 led to increased angiogenesis in vitro. In a xenograft model, overexpression of WNT2 in HCT116 led to enhanced tumor volume and vessel density. Moreover, WNT2 expression correlates with vessel markers in human CRC. Secretome profiling of CAFs revealed that proteins related to angiogenesis and extracellular matrix (ECM) remodeling are regulated by WNT2. Thus, stroma-derived WNT2 positively affects angiogenesis in CRC by shifting the balance towards pro-angiogenic signals.
2020-05-26 | PXD014019 | Pride