MicroRNA-653-5p Promotes Gastric Cancer Proliferation and Metastasis by Targeting the SOCS6-STAT3 Pathway.
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ABSTRACT:
SUBMITTER: Li Z
PROVIDER: S-EPMC8082248 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background:MicroRNA (miRNA) array analysis has reported that the expression of miR-593-5p is associated with lymph node metastasis in gastric cancer (GC); however, the function and mechanism of miR-593-5p in GC have not been described yet. miR-593-5p has also not been elucidated widely in other cancers. Methods:miR-593-5p expression was detected by quantitative RT-PCR (qRT-PCR) in human GC tissues and cell lines. Cell proliferation was investigated using CCK-8 assays, cell cycle was detected by flow cytometric method, and cell migration and invasion abilities were evaluated by wound-healing and transwell assays. miR-593-5p-influenced gene expression profiles were detected by total gene expression chip method in MGC-803 cells, and miR-593-5p candidate target genes were predicted using bioinformatics methods. The candidate target gene and downstream of miR-593-5p were determined by qRT-PCR, Western blot, and dual-luciferase reporter assays. The effects of miR-593-5p on the growth and metastasis of GC were evaluated by tumor xenograft experiment in vivo. Results:miR-593-5p was frequently downregulated in GC patients and GC cell lines. miR-593-5p was significantly correlated with tumor size and distant metastasis in GC patients. miR-593-5p inhibited cell proliferation, migration, and invasion and also arrested cell cycle at the G0/G1 phase in SGC-7901 and MGC-803 cells in vitro. miR-593-5p also suppressed tumor growth and metastasis in vivo. miR-593-5p influenced gene expression profile in MGC-803 cells. MST4 was indirectly targeted by miR-593-5p. miR-593-5p also downregulated FAK, MMP12, and JUN protein expression. Conclusion:Our study suggests that miR-593-5p may function as a tumor suppressor in GC through a mechanism that regulates JUN pathway via indirectly targeting the MST4 gene.
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Project description:MicroRNAs (miRNAs) have been demonstrated to affect the biological processes of cancers and showed great potential for prognostic biomarkers. In this study, we screened differentially expressed miRNAs in ccRCC based on three dimensions of metastasis, prognosis, and differential expression compared to normal tissue using bioinformatics algorithms. MiR-153-5p was identified as a candidate miRNA to promote ccRCC occurrence and progression. Clinically, we found that miR-153-5p was significantly upregulated and related to unfavorable clinical features in ccRCC. Besides, miR-153-5p served as an independent prognostic biomarker. Functionally, miR-153-5p depletion remarkably inhibited the proliferation and metastasis of ccRCC via the phosphatidylinositol 3-kinase (PI3K)/Akt signaling. Furthermore, AGO1 was proved to be a direct target of miR-153-5p. AGO1 is associated with favorable clinical features and exhibited independent prognostic value in ccRCC. Besides, we observed that AGO1 knockdown significantly promoted tumor proliferation and metastasis. Downregulation of AGO1 partly abolished the oncogenic effects of miR-153-5p knockdown. Furthermore, miR-153-5p combined with AGO1 showed more robust prognostic significance in ccRCC. In conclusion, we found that the newly identified miR-153-5p/AGO1 axis was responsible for tumor occurrence and progression via PI3K/Akt signaling, which may therefore provide promising therapeutic targets and prognostic biomarkers for patients with ccRCC.
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Project description:As a vital feature of the microenvironment, hypoxia, especially long-term hypoxia, is known to promote metastasis and lead to poor prognosis in solid tumors. Circular RNAs (circRNAs) participate in important processes of cell proliferation and metastasis in cancers. However, the contribution of circRNAs to metastasis under long-term hypoxia is obscure. In this study, we aim to explore specific functions of circHIPK3 in long-term hypoxia-promoting metastasis of gastric cancer (GC). The hypoxic resistant gastric cancer (HRGC) cell lines we established previously, which were tolerant to 2% O2 conditions, were used as the long-term hypoxia model. We found that circHIPK3 was upregulated by HIF-2α in HRGC cells, and circHIPK3 facilitated the migration and invasion ability of HRGC cells. Further investigation proved that circHIPK3 promoted metastasis of HRGC cells directly by interacting with miR-653-5p and miR-338-3p to relieve the suppression of neuropilin 1 (NRP1), resulting in the activation of downstream ERK and AKT pathways. Our study identified oncogene functions of circHIPK3 under a long-term hypoxic microenvironment and the possibility of using circHIPK3 as a potential biomarker of long-term hypoxia in GC. In conclusion, circHIPK3 could promote GC metastasis via the miR-653-5p/miR-338-3p-NRP1 axis under a long-term hypoxic microenvironment.
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Project description:BackgroundMore and more studies have shown that circular RNAs (circRNAs) play a critical regulatory role in many cancers. However, the potential molecular mechanism of circRNAs in prostate cancer (PCa) remains largely unknown.MethodsDifferentially expressed circRNAs were identified by RNA sequencing. The expression of hsa_circ_0003258 was evaluated using quantitative real-time PCR and RNA in situ hybridization. The impacts of hsa_circ_0003258 on the metastasis of PCa cells were investigated by a series of in vitro and in vivo assays. Lastly, the underlying mechanism of hsa_circ_0003258 was revealed by Western blot, biotin-labeled RNA pulldown, RNA immunoprecipitation, luciferase assays and rescue experiments.ResultsIncreased expression of hsa_circ_0003258 was found in PCa tissues and was associated with advanced TNM stage and ISUP grade. Overexpression of hsa_circ_0003258 promoted PCa cell migration by inducing epithelial mesenchymal transformation (EMT) in vitro as well as tumor metastasis in vivo, while knockdown of hsa_circ_0003258 exerts the opposite effect. Mechanistically, hsa_circ_0003258 could elevate the expression of Rho GTPase activating protein 5 (ARHGAP5) via sponging miR-653-5p. In addition, hsa_circ_0003258 physically binds to insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) in the cytoplasm and enhanced HDAC4 mRNA stability, in which it activates ERK signalling pathway, then triggers EMT programming and finally accelerates the metastasis of PCa.ConclusionsUpregulation of hsa_circ_0003258 drives tumor progression through both hsa_circ_0003258/miR-653-5p/ARHGAP5 axis and hsa_circ_0003258/IGF2BP3 /HDAC4 axis. Hsa_circ_0003258 may act as a promising biomarker for metastasis of PCa and an attractive target for PCa intervention.
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Project description:Osteosarcoma is a highly malignant tumor that occurs in the bone. Previous studies have shown that multiple microRNAs (miRNAs) regulate the development of osteosarcoma. This study aimed to explore the role of miR-629-5p and its target gene, caveolin 1 (CAV1), in osteosarcoma development. To analyze the expression of miR-629-5p and CAV1 mRNA in osteosarcoma tissues and cell lines, qRT-PCR analysis was performed. Dual-luciferase reporter experiments were subsequently performed to validate the relationship between CAV1 and miR-629-5p. CCK8 assay was used to measure osteosarcoma cell proliferation, and wound-healing assay was performed to study their migratory phenotype. Our findings revealed that miR-629-5p was overexpressed in osteosarcoma tissues and cells, and thereby enhanced cell proliferation and migration. Further, we validated that miR-629-5p targets CAV1 mRNA directly. CAV1 expression, which was negatively correlated with miR-629-5p expression, was found to be downregulated in osteosarcoma tissue samples. Moreover, our data showed that an increase in CAV1 level led to a decline in osteosarcoma cell proliferation and migration, which could be rescued by miR-629-5p upregulation. Overall, our study confirmed that miR-629-5p promoted osteosarcoma proliferation and migration by directly inhibiting CAV1.
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Project description:BackgroundBreast cancer is the most common cancer type in female. As microRNAs play vital role in breast cancer, this study aimed to explore the molecular mechanism and clinical value of miR-21 in breast cancer.MethodsqRT-PCR was performed to detect miR-21 levels in plasma of 127 healthy controls, 82 benign breast tumor, 252 breast cancer patients, as well as in breast cancer cell lines. Transwell and wound healing assay were used to analyze breast cancer metastasis in response to miR-21 inhibitor. Colony formation and eFluor™ 670 based flow cytometric analysis were used to test breast cancer proliferation following miR-21 inhibitor treatment. Leucine zipper transcription factor-like 1 (LZTFL1), the target gene of miR-21 was predicted by MIRDB, TargetScan 5.1, PicTar and miRanda. Survival analysis of LZTFL1 levels in breast cancer prognosis was estimated with the Kaplan-Meier method by log-rank test according to data from the Cancer Genome Atlas. Luciferase activity assay was performed to confirm the regulation of miR-21 on LZTFL1. LZTFL1 siRNA and miR-21 inhibitor were co-transfected to breast cancer cells, then cell proliferation, migration and epithelial-mesenchymal transition (EMT) makers were tested. BALB/c nude mice were injected in situ with Hs578T cells stably overexpressing miR-21. Breast tumor growth, metastasis and the expression of EMT markers or LZTFL1 were detected in vivo.ResultsPlasma miR-21 levels were elevated in breast cancer patients compared with healthy controls and benign breast tumor patients, and the miR-21 levels were significantly decreased after surgery comparing with pre operation in 44 patients. Inhibition of miR-21 suppressed cell proliferation and metastasis in breast cancer cells. LZTFL1 was identified as a novel target gene of miR-21. Knockdown of LZTFL1 overcame the suppression of miR-21 inhibitor on cell proliferation, metastasis and the expression of EMT markers in breast cancer cells. miR-21 overexpression promoted breast cancer cell proliferation and metastasis in vivo.ConclusionsThese results indicate that plasma miR-21 level is a crucial biomarker for breast cancer diagnosis and targeting miR-21-LZTFL1-EMT axis might be a promising strategy in breast cancer therapy.Trial registrationRetrospectively registered.
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Project description:Gallbladder carcinoma (GBC), the most common malignant tumour of the bile duct, is highly aggressive and has a poor prognosis. MicroRNA-30a-5p (miR-30a-5p) is an important tumour suppressor that participates in many aspects of carcinogenesis and cancer development. However, the role of miR-30a-5p in GBC development remains to be determined, as do the mechanisms underlying its effects in GBC. Using samples collected from 42 subjects with gallbladder carcinoma (GBC), we showed decreased miR-30a-5p expression in the primary lesions vs. non-tumour adjacent tissues (NATs). Decreased miR-30a-5p was associated with shorter disease-free survival (DFS) and overall survival (OS). Inhibiting miR-30a-5p expression in 2 representative GBC cell lines (GBC-SD and NOZ) increased cell proliferation, migration, invasiveness, as well as β-catenin nuclear translocation, vice versa. In nude mice, NOZ cells transfected with miR-30a-5p mimics grew slower (vs. miR-NC) upon subcutaneous inoculation, and had lower rate of hepatic metastasis upon spleen inoculation. Dual luciferase assay confirmed that E2F transcription factor 7 (E2F7) was a direct target of miR-30a-5p and antagonized the effects induced by miR-30a-5p downregulation in GBC cells. MiR-30a-5p attenuates the EMT and metastasis in GBC cells by targeting E2F7, suggesting miR-30a-5p is a tumour suppressor that may serve as a novel potential prognostic biomarker or molecular therapeutic target for GBC.
| S-EPMC5852001 | biostudies-literature
Project description:BackgroundExtracellular vesicles (EVs) derived from tumor-associated macrophages are implicated in the progression and metastasis of gastric cancer (GC) via the transfer of molecular cargo RNAs. We aimed to decipher the impact of microRNA (miR)-15b-5p transferred by M2 macrophage-derived EVs in the metastasis of GC.MethodsExpression of miR-15b-5p was assessed and the downstream genes of miR-15b-5p were analyzed. GC cells were subjected to gain- and loss-of function experiments for miR-15b-5p, BRMS1, and DAPK1. M2 macrophage-derived EVs were extracted, identified, and subjected to co-culture with GC cells and their biological behaviors were analyzed. A lung metastasis model in nude mice was established to determine the effects of miR-15b-5p on tumor metastasis in vivo.ResultsmiR-15b-5p was upregulated in GC tissues and cells as well as in M2 macrophage-derived EVs. miR-15b-5p promoted the proliferative and invasive potentials, and epithelial-mesenchymal transition (EMT) of GC cells. M2 macrophage-derived EVs could transfer miR-15b-5p into GC cells where it targeted BRMS1 by binding to its 3'UTR. BRMS1 was enriched in the DAPK1 promoter region and promoted its transcription, thereby arresting the proliferative and invasive potentials, and EMT of GC cells. In vivo experiments demonstrated that orthotopic implantation of miR-15b-5p overexpressing GC cells in nude mice displayed led to enhanced tumor metastasis by inhibiting the BRMS1/DAPK1 axis.ConclusionsOverall, miR-15b-5p delivered by M2 macrophage-derived EVs constitutes a molecular mechanism implicated in the metastasis of GC, and may thus be considered as a novel therapeutic target for its treatment.
| S-EPMC9027839 | biostudies-literature