Epidermal growth factor receptor-regulated miR-125a-5p--a metastatic inhibitor of lung cancer.
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ABSTRACT:
SUBMITTER: Wang G
PROVIDER: S-EPMC2776928 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The epithelial-to-mesenchymal transition (EMT) that occurs during embryonic development is recapitulated during tumor metastasis. Important regulators of this process include growth factors, transcription factors, and adhesion molecules. New evidence suggests that microRNA (miRNA) activity contributes to metastatic progression and EMT; however, the mechanisms leading to altered miRNA expression during cancer progression remain poorly understood. Importantly, overexpression of the epidermal growth factor receptor (EGFR) in ovarian cancer correlates with poor disease outcome and induces EMT in ovarian cancer cells. We report that EGFR signaling leads to transcriptional repression of the miRNA miR-125a through the ETS family transcription factor PEA3. Overexpression of miR-125a induces conversion of highly invasive ovarian cancer cells from a mesenchymal to an epithelial morphology, suggesting miR-125a is a negative regulator of EMT. We identify AT-rich interactive domain 3B (ARID3B) as a target of miR-125a and demonstrate that ARID3B is overexpressed in human ovarian cancer. Repression of miR-125a through growth factor signaling represents a novel mechanism for regulating ovarian cancer invasive behavior.
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Project description:Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly cancers world-wide. miR-125a-5p is a tumor suppressor in HCC and other cancers, but its mechanisms of action during HCC tumorigenesis remain largely unknown. In this study, we found that miR-125a-5p expression was significantly lower in HCC tissues and cell lines than matched normal tissues and liver cells. miR-125a-5p overexpression inhibited HCC cell proliferation and induced apoptosis in vitro and in vivo, while miR-125a-5p knockdown had the opposite effects. In addition, PTPN1 and MAP3K11 were identified as targets of miR-125a-5p. Knocking down PTPN1 and MAP3K11 activated the JNK MAPK signaling pathway to suppress HCC cell proliferation and induce apoptosis. Our findings suggest that miR-125a-5p may be a useful therapeutic target for treatment of HCC patients.
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Project description:ObjectiveThis study was carried out to explore the potential involvement of miR-125a-5p in the oncogenic effects of EphA2, TAZ, and TEAD2 and the activity of the Hippo signaling pathway in gastric cancer progression.MethodsIn vitro transfection of miR-125a-5p mimics or inhibitors, qRT-PCR, colony formation assays, and cell invasion assays were used to assess the effect of miR-125a-5p on the growth and invasion in gastric cancer (GC). Male nude mice bearing tumors derived from human GC cells were used for evaluating the effects of miR-125a-5p on tumor growth. Luciferase reporter assay, immunofluorescence, immunohistochemistry, qRT-PCR, and immunoblotting were performed to explore the role of miR-125a-5p in the epithelial-mesenchymal transition (EMT) and association among miR-125a-5p, EphA2, TAZ, and TEAD2 in GC cells.ResultsMiR-125a-5p enhanced GC cell viability and invasion in vitro, whereas inhibition of miR-125a-5p using a specific inhibitor and antagomir suppressed cancer cell invasion and tumor growth. Moreover, inhibition of miR-125a-5p reversed EMT in vitro. miR-125a-5p upregulated the expression of EphA2, TAZ, and TEAD2, promoted TAZ nuclear translocation, and induced changes in the activity of the Hippo pathway by enhancing the expression of TAZ target genes. Finally, miR-125a-5p was overexpressed in late-stage GCs, and positive correlations were observed with its targets EphA2, TAZ, and TEAD2.ConclusionmiR-125a-5p can promote GC growth and invasion by upregulating the expression of EphA2, TAZ, and TEAD2.
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Project description:BackgroundTwo mature microRNAs (miRNAs), hsa-miR-125a-3p and hsa-miR-125a-5p (collectively referred to as hsa-miR-125a-3p/5p), are derived from 3' and 5' ends of pre-miR-125a, respectively. Although impaired regulation of hsa-miR-125a-5p has been observed in some tumors, the role of this miRNA in invasion and metastasis remains unclear, and few studies have examined the function of hsa-miR-125a-3p. In order to characterize the functions of hsa-miR-125a-3p/5p in invasion and metastasis of non-small cell lung cancer (NSCLC), we investigated the relationships between hsa-miR-125a-3p/5p expression and lymph node metastasis in NSCLC tissues. We also explored the impact of expression of these miRNAs on invasive and migratory capabilities of lung cancer cells.MethodsExpression of hsa-miR-125a-3p/5p in NSCLC tissues was explored using real-time PCR. The relationships between hsa-miR-125a-3p/5p expression and pathological stage or lymph node metastasis were assessed using the Spearman correlation test. For in vitro studies, lung cancer cells were transfected with sense and antisense 2'-O-methyl oligonucleotides for gain-of-function and loss-of-function experiments. Transwell experiments were performed to evaluate cellular migration and invasion.ResultsExpression of hsa-miR-125a-3p/5p was lower in NSCLC tissues than in adjacent normal lung tissues (LAC). Furthermore, the results from the Spearman correlation test showed a negative relationship between hsa-miR-125a-3p expression and pathological stage or lymph node metastasis and an inverse relationship between hsa-miR-125a-5p expression and pathological stage or lymph node metastasis. In vitro gain-of-function experiments indicated that hsa-miR-125a-3p and hsa-miR-125a-5p function in an opposing manner, suppressing or enhancing cell migration and invasion in A549 and SPC-A-1 cell lines, respectively. These opposing functions were further validated by suppression of hsa-miR-125a-3p and hsa-miR-125a-5p expression in loss-of-function experiments.ConclusionHsa-miR-125a-3p and hsa-miR-125a-5p play distinct roles in regulation of invasive and metastatic capabilities of lung cancer cells, consistent with the opposing correlations between the expression of these miRNAs and lymph node metastasis in NSCLC. These results provide new insights into the roles of miR-125a family members in the development of NSCLC.
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Project description:The vital roles of long noncoding RNAs (lncRNAs) in the nonsmall cell lung cancer (NSCLC) tumorigenesis are increasingly important. This work aims to investigate the role of lncRNA LINC00460 in the gefitinib resistance of NSCLC cells and discover its relevant mechanism. Our finding reveals that the expression of lncRNA LINC00460 is upregulated in the gefitinib-resistant NSCLC tissue and cells, and closely correlated with advanced tumor stage and clinical poor prognosis outcome. Gain and loss functional assays are performed in gefitinib-resistant NSCLC cells (A549/GR), stating that LINC00460 facilitates the 50% inhibitive concentration of gefitinib for NSCLC cells, multidrug-resistant-related proteins (P-gp, MRP1, and BCRP), as well as the invasion. In vivo, LINC00460 silencing represses the tumor growth. Bioinformatics prediction tools and luciferase analysis confirm that the upregulated LINC00460 sponged miR-769-5p in NSCLC cells; moreover, epidermal growth factor receptor (EGFR) is identified as a direct target gene of miR-769-5p. Verification experiments confirm that the restoration of EGFR could weaken the sensibility of NSCLC cells toward the gefitinib. In conclusion, our result demonstrates that LINC00460 plays a pivotal role in gefitinib resistance of NSCLC cells by targeting EGFR through sponging miR-769-5p. This finding might serve as a therapeutic target for NSCLC.
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Project description:The epidermal growth factor receptor (EGFR) is frequently activated in a wide range of solid tumours and represents an important therapeutic target. MicroRNAs (miRNAs) have recently been recognized as a rational and potential modality for anti-EGFR therapies. However, more EGFR-targeting miRNAs need to be explored. In this study, we identified a novel EGFR-targeting miRNA, miRNA-134 (miR-134), in non-small-cell lung cancer (NSCLC) cell lines. Luciferase assays confirmed that EGFR is a direct target of miR-134. In addition, the overexpression of miR-134 inhibited EGFR-related signaling and suppressed NSCLC cells proliferation by inducing cell cycle arrest and/or apoptosis, suggesting that miR-134 functions as a tumour suppressor in NSCLC. Further mechanistic investigation including RNAi and rescue experiments suggested that the down-regulation of EGFR by miR-134 partially contributes to the antiproliferative role of miR-134. Last, in vivo experiments demonstrated that miR-134 suppressed tumour growth of A549 xenograft in nude mice. Taken together, our findings suggest that miR-134 inhibits non-small cell lung cancer growth by targeting the EGFR.
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Project description:Gastric cancer (GC) is the fourth most common malignant neoplasm and the second leading cause of cancer death. Identification of key molecular signaling pathways involved in gastric carcinogenesis and progression facilitates early GC diagnosis and the development of targeted therapies for advanced GC patients. Emerging evidence has revealed a close correlation between forkhead box (FOX) proteins and cancer development. However, the prognostic significance of forkhead box S1 (FOXS1) in patients with GC and the function of FOXS1 in GC progression remain undefined. In this study, we found that upregulation of FOXS1 was frequently detected in GC tissues and strongly correlated with an aggressive phenotype and poor prognosis. Functional assays confirmed that FOXS1 knockdown suppressed cell proliferation and colony numbers, with induction of cell arrest in the G0/G1 phase of the cell cycle, whereas forced expression of FOXS1 had the opposite effect. Additionally, forced expression of FOXS1 accelerated tumor growth in vivo and increased cell migration and invasion through promoting epithelial-mesenchymal transition (EMT) both in vitro and in vivo. Mechanistically, the core promoter region of FOXS1 was identified at nucleotides -660~ +1, and NFKB1 indirectly bind the motif on FOXS1 promoters and inhibit FOXS1 expression. Gene set enrichment analysis revealed that the FOXS1 gene was most abundantly enriched in the hedgehog signaling pathway and that GLI1 expression was significantly correlated with FOXS1 expression in GC. GLI1 directly bound to the promoter motif of FOXS1 and significantly decreased FOXS1 expression. Finally, we found that miR-125a-5p repressed FOXS1 expression at the translational level by binding to the 3' untranslated region (UTR) of FOXS1. Together, these results suggest that FOXS1 can promote GC development and could be exploited as a diagnostic and prognostic biomarker for GC.
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Project description:Emerging evidence suggests that microRNAs (miRNAs) serve an important role in tumourigenesis and development. Although the low expression of miR-125a-5p in non-small-cell lung cancer (NSCLC) has been reported, the underlying mechanism remains unknown. In the current study, the low expression of miR-125a-5p in NSCLC was verified in paired cancer tissues and adjacent non-tumour tissues. Furthermore, the CpG island in the miR-125a-5p region was hypermethylated in the tumour tissues, and the hypermethylation was negatively correlated with miR-125a-5p expression. Target gene screening showed that the histone methyltransferase Suv39H1 was one of the potential target genes. In vitro studies showed that miR-125a-5p could directly suppress Suv39H1 expression and decrease the H3K9me3 levels. On the other hand, Suv39H1 could induce demethylation of miR-125a-5p, resulting in re-activation of miR-125a-5p. What is more, overexpessing miR-125a-5p could also self-activate the silenced miR-125a-5p in NSCLC cells, which suppressed cell migration, invasion and proliferation in vitro and inhibited cancer progression in vivo Thus, we found that the epigenetic silenced miR-125a-5p could be self-activated through targeting Suv39H1 in NSCLC, suggesting that miR-125a-5p might not only have the potential prognostic value as a tumour biomarker but also be a potential therapeutic target in NSCLC.
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Project description:BackgroundMiR-125a-5p has been reported to be involved in the development and progression of various cancers. However, the biological function and underlying mechanisms in colorectal cancer(CRC) still remain unclear. Here, we explored the potential biological roles of miR-125a-5p in CRC.MethodsThe expression of miR-125a-5p was detected using quantitative real-time PCR (qRT-PCR), biological functions of miR-125a-5p were assessed by cell counting kit-8, wound-healing, transwell invasion, and human umbilical vein endothelial cell (HUVEC) tube formation assays in vitro and animal experiments in vivo.ResultsWe found that miR-125a-5p was downregulated in CRC tissues and cell lines, it inhibited CRC cell proliferation, migration, and invasion and reduced the ability of HUVECs to form tubes. Moreover, we verifed that miR-125a-5p suppressed CRC growth and metastasis in vivo. Additionally, we showed that VEGFA, a direct target gene of miR-125a-5p, could reverse the inhibitory effect caused by miR-125a-5p overexpression.ConclusionmiR-125a-5p might serve as a tumor suppressor in CRC and could be regarded as a potential therapeutic candidate for CRC.
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Project description:Macrophage activation is a central event in immune responses. Macrophages undergoing classical activation (M1 macrophages) are proinflammatory, whereas alternatively activated macrophages (M2 macrophages) are generally anti-inflammatory. miRNAs play important regulatory roles in inflammatory response. However, the manner in which miRNAs regulate macrophage activation in response to different environmental cues has not been well defined. In this study, we found that M-BMM macrophages (M2) express greater levels of miR-125a-5p than do GM-BMM macrophages (M1). Stimulation of macrophages through TLR2 and TLR4 but not through TLR3 enhanced miR-125a-5p expression. Up-regulation of miR-125a-5p after TLR2/4 activation requires the adaptor MYD88 but not TRIF. Overexpression of miR-125a-5p diminished M1 phenotype expression induced by LPS but promoted M2 marker expression induced by IL-4. In contrast, knockdown of miR-125a-5p promoted M1 polarization and diminished IL-4-induced M2 marker expression. We found that miR-125a-5p targets KLF13, a transcriptional factor that has an important role in T lymphocyte activation and inflammation. KLF13 knockdown had similar effects on M1 activation as did miR-125a-5p overexpression. In addition, miR-125a-5p regulates phagocytic and bactericidal activities of macrophages. Our data suggest that miR-125a-5p has an important role in suppressing classical activation of macrophages while promoting alternative activation.
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