MiR-512-5p suppresses the progression of non-small cell lung cancer by targeting β-catenin.
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ABSTRACT:
SUBMITTER: Wang Z
PROVIDER: S-EPMC6923952 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:MicroRNAs (miRNAs) comprise a class of short, non-coding RNAs that directly target 3'UTR of mRNA, causing subsequent degradation or suppression of translation. Here, we verified that miR-199a-5p was significantly down-regulated in mouse NSCLC tissues and human patient samples. To further study the function of miR-199a-5p, lentivirus system was adopted to construct stably over-expressing miR-199a-5p A549, SPC-A1 and H1299 cell lines. Then, miR-199a-5p played a tumor suppression role via directly targeting MAP3K11 gene in non-small cell lung cancer (NSCLC). Elevated miR-199a-5p suppressed cell proliferation and arrested cell cycle in G1 phase. We found that MAP3K11 was negatively correlated with miR-199a-5p in NSCLC patient tissues and mouse xenograft tumors. Our results suggest that miR-199a-5p together with its target gene MAP3K11 is a key factor and constitutes a complicated regulation network in NSCLC.
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Project description:Dysregulated microRNAs (miRNAs) play crucial roles in the regulation of cancer stem cells (CSCs), and CSCs are closely associated with tumor initiation, metastasis, and recurrence. Here we found that miR-150-5p was significantly downregulated in CSCs of non-small-cell lung cancer (NSCLC) and its expression level was negatively correlated with disease progression and poor survival in patients with NSCLC. Inhibition of miR-150-5p increased the CSC population and sphere formation of NSCLC cells in vitro and stimulated NSCLC cell tumorigenicity and metastatic colonization in vivo. In contrast, miR-150-5p overexpression potently inhibited sphere-formed NSCLC cell tumor formation, metastatic colonization, and recurrence in xenograft models. Furthermore, we identified that miR-150-5p significantly inhibited wingless (Wnt)-β-catenin signaling by simultaneously targeting glycogen synthase kinase 3 beta interacting protein (GSKIP) and β-catenin in NSCLC cells. miR-150-5p also targeted high mobility group AT-hook 2 (HMGA2), another regulator of CSCs, and Wnt-β-catenin signaling. The restoration of HMGA2 and β-catenin blocked miR-150-5p overexpression-induced inhibition of CSC traits in NSCLC cells. These findings suggest that miR-150-5p functions as a CSC suppressor and that overexpression of miR-150-5p may be a novel strategy to inhibit CSC-induced metastasis and recurrence in NSCLC.
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Project description:Non?small?cell lung cancer (NSCLC) is well established as one of the major subtypes of human lung cancer. NSCLC is characterized by a high incidence rate and poor patient prognosis. Previous studies have identified that long intergenic non-coding RNA (lincRNA) serves a key role in the development of tumor and malignant metastasis. However, the majority of the underlying mechanisms for lincRNA deregulation in various diseases, including cancer and diabetes, have not been completely elucidated. In the present study, the deregulation of lincRNA?p21 in NSCLC tumor tissues in comparison to adjacent healthy tissues was examined using reverse transcription?quantitative polymerase chain reaction. Furthermore, the effect of lincRNA?p21 overexpression and knockdown on different NSCLC cell lines was further investigated in vitro. The association between lincRNA?p21 expression and microRNA (miR)?17?5p level in NSCLC tumor cells was also investigated to clarify the underlying mechanism. The influence of miR?17?5p on different NSCLC cell lines A549 and PC9 were also examined in vitro using miR?17?5p mimics and inhibitors. Bioinformatics and luciferase assays were conducted to verify the direct binding sites on lincRNA?p21 for miR?17?5p. The results demonstrated that there was a significant low?expression of lincRNA?p21 in NSCLC tumor tissues, and lincRNA?p21 effectively inhibited the progression of lung cancer cells by suppressing cell proliferation and migration and promoting cell apoptosis. An evident negative association between lincRNA?p21 and miR?17?5p expression was observed, and the inhibitory effect of overexpressed lincRNA?p21 on lung cancer cells was counteracted by miR?17?5p. Bioinformatics and luciferase reporter analysis results confirmed that miR?17?5p is a direct target for lincRNA?p21. The present study provides evidence for lincRNA?p21 to inhibit the progression of NSCLC via direct targeting of a miR?17?5p associated signaling pathway.
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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:MicroRNA-302a-5p (miR-302a-5p) has been implicated in several cancers; however, its role in human non-small cell lung carcinoma (NSCLC) remains unknown. In this study, we showed that miR-302a-5p is downregulated in NSCLC tissues and cell lines. Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays showed that overexpression of a miR-302a-5p mimic suppressed NSCLC cell proliferation, which was confirmed by the results of a cell cycle assay. Overexpression of miR-302a-5p also reduced the migration and invasion of NSCLC cells. Additionally, miR-302a-5p overexpression significantly inhibited NSCLC growth and metastasis in a mouse xenograft model. With regard to the underlying mechanism, integrin α6 (ITGA6) mRNA was shown to be a novel target of miR-302a-5p, and overexpression of ITGA6 attenuated the inhibitory effects of miR-302a-5p on the proliferation and migration of NSCLC cells. In clinical NSCLC samples, miR-302a-5p expression was negatively correlated with ITGA6 expression, which was high in the samples. Collectively, these results indicate that miR-302a-5p acts as a tumor suppressor in NSCLC by directly targeting ITGA6 mRNA and may be useful as a theranostic biomarker of NSCLC.
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Project description:Background: Increasing circular RNAs (circRNAs) are reported to participate in cancer progression. Nonetheless, the role of circRNAs in nasopharyngeal carcinoma (NPC) has not been fully clarified. This work is aimed to probe the role of circ_0000215 in NPC. Methods: Circ_0000215 expression in NPC tissues and cell lines was examined by quantitative real-time polymerase chain reaction (qRT-PCR). Cell counting kit-8 (CCK-8) assay, 5-bromo-2'-deoxyuridine (BrdU) assay, scratch healing assay and Transwell experiment were executed to investigate the regulatory function of circ_0000215 on the proliferation, migration and invasion of NPC cells. RNA immunoprecipitation (RIP), pull-down and dual-luciferase reporter experiments were utilized to determine the binding relationship between circ_0000215 and miR-512-5p, and between miR-512-5p and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) 3'UTR. The effects of circ_0000215 on NPC growth and metastasis in vivo were examined with nude mice model. Western blot was applied to detect the regulatory effects of circ_0000215 and miR-512-5p on PIK3R1 expression. Results: Circ_0000215 was overexpressed in NPC tissues and cell lines. The functional experiments confirmed that knockdown of circ_0000215 impeded the growth and metastasis of NPC cells in vitro and in vivo. Additionally, circ_0000215 could also work as a molecular sponge to repress miR-512-5p expression. PIK3R1 was validated as a target gene of miR-512-5p, and circ_0000215 could increase the expression level of PIK3R1 in NPC cells via suppressing miR-512-5p. Conclusion: Circ_0000215 is overexpressed in NPC and exerts oncogenic effects in NPC through regulating miR-512-5p/PIK3R1 axis.
| S-EPMC8577859 | biostudies-literature
Project description:Sulforaphane is a common antioxidant selectively abundant in cruciferous plants, which exhibits effective anti-cancer actions in control of tumorigenesis or progression of various cancers. A recent study has shown that sulforaphane attenuates the EGFR signaling pathway in non-small cell lung cancer (NSCLC), suggesting its potential anti-metastatic effects. In this study we assessed the involvement of sulforaphane and miR-616-5p in epithelial-mesenchymal transition (EMT) and NSCLC metastasis. Sulforaphane suppressed the cell proliferation in human NSCLC cell lines H1299, 95C and 95D with IC50 values of 9.52±1.23, 9.04±1.90 and 17.35±2.03 μmol/L, respectively. At low concentrations (1-5 μmol/L), sulforaphane dose-dependently inhibited the migration and invasion of 95D and H1299 cells with relatively high metastatic potential. The anti-metastatic action of sulforaphane was confirmed in 95D and H1299 cell xenografts in vivo. In fresh NSCLC tissue samples from 179 patients, miR-616-5p levels were upregulated in late-stage NSCLCs, and strongly correlated with risk of NSCLC recurrence and metastasis. Consistent with the clinic observation, miR-616-5p levels in the 3 NSCLC cell lines were correlated with their metastatic ability, and were decreased by sulforaphane treatment. Silencing miR-616-5p markedly suppressed the migration and invasion of 95D cells in vitro and NSCLC metastasis in vivo. Further studies revealed that miR-616-5p directly targeted GSK3β and decreased its expression, whereas sulforaphane decreased miR-616-5p levels by histone modification, and followed by inactivation of the GSK3β/β-catenin signaling pathway and inhibition of EMT, which was characterized by loss of epithelial markers and acquisition of a mesenchymal phenotype in NSCLC cells. Our findings suggest that sulforaphane is a potential adjuvant chemotherapeutic agent for the prevention of NSCLC recurrence and metastasis, and miR-616-5p can be clinically utilized as a biomarker or therapeutic target to inhibit metastasis.
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Project description:The class III histone deacetylase silent information regulator 1 (SIRT1) is frequently overexpressed in a variety of tumors, including lung cancer; however, its regulatory mechanisms are largely unknown. In this study, we found that an inconsistent trend between SIRT1 protein and mRNA levels in human lung cancer tissues, suggesting that a post-transcriptional mechanism may involved in SIRT1 regulation. Because microRNAs are important post-transcriptional regulators of gene expression, candidate miRNAs that could potentially bind SIRT1 were gained through bioinformatics analyses. We further experimentally validated SIRT1 as the direct target of miR-30a by evaluating SIRT1 expression in lung cancer cells after the overexpression or knockdown of miR-30a and by luciferase assay. Moreover, we showed that miR-30a inhibited proliferation, invasion and promoted apoptosis of lung cancer cells by inhibiting SIRT1 in vitro and in vivo. Taken together, this study identified a new regulatory axis in which miR-30a and SIRT1 regulate the proliferation, invasion and apoptosis of lung cancer cells and lung tumorigenesis.
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Project description:Accumulated evidence indicates that miR-455-5p functions as tumor suppressor in the progression of various cancers. However, the mechanism through which miR-455-5p influences the tumorigenesis of human prostate cancer (PCa) remains undetermined. In this study, reanalysis of data obtained from the Memorial Sloan Kettering Cancer Center showed that miR-455-5p can be used as biomarker for PCa diagnosis and predictor of poor prognosis. Functional assays indicated that miR-455-5p overexpression could suppress cellular proliferation, inhibit tumor growth, and trigger apoptosis by activating and cleaving caspase 3. We experimentally verified that miR-455-5p negatively regulated the C-C motif chemokine receptor 5 (CCR5). Overall, our data demonstrate that miR-455-5p suppressed PCa cellular proliferation and induced cell apoptosis by downregulating CCR5. Thus, miR-455-5p may be considered a new therapeutic strategy for PCa.
| S-EPMC6487172 | biostudies-literature
Project description:BackgroundWe aimed to investigate the correlation of Circ-SMARCA5 with disease severity and prognosis in multiple myeloma (MM), and its underlying mechanisms in regulating cell proliferation and apoptosis.MethodsBone marrow samples from 105 MM patients and 36 healthy controls were collected for Circ-SMARCA5 expression measurement. And the correlation of Circ-SMARCA5 expression with patients' characteristics and survival was determined. In vitro, the effect of Circ-SMARCA5 on MM cell proliferation and apoptosis was evaluated by altering Circ-SMARCA5 expression through transfection. Rescue experiments and luciferase assay were further performed to explore the mechanism of Circ-SMARCA5 as well as its potential target miR-767-5p in regulating MM cell activity.ResultsCirc-AMARCA5 was downregulated in MM and presented a good value in distinguishing MM patients from controls and it was also negatively correlated with Beta-2-microglobulin (β2-MG) level and International Staging System (ISS) stage. Additionally, Circ-SMARCA5 high expression was associated with higher CR as well as better PFS and OS. As for in vitro experiments, Circ-SMARCA5 expression was lower in MM cell lines compared with normal cells, and Circ-SMARCA5 overexpression inhibited cell proliferation but promoted cell apoptosis in RPMI8226 cells. Rescue experiments disclosed that the effect of Circ-SMARCA5 on cell activity was attenuated by miR-767-5p, and luciferase reporter assay revealed direct binding between Circ-SMARCA5 and miR-767-5p.ConclusionsCirc-SMARCA5 is downregulated and correlated with lower β2-MG level and ISS stage as well as better prognosis in MM patients, and it inhibits proliferation but promotes apoptosis of MM cells via directly sponging miR-767-5p.
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