MicroRNA-590-3p inhibits invasion and metastasis in triple-negative breast cancer by targeting Slug.
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ABSTRACT:
SUBMITTER: Yan M
PROVIDER: S-EPMC7136920 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Lacking of treatment methods for the patients with triple negative breast cancer (TNBC) underscores the pivotal needs to further understand its biology as well as to find better biomarkers and develop novel therapeutic strategies. Increasing evidences support that aberrantly expressed microRNAs (miRNAs) are involved in tumorigenesis and may serve as biomarkers for diagnostic and prognostic purposes of various cancers. In current study, we found that miR-455-3p and miR-196a-5p were intensively overexpressed in TNBC compared with the hormone receptor (HR) positive breast cancer whereas miR-425-5p was down-regulated by miRNA microarray analysis. qRT-PCR analysis confirmed that the expression of miR-455-3p in TNBC cell lines MDA-MB-231 and MDA-MB-468 was higher than that in HR positive breast cancer cell line MCF-7(p<0.01). Functional experiments in vitro showed that miR-455-3p enhanced cell proliferative, invasive and migrational abilities in TNBC cell lines. miRNA targets prediction showed SMAD2, LTBR and etoposide induced 2.4 (EI24) were potential target genes of miR-455-3p, and then it was confirmed by qRT-PCR assay. Dual luciferase reporter assay showed the specific binding of miR-455-3p to 3' UTR of EI24 in TNBC. Then we found miR-455-3p inhibited the EI24 expression at the levels of mRNA and protein. Through small interfering RNA (siRNA) targeting EI24 gene, there were strengthened capabilities of invasion and migration of TNBC cells, and increased expression of EI24 had the inverse effects. In conclusion, the data suggest that miRNA455-3p promotes invasion and migration by targeting tumor suppressor EI24 and might be a potential prognostic biomarker and therapeutic target in TNBC.
| S-EPMC5386697 | biostudies-literature
Project description:BackgroundColorectal cancer (CRC) is one of the most common malignances worldwide. Metastasis is responsible for the rapid recurrence and poor prognosis of CRC. However, the underlying molecular mechanism of CRC metastasis remains largely unclear. In this study we purposed to investigate the expression and biological functions of miR-490-3p in CRC metastasis, as well as to identify its downstream target genes and influenced pathway.MethodsThe expression level of miR-490-3p in CRC cell lines, CRC adjacent normal tissues, non-metastasis and metastasis tissues were assessed by quantitative real-time PCR. Patient survivals were follow-up up to 7 years. Gain-of-function and loss-of-function study on cell migration and invasion abilities were carried out by transfection of miR-490-3p mimics or inhibitors respectively. The molecular targets of miR-490-3p were computationally identified and experimentally verified by dual-luciferase reporter assay and western blot. Functional rescue was also conducted to confirm miR-490-3p inhibits CRC metastasis by targeting TGF-β signaling pathway.ResultsmiR-490-3p expression was persistently downregulated during CRC malignant progression, as well as in CRC cell lines. Artificially overexpression miR-490-3p in CRC cell lines inhibited cell migration and invasion abilities while knockdown miR-490-3p expression caused the reverse effects. TGFβR1 and MMP2/9 were the downstream targets of miR-490-3p in CRC. Inhibition of TGFβR1 could partially recover the tumor suppression effect of miR-490-3p.ConclusionmiR-490-3p is downregulated during CRC malignant progression. miR-490-3p represses CRC cell migration and invasion abilities, partially by targeting to the TGF-β signaling pathway. Taken together, miR-490-3p is acting as a tumor suppressor in CRC.
| S-EPMC4696296 | biostudies-literature
Project description:Triple‑negative breast cancer (TNBC) is associated with a poor prognosis; however, treatments for TNBC are limited, with poor outcomes. MicroRNAs (miRNAs/miRs) are small non‑coding RNA molecules that are able to regulate gene expression. The present study aimed to identify differentially expressed miRNAs in patients with breast cancer, and to investigate the functional role of the identified miRNA targets and their effects in vitro and in vivo. Transfection with miR‑606 suppressed TNBC cell proliferation, migration, invasion and tumor sphere‑forming ability, as determined using trypan blue, Transwell and sphere formation assays. Moreover, miR‑606 induced the apoptosis of TNBC cells, as determined by flow cytometric analysis. Furthermore, intratumoral injections of miR‑606 mimics suppressed tumor growth in MDA‑MB‑231 xenografts. In addition, MDA‑MB‑231 cells transfected with miR‑606 mimics exhibited decreased lung metastatic nodules in a mouse tail vein injection model. Notably, miR‑606 and STC1 expression had opposing effects on the overall survival of patients with TNBC. The results of the present study suggested a novel tumor suppressor function for miR‑606 in TNBC, thus indicating its potential application in the development of anticancer miRNA therapeutics.
| S-EPMC10688449 | biostudies-literature
Project description:microRNA (miR)-590 has been found to serve potential roles in cancer development; however, the expression and function of miR-590 in human gliomas remains to be elucidated. The present study aimed to investigate the expression of miR-590 in human glioma tissues and radioresistant human glioblastoma cells (U251R), and to determine the effect and related molecular mechanism of miR-590-3p on the radiosensitivity of U251R cells in vitro. The results from reverse transcription-quantitative polymerase chain reaction indicated that miR-590-3p was upregulated in human glioma tissues and radioresistant human glioblastoma cells, and that miR-590-3p expression was higher in high grade than in low grade gliomas. In vitro experiments revealed that the miR-590-3p inhibitor enhanced the radiosensitivity of U251R cells by suppressing cell viability, decreasing colony formation capacity and increasing cell apoptosis rate, as demonstrated by MTT, colony formation and flow cytometry analyses. A luciferase reporter assay demonstrated that leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) was a direct target of miR-590-3p. Furthermore, it was demonstrated that the effect of miR-590-3p suppression on cell viability, colony formation capacity and cell apoptosis rate was attenuated by the knockdown of LRIG1 in the U251R cells. In conclusion, the present study revealed that miR-590-3p was upregulated in human glioma tissues and radioresistant human glioblastoma cells, and miR-590-3p contributes to the radioresistance of human glioblastoma cells by directly targeting LRIG1. These findings may provide potential therapeutic strategies to prevent radioresistance in human gliomas.
| S-EPMC5526158 | biostudies-other
Project description:BackgroundTriple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer (BC). The circRNA-miRNA‒mRNA axis is a promising biomarker for the early diagnosis and prognosis of BC. However, the critical circRNA mediators involved in TNBC progression and the underlying regulatory mechanism involved remain largely unclear.MethodsIn this study, we carried out a circRNA microarray analysis of 6 TNBC patients and performed a gene ontology (GO) analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was used to characterize important circRNAs involved in TNBC progression. The interaction between circRNAs and miRNAs was determined by dual luciferase and RNA immunoprecipitation (RIP) assays. Moreover, Transwell, wound healing and Cell Counting Kit-8 (CCK8) assays were performed with altered circRNA or miRNA expression in MDA-MB-231 and BT-549 cells to investigate the roles of these genes in cell invasion, migration and proliferation.ResultsA total of 78 circRNAs were differentially expressed in TNBC tissues, and the hsa_circ_0045881 level was significantly decreased in TNBC tissues and cells. Lentivirus-mediated hsa_circ_0045881 overexpression in MDA-MB-231 and BT-549 cells significantly reduced cell invasion and migration capacity. Additionally, hsa_circ_0045881 interacted with miR-214-3p in MDA-MB-231 cells. miR-214-3p mimics in MDA-MB-231 and BT-549 cells significantly enhanced cell invasion, migration and proliferation, but the other combinations of inhibitors had opposite effects on cell activity.ConclusionsOur data indicated that the circRNA has_circ_0045881 plays key roles in TNBC progression and that hsa_circ_0045881 might act as a sponge for miR-214-3p to modulate its levels in TNBC cells, thereby regulating cell invasion, metastasis and proliferation. hsa_circ_004588 might be a potential prognostic marker and therapeutic target for TNBC.
| S-EPMC10905830 | biostudies-literature
Project description:Correspondence to: Yonghui Chen; Wei Xue. Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China. Email: cyh1488@163.com; xuewei@renji.com.BackgroundAberrantly expressed microRNAs play important biological functions in the pathogenesis, progression and metastasis of numerous malignancies. Thus, further identification of these non-coding transcriptions is warranted.MethodsmiRNAs expression data of renal cell carcinoma (RCC) as well as the normal renal tissue samples was downloaded from TCGA and GEO database, and was analyzed by both computational and experimental approaches. The bio-functional role of the miRNA was then moreover identified by over-expression and inhibition assays. Beyond that, Western blots, luciferase assays, along with immunohistochemistry (IHC) tests were conducted for further study of the potential mechanisms.ResultsIn this study, a novel regulatory miRNA, miR-30a-3p, was identified along with its biological function as well as prognostic value in RCC. Functionally, miR-30a-3p inhibits RCC cell invasion and migration. miR-30a-3p targets autophagy related 12 (ATG12), which we confirmed by luciferase reporter assays and Western blotting.ConclusionsIn conclusion, miR-30a-3p, as a new prognostic marker in RCC, down-regulates RCC cell invasion and migration by targeting ATG12. This consistently improves the overall survival of RCC patients.
| S-EPMC7214999 | biostudies-literature
Project description:Cervical cancer (CC) is the most common malignant tumor in gynecology, and metastasis is an important cause of patient death. MiRNAs (microRNAs) have been found to play key roles in cervical cancer metastasis, but the effect of miR-362-3p in CC is unclear. This study aimed to investigate the role of miR-362-3p in cervical cancer migration and invasion. We compared the expression levels of miR-362-3p in cervical cancer tissues and adjacent normal cervical tissues. In CC tissues, miR-362-3p expression was significantly down-regulated, which is related to the cancer stage and patient survival. MiR-362-3p can effectively inhibit the migration and invasion of cervical cancer cells. The dual-luciferase reporter assay results showed that BCAP31 (B cell receptor associated protein 31) is a direct target protein of miR-362-3p. The results of the immunohistochemical examination of clinical tissue samples showed that BCAP31 was abnormally highly expressed in cervical cancer, which was positively correlated with the clinical stage. BCAP31 knockdown exerted similar effects as miR-362-3p overexpression. Further GSEA analysis showed that BCAP31 may participate in multiple biological processes, such as protein transport, metabolism, and organelle organization. Our results suggest that miR-362-3p inhibits migration and invasion via directly targeting BCAP31 in cervical cancer, and restoring miR-362-3p levels may be a new treatment strategy for cervical cancer in the future.
| S-EPMC7296163 | biostudies-literature
Project description:BackgroundTriple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancer in women globally. This subtype often has early and high recurrence rates, resulting in poor survival, partially due to lack of targeted therapies. To date, the detailed molecular mechanisms underlying TNBC progression are unclear. Given the crucial role of microRNAs (miRNAs) in cancer metastasis, we aimed to analyse the expression and function of a metastasis-associated miRNA named miR-211-5p in TNBC.MethodsMiRNA array analysis was performed to search for metastasis-associated miRNAs in TNBC. The miR-211-5p expression in tumour tissues, adjacent non-tumourous breast tissues of TNBC patients and cell lines were evaluated by real-time PCR. The protein expression levels were analysed by western blot, immunohistochemistry and in situ hybridisation. Luciferase reporter assays were employed to validate the target of miR-211-5p. The effect of miR-211-5p on TNBC progression was investigated in vitro and in vivo.ResultsMiR-211-5p was significantly downregulated in TNBC, and its expression level was associated with overall survival in TNBC. The expression of miR-211-5p suppressed TNBC cell proliferation, invasion, migration and metastasis in vitro and in vivo. Furthermore, SETBP1 was identified as a target of miR-211-5p. Through gain-of-function and loss-of-function studies, SETBP1 was shown to significantly affect colony and cell number in vitro. Enforced expression of miR-211-5p inhibited the expression of SETBP1 significantly and the restoration of SETBP1 expression reversed the inhibitory effects of miR-211-5p on TNBC cell proliferation and metastasis.ConclusionsThese findings collectively demonstrate a tumour suppressor role of miR-211-5p in TNBC progression by targeting SETBP1, suggesting that miR-211-5p could serve as a potential prognostic biomarker and therapeutic target for TNBC.
| S-EPMC5520212 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) commonly have aggressive properties. microRNA-582-5p (miR-582-5p) modulates the progression of several cancers. Yet, the role of miR-582-5p in TNBC progression is undetermined. In the current study, we investigated miR-582-5p expression levels and clinical significance in TNBC. The impact of miR-582-5p modulation on the biological behaviors of TNBC cells were measured. The downstream gene(s) regulated by miR-582-5p in TNBC was explored. We showed that compared to adjacent normal breast tissues, the miR-582-5p level was elevated in TNBC samples. The upregulation of miR-582-5p correlated with lymph node metastasis. Overexpression of miR-582-5p enhanced TNBC cell migration and invasion, whereas knockdown of miR-582-5p had an adverse impact on aggressive phenotype. In vivo xenograft mouse studies demonstrated that miR-582-5p overexpression accelerated TNBC growth and metastasis. Mechanistically, miR-582-5p selectively inhibited CMTM8, leading to a reduction of CMTM8 expression. CMTM8 showed suppressive effects on TNBC cell migration and invasion. Rescue experiments revealed that overexpression of CMTM8 impaired miR-582-5p-induced migration and invasion in TNBC cells. Overall, our data uncover an oncogenic role for miR-582-5p in TNBC metastasis through inhibition of CMTM8. We suggest miR-582-5p as a promising target for managing TNBC.
| S-EPMC8810067 | biostudies-literature
Project description:Most triple-negative breast cancers (TNBCs) exhibit gene expression patterns associated with epithelial-to-mesenchymal transition (EMT), a feature that correlates with a propensity for metastatic spread. Overexpression of the EMT regulator Slug is detected in basal and mesenchymal-type TNBCs and is associated with reduced E-cadherin expression and aggressive disease. The effects of Slug depend, in part, on the interaction of its N-terminal SNAG repressor domain with the chromatin-modifying protein lysine demethylase 1 (LSD1); thus, we investigated whether tranylcypromine [also known as trans-2-phenylcyclopropylamine hydrochloride (PCPA) or Parnate], an inhibitor of LSD1 that blocks its interaction with Slug, suppresses the migration, invasion, and metastatic spread of TNBC cell lines. We show here that PCPA treatment induces the expression of E-cadherin and other epithelial markers and markedly suppresses migration and invasion of TNBC cell lines MDA-MB-231 and BT-549. These effects were phenocopied by Slug or LSD1 silencing. In two models of orthotopic breast cancer, PCPA treatment reduced local tumor growth and the number of lung metastases. In mice injected directly in the blood circulation with MDA-MB-231 cells, PCPA treatment or Slug silencing markedly inhibited bone metastases but had no effect on lung infiltration. Thus, blocking Slug activity may suppress the metastatic spread of TNBC and, perhaps, specifically inhibit homing/colonization to the bone.
| S-EPMC4557365 | biostudies-literature