MiR-182-3p targets TRF2 and impairs tumor growth of triple negative breast cancer
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ABSTRACT:
SUBMITTER: Roberto Dinami
PROVIDER: S-SCDT-10_15252-EMMM_202216033 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:BackgroundTriple-negative breast cancer (TNBC), in part because of the high metastasis rate, is one of the most prevalent causes of malignancy-related mortality globally. Ubiquitin specific peptidase 6 N-terminal like (USP6NL) has been unmasked to be implicated in some human cancers. However, the precise biological function of USP6NL in TNBC has not been defined.MethodsRNA expression was examined by real-time quantitative PCR (RT-qPCR), while USP6NL protein level was tested through western blot. Besides, cell proliferation was assessed by using colony formation assay, whereas cell apoptosis estimated by flow cytometry analysis, JC-1 assay and TUNEL assay. Transwell assays were adopted to detect the migration and invasion of indicated TNBC cells. Immunofluorescence (IF) assay evaluated epithelial-mesenchymal transitions (EMT) progress in TNBC. Further, RNA immunoprecipitation (RIP), RNA pull down and luciferase reporter assays were implemented for measuring the mutual interplay among USP6NL, miR-142-3p and long intergenic non-protein coding RNA 689 (LINC00689).ResultsElevated USP6NL level was uncovered in TNBC cells. RNA interference-mediated knockdown of USP6NL inhibited TNBC cell growth, motility and EMT. Further, USP6NL was proved as the target of a tumor-inhibitor miR-142-3p, and LINC00689 augmented USP6NL expression by absorbing miR-142-3p. Importantly, miR-142-3p deficiency or USP6NL overexpression fully abolished the inhibitory effect of LINC00689 silence on TNBC cellular behaviors.ConclusionAll data revealed the important role of USP6NL/LINC00689/miR-142-3p signaling in TNBC. The findings might provide a new and promising therapeutic biomarker for treating patients with TNBC.
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Project description:MicroRNAs (miRNAs) are emerging as critical mediators in tumors, including triple-negative breast cancer (TNBC). The role of miR-518a-3p in TNBC was investigated to identify potential therapeutic target. Data from KM Plotter database (www.kmplot.com) showed that high miR-518a-3p expression was significantly associated with overall survival of patients with TNBC (p = 0.04). The expression of miR-518a-3p was dysregulated in TNBC cells. Functional assays revealed that over-expression of miR-518a-3p inhibited cell invasion and migration of TNBC. Additionally, miR-518a-3p could target TMEM2 (transmembrane protein 2), and decreased protein and mRNA expression of TMEM2 in TNBC cells. Knockdown of TMEM2 suppressed cell invasion and migration through inhibiting phospho (p)-JAK1 (Janus kinase 1) and p-STAT (signal transducer and activator of transcription protein) 1/2. Moreover, over-expression of TMEM2 counteracted the suppressive effect of miR-518a-3p on TNBC invasion and migration through promoting the levels of p-JAK1 and p-STAT1/2. In conclusion, miR-518a-3p negatively regulates the JAK/STAT pathway via targeting TMEM2 and suppresses invasion and migration in TNBC, suggesting that miR-518a-3p may be a potential therapeutic target in TNBC.
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Project description:Triple-negative breast cancer shows worse outcome compared with other subtypes of breast cancer. The discovery of dysregulated microRNAs and their roles in the progression of triple-negative breast cancer provide novel strategies for the treatment of patients with triple-negative breast cancer. In this study, we identified the significant reduction of miR-133 in triple-negative breast cancer tissues and cell lines. Ectopic overexpression of miR-133 suppressed the proliferation, colony formation, and upregulated the apoptosis of triple-negative breast cancer cells. Mechanism study revealed that the YES Proto-Oncogene 1 was a target of miR-133. miR-133 bound the 3'-untranslated region of YES Proto-Oncogene 1 and decreased the level of YES Proto-Oncogene 1 in triple-negative breast cancer cells. Consistent with miR-133 downregulation, YES1 was significantly increased in triple-negative breast cancer, which was inversely correlated with the level of miR-133. Restoration of YES Proto-Oncogene 1 attenuated the inhibitory effects of miR-133 on the proliferation and colony formation of triple-negative breast cancer cells. Consistent with the decreased expression of YES Proto-Oncogene 1, overexpression of miR-133 suppressed the phosphorylation of YAP1 in triple-negative breast cancer cells. Our results provided novel evidence for the role of miR-133/YES1 axis in the development of triple-negative breast cancer, which indicated miR-133 might be a potential therapeutic strategy for triple-negative breast cancer.
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Project description:ObjectiveTriple-negative breast cancer (TNBC) is an aggressive but heterogeneous subtype of breast cancer. This study aimed to identify and validate a prognostic signature for TNBC patients to improve prognostic capability and to guide individualized treatment.MethodsWe retrospectively analyzed the prognostic performance of clinicopathological characteristics and miRNAs in a training set of 58 patients with invasive ductal TNBC diagnosed between 2002 and 2012. A prediction model was developed based on independent clinicopathological and miRNA covariates. The prognostic value of the model was further validated in a separate set of 41 TNBC patients diagnosed between 2007 and 2008.ResultsOnly lymph node status was marginally significantly associated with poor prognosis of TNBC (P = 0.054), whereas other clinicopathological factors, including age, tumor size, histological grade, lymphovascular invasion, P53 status, Ki-67 index, and type of surgery, were not. The expression levels of miR-27b-3p, miR-107, and miR-103a-3p were significantly elevated in the metastatic group compared with the disease-free group (P value: 0.008, 0.005, and 0.050, respectively). The Cox proportional hazards regression analysis revealed that lymph node status and miR-27b-3p were independent predictors of poor prognosis (P value: 0.012 and 0.027, respectively). A logistic regression model was developed based on these two independent covariates, and the prognostic value of the model was subsequently confirmed in a separate validation set. The two different risk groups, which were stratified according to the model, showed significant differences in the rates of distant metastasis and breast cancer-related death not only in the training set (P value: 0.001 and 0.040, respectively) but also in the validation set (P value: 0.013 and 0.012, respectively).ConclusionThis model based on miRNA and node status covariates may be used to stratify TNBC patients into different prognostic subgroups for potentially individualized therapy.
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Project description:Despite N6-methyladenosine (m6A) is functionally important in various biological processes, its role in the underlying regulatory mechanism in TNBC are lacking. In this study, we investigate the pathological role and the underlying mechanism of the m6A methylated RNA level and its major methyltransferase METTL3 in the TNBC progression. We found that the m6A methylated RNA was dramatically decreased in TNBC tissues and cell lines. Functionally, we demonstrated that METTL3 inhibits the proliferation, migration, and invasion ability of TNBC cells. Moreover, we found METTL3 is repressed by miR-34c-3p in TNBC cells. On the mechanism, we found that circMETTL3 could act as a sponge for miR-34c-3p and inhibits cell proliferation, invasion, tumor growth and metastasis by up-regulating the expression of miR-34c-3p target gene METTL3. In conclusion, our study demonstrates the functional importance and regulatory mechanism of METTL3 in suppressing the tumor growth of TNBC.
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Project description:BackgroundIncreasing evidence has suggested that circular RNAs (circRNAs) may act as an important regulatory factor in tumor progression. However, how circRNAs exert their functions in triple-negative breast cancer (TNBC) remains not clearly understood.MethodsFirst, circRNA microarrays were conducted to identify aberrantly expressed circRNAs in TNBC tissues. Kaplan-Meier survival analysis was conducted to calculate the correlation between the level of hsa_circRNA_102229 and outcomes of patients with TNBC. The effect of hsa_circRNA_102229 and serine/threonine-protein kinase PFTAIRE 1 (PFTK1) on TNBC cells was clarified by cell counting kit-8, transwell and wound healing assays, as well as by a flow cytometry. The molecular mechanism of hsa_circRNA_102229 was clarified through bioinformatics, a dual-luciferase reporter assay, western blotting, fluorescence in situ hybridization and real-time polymerase chain reaction. Tumor xenograft experiments were performed to analyze growth and metastasis of TNBC in vivo.ResultsIn TNBC tissues and cells, hsa_circ_102229 was remarkably up-regulated. Patients with TNBC presenting high hsa_circ_102229 exhibited poor prognosis. Moreover, hsa_circ_102229 could promote the migration, proliferation and invasion, whereas it inhibited the apoptosis of TNBC cells. Furthermore, hsa_circ_102229 directly targeted miR-152-3p and could regulate the expression of PFTK1 by targeting miR-152-3p. Rescue assays suggested that hsa_circ_102229 may exert its function in TNBC cells by regulating PFTK1. Additionally, knockdown of hsa_circ_102229 slowed down TNBC tumorigenesis and lung metastasis in a tumor xenograft animal model.ConclusionsHsa_circ_102229 might serve as a competing endogenous RNA (ceRNA) to modulate PFTK1 expression via regulating miR-152-3p to affect the functions of TNBC cells. Hsa_circ_102229 acts as a newly discovered biomarker for TNBC treatment.
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