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Reduced miR-550a-3p leads to breast cancer initiation, growth, and metastasis by increasing levels of ERK1 and 2.

ABSTRACT: Hyperactivation of the Ras/ERK pathway contributes to breast cancer initiation and progression, and recent evidence suggests aberrant signaling of miRNAs that regulate the Ras/ERK pathway play important roles during carcinogenesis and cancer progression. In this study, we demonstrate that miR-550a-3p expression is negatively correlated with levels of ERK1 and ERK2, two pivotal effectors in the Ras/ERK pathway. MiR-550a-3p gradually decreased during breast cancer initiation and progression and this reduction was a prognostic indicator of poorer overall survival (OS) and disease-free survival (DFS) among breast cancer patients. Our mechanistic studies demonstrated that miR-550a-3p exerts its tumor-suppressor role by directly repressing ERK1 and ERK2 protein expression, thereby suppressing the oncogenic ERK/RSK cascades, which reduced breast cancer cell viability, survival, migration, invasion, tumorigenesis, and metastasis. The inhibitory effects of miR-550a-3p were rescued by ectopic expression of ERK1 and/or ERK2. The novel connection between miR-550a-3p and ERK defines a new diagnostic and prognostic role for miR-550a-3p and highlights ERK inhibition as a candidate therapeutic target for breast cancers exhibiting hyperactivated Ras/ERK signaling.

SUBMITTER: Ho JY

PROVIDER: S-EPMC5288226 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Reduced miR-550a-3p leads to breast cancer initiation, growth, and metastasis by increasing levels of ERK1 and 2.

Ho Jar-Yi JY Hsu Ren-Jun RJ Wu Chih-Hsi CH Liao Guo-Shiou GS Gao Hong-Wei HW Wang Tong-Hong TH Yu Cheng-Ping CP

Oncotarget 20160801 33

Hyperactivation of the Ras/ERK pathway contributes to breast cancer initiation and progression, and recent evidence suggests aberrant signaling of miRNAs that regulate the Ras/ERK pathway play important roles during carcinogenesis and cancer progression. In this study, we demonstrate that miR-550a-3p expression is negatively correlated with levels of ERK1 and ERK2, two pivotal effectors in the Ras/ERK pathway. MiR-550a-3p gradually decreased during breast cancer initiation and progression and th ...[more]

PMID: 27462780

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Project description:BackgroundEpstein-Barr virus (EBV) is ubiquitously associated with nasopharyngeal carcinoma (NPC). EBV encodes two groups of microRNAs (miRNAs) which are divided into BamHI fragment H rightward open reading frame 1 (BHRF1) and BamHI-A rightward transcripts (BART) microRNAs. EBV miR-BART has been found to be involved in the development and progression of NPC. However, so far the role of EBV-miR-BART8-3p in NPC progression remains unknown. This study aimed to investigate the role of EBV-miR-BART8-3p in NPC and explore the underlying mechanisms.MethodsmiRNA expression was profiled in NPC and normal nasopharyngeal mucosal specimens using miRNA sequencing. EBV-miR-BART8-3p and RNF38 expression was quantified with qPCR assay. The migration, invasion and metastasis of NPC cells were evaluated using CCK-8, colony-forming, wound-healing, and migration and invasion assays. The expression levels of epithelial-mesenchymal transition (EMT)-related markers,metastasis-related markers and NF-κB and Erk1/2 signaling proteins were determined using Western blotting. Tumorigenic assay was performed to evaluate the pulmonary metastatic ability of NPC cells in vivo.ResultsEBV BART miRNAs were highly over-expressed and co-expressed in NPC and might be associated with deactivated immune response in NPC according to the sequencing analysis. EBV-miR-BART8-3p expression was significantly higher in human NPC specimens than in normal nasopharyngeal mucosal specimens. EBV-miR-BART8-3p was found to promote NPC migration, invasion and metastasis, drove an EMT process and upregulated expression of metastasis-related proteins expression in NPC cells. Our data showed EBV-miR-BART8-3p directly targeted RNF38 in NPC cells.ConclusionThe present study demonstrates that EBV-miR-BART8-3p plays a significant role in inducing EMT and promoting metastasis through directly targeting RNF38 in NPC cells via the activation of NF-κB and Erk1/2 signaling pathways. Our findings suggest that EBV-miR-BART8-3p is a potential therapeutic target for NPC.

Project description:ObjectiveTo identify the prognostic indicators of esophageal adenocarcinoma (EAC) for future EAC diagnosis and treatment.MethodsThe EAC dataset from The Cancer Genome Atlas was screened for differentially expressed microRNAs (miRNAs) and mRNAs associated with EAC. Weighted gene coexpression network analysis was performed to cluster miRNAs or mRNA with similar expression patterns to identify the miRNAs or mRNA that are highly associated with EAC. Prognostic miRNAs for overall survival (OS) were identified using Cox proportional-hazards regression analysis and least absolute shrinkage and selection operator based on survival duration and status. Two types of miRNAs were selected to develop a prognostic signature model for EAC using multiple Cox regression analysis. Furthermore, the signature was validated using internal validation sets 1 and 2. The receiver operating characteristic curve and concordance index were used to evaluate the accuracy of the signature and validation sets. The expression of miR-421, miR-550a-3p, and miR-550a-5p was assessed using quantitative polymerase chain reaction (qPCR). The proliferation, invasion, and migration of EAC cells were assessed using CCK8 and transwell assays. The OS of target mRNAs was assessed using Kaplan-Meier analysis. Functional enrichment analysis of the target mRNAs was performed using Metascape.ResultsThe prognostic signature and validation sets comprising mir-421 and mir-550a-1 had favorable predictive power in OS. Compared with the patients with EAC in the high-expression group, those assigned to the low-expression group displayed increased OS according to survival analysis. Differential and qPCR analysis showed that miR-421, miR-550a-3p, and miR-550a-5p were highly expressed in the EAC tissues and cell lines. Moreover, the downregulation of miR-421 and miR-550a-3p with inhibitor markedly suppressed the proliferation, invasion, and migration in OE33 cells compared with the negative control. A total of 20 target mRNAs of three miRNAs were predicted, among which seven target mRNAs-ASAP3, BCL2L2, LMF1, PPM1L, PTPN21, SLC18A2, and NR3C2-had prognostic value; PRKACB, PDCD4, RPS6KA5, and BCL2L2 were enriched in the miRNA cancer pathway.ConclusionPrognostic indicators of EAC may be useful in future EAC diagnosis and treatment.

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Reduced miR-550a-3p leads to breast cancer initiation, growth, and metastasis by increasing levels of ERK1 and 2.

Publications

Reduced miR-550a-3p leads to breast cancer initiation, growth, and metastasis by increasing levels of ERK1 and 2.

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