Hsa-miR-199a-3p is an oncosuppressor microRNA in papillary thyroid carcinoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE49415 | GEO | 2014/06/30
SECONDARY ACCESSION(S): PRJNA213867
REPOSITORIES: GEO
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-06-30 | E-GEOD-49415 | biostudies-arrayexpress
Project description:Thyroid cancer incidence is rapidly increasing. Papillary Thyroid Carcinoma (PTC), the most frequent hystotype, usually displays good prognosis, but no effective therapeutic options are available for the fraction of progressive PTC patients. BRAF and RET/PTC are the most frequent driving genetic lesions identified in PTC. We developed two complementary in vitro models based on RET/PTC1 oncogene, starting from the hypothesis that miRNAs modulated by a driving PTC-oncogene are likely to have a role in thyroid neoplastic processes. Through this strategy, we identified a panel of deregulated miRNAs. Among these we focused on miR-199a-3p and showed its under-expression in PTC specimens and cell lines. We demonstrated that miR-199a-3p restoration in PTC cells reduces MET and mTOR protein levels, impairs migration and proliferation and, more interesting, induces lethality through an unusual form of cell death similar to methuosis, caused by macropinocytosis dysregulation. Silencing MET or mTOR, both involved in survival pathways, does not recapitulate miR-199a-3p-induced cell lethality, thus suggesting that the cooperative regulation of multiple gene targets is necessary. Integrated analysis of miR-199a-3p targets unveils interesting networks including HGF and macropinocytosis pathways. Overall our results indicate miR-199a-3p as a tumor suppressor miRNA in PTC.
| S-EPMC4058023 | biostudies-literature
Project description:BackgroundIt was previously demonstrated that miR-199a-3p plays an important role in tumor progression; especially, its down-regulation in papillary thyroid cancer (PTC) is associated with cancer cell invasion and proliferation. In the present report, we investigated the mechanism involved in the down-regulation of miR-199a-3p in PTC and how miR-199a-3p regulates PTC invasion both in vivo and in vitro.MethodsqRT-PCR and Western blot assays were used to determine the expression of the investigated genes. Bisulfite sequencing PCR was used to investigate miR-199a-3p methylation. The functions of miR-199a-3p were investigated by a series of in vitro and in vivo experiments.ResultsOur results showed hypermethylation of the miR-199a-3p promoter, which resulted in decreased miR-199a-3p expression both in PTC cell lines and PTC tissues. DNA-methyltransferase 3a (DNMT3a), a target gene of miR-199a-3p, was increased both in PTC cell lines and PTC tissues, while 5-aza-2'-deoxycytidine (methyltransferase-specific inhibitor) or knock-down using DNMT3a Small-Interfering RNA could restore the expression of miR-199a-3p, and the over-expression of miR-199a-3p could decrease the expression of DNMT3a; this suggests that miR-199a-3p/DNMT3a constructs a regulatory circuit in regulating miR-199a-3p/DNMT3a expression. Moreover, gain- and loss-of-function studies revealed that miR-199a-3p is involved in cancer cell migration, invasion, and growth. Meanwhile, we found that RAP2a was also a direct target of miR-199a-3p, which might mediate the tumor-growth-inhibiting effect of miR-199a-3p. To further confirm the tumor-suppressive properties of miR-199a-3p, stable overexpression of miR-199a-3p in a PTC cell line (BCPAP cells) was xenografted to athymic BALB/c nude mice, resulting in delayed tumor growth in vivo. In clinical PTC samples, the expression of RAP2a and DNMT3a was increased significantly, and the expression of RAP2a was inversely correlated with that of miR-199a-3p.ConclusionOur studies demonstrate that an epigenetic change in the promoter region of miR-199a contributes to the aggressive behavior of PTC via the miR-199a-3p/DNMT3a regulatory circuit and directly targets RAP2a.
| S-EPMC7750465 | biostudies-literature
Project description:ObjectiveTo investigate the associations of polymorphisms in the following DNA double-strand break repair (DSBR) genes with papillary thyroid carcinoma (PTC) risk (including RAD51 rs11852786, RAD51B rs963917, BRCA1 rs12516 and rs8176318, BRCA2 rs15869, XRCC4 rs2035990 and XRCC5 rs2440).Materials and methodsA matched case-control study was implemented to examine associations between PTC risk and the above polymorphisms. Subsequently, we evaluated the effects of the potential PTC susceptibility-related variant rs15869 on BRCA2 mRNA secondary structure and BRCA2 expression through bioinformatics analysis and experiment validation. Additionally, luciferase assay was used to identify whether rs15869 polymorphism can substantially affect the binding of hsa-miR-1178-3p to BRCA2 mRNA. Finally, Pearson correlation analysis was performed to determine the correlation between the expression of hsa-miR-1178-3p and BRCA2 mRNA and protein in thyroid tissues harboring rs15869 different genotypes.ResultsBRCA2 rs15869 CC genotype was associated with a higher risk of PTC than its AA genotype. Subsequently, stratified analyses came to the same conclusion in the female or age<50 population. Furthermore, we confirmed that the A-to-C substitution of rs15869 changed BRCA2 mRNA secondary structure and contributed to a decreased BRCA2 expression. Mechanistically, a significantly decreased luciferase activity verified a greater binding between hsa-miR-1178-3p and rs15869 C allele, but not the A allele, which was evidenced by the significant negative correlation between hsa-miR-1178-3p with BRCA2 mRNA and protein levels in thyroid tissues with AC and CC genotype but not AA genotype at rs15869.ConclusionBRCA2 rs15869 is characterized as a potential biomarker associated with PTC risk, highlighting the contribution of the hsa-miR-1178-3p via functional exploration.
| S-EPMC8112253 | biostudies-literature
Project description:Papillary thyroid carcinoma (PTC) is the most common endocrine cancer with a significantly increase of the incidence recently. Several cytokines, such as thyroid peroxidase (TPO), cluster of differentiation 56 (CD56), Galectin-3, mesothelial cell (MC), cytokeratin 19 (CK19) and BRAF (B-raf) were recommended to be tested by immunohistochemistry (IHC) for a definitive diagnosis, but were still limited in clinical use because of their relative lower sensitivity and specificity. MicroRNA (miRNA), as a new molecular biomarkers, however, has not been reported yet so far. To address this, hsa-miR-200a-5p, a miRNA, was selected and detected in PTC patients by in situ hybrization with benign thyroid tumor with papillary hyperplasia as a control, and the differential expression of hsa-miR-200a-5p between fresh PTC tissues and control was detected by qRT-PCR. Expressive levels of cytokines of TPO, CD56, Galectin-3, MC, CK19 and B-raf were also detected by immunohistochemistry. The correlation was analyzed by SPSS software using Spearman methods. As expected, the hsa-miR-200a-5p expressive level was significantly increased in PTC patients, compared to that of control, and was consistent with that of TPO, CD56, Galectin-3, MC, CK19 and B-raf. In addition, expression of hsa-miR-200a-5p showed negative correlation to that of TPO (rs = - 0.734; **: P < 0.01) and CD56 (rs = - 0.570; **: P < 0.01), but positive correlation to that of Galectin-3 (rs = 0.601; **: P < 0.01), MC (rs = 0.508; **: P < 0.01), CK19 (rs = 0.712; **: P < 0.01) and B-raf (rs = 0.378; **: P < 0.01). PTC and papillary benign thyroid papillary hyperplasia are difficult to distinguish in morphology, so requiring immunohistochemistry to further differentiate the diagnosis, however, for the existing clinical common diagnostic marker for immunohistochemistry, the sensitivity and accuracy are low, it is easy to miss diagnosis. Therefore, there is an urgent need for a rapid and sensitive molecular marker. So miR-200a-5p can be used to assist in the diagnosis of PTC at the molecular level, and as a biomarker, can be effectively used to distinguish between PTC and benign thyroid tumor with papillary hyperplasia.
| S-EPMC6044525 | biostudies-literature
Project description:ObjectivesPapillary thyroid carcinoma (PTC) is the most common endocrine system malignant thyroid cancer, and patients with lymph node metastasis typically exhibit poor prognosis. MicroRNAs (miRNAs) can act as either oncogenes or tumor suppressors in PTC. This study was aimed at using PTC transcriptome data obtained from The Cancer Genome Atlas (TCGA) to identify differentially expressed, survival-related miRNAs and target genes.MethodsWe analyzed the TCGA datasets to identify differentially expressed mRNAs/miRNAs in 493 PTC patients with stage I_II group (stages I and II) versus stage III_IV group (stages III and IV) according to TNM staging. The Kaplan-Meier survival analysis, the Cox regression analysis, and the log-rank test were performed to investigate survival-related miRNAs.ResultsWe identified 36 significantly differentially expressed miRNAs in the stage I_II group versus the stage III_IV group, in which 31 were upregulated and only 5 were downregulated (i.e., hsa-miR-891a-5p, hsa-miR-892a, hsa-miR-888-5p, hsa-miR-891b, and hsa-miR-892b). Additionally, five signature miRNAs (hsa-miR-206, hsa-miR-299-3p, hsa-miR-299-5p, hsa-miR-496, and hsa-miR-509-3-5p) were associated with the overall survival of PTC patients. We also found that LMX1B, whose expression was inversely correlated with hsa-miR-206 expression, was a putative target gene of hsa-miR-206 and LMX1B was likely to serve as a tumor suppressor in PTC.Conclusionhsa-miR-206b might be involved in promoting TNM staging in PTC via targeting of LMX1B.
| S-EPMC8948606 | biostudies-literature
Project description:During the dissemination of ovarian cancer cells, the cells float in the peritoneal cavity without access to a vascular supply and so are exposed to hypoxic conditions, which may cause the ovarian cancer cells to acquire a more aggressive and malignant phenotype. In this study, we screened microRNAs (miRNAs) to identify those that displayed altered expression patterns under hypoxic conditions and then analyzed their functional roles in ovarian cancer progression. miRNA PCR arrays performed on cells from 2 ovarian cancer cell lines (CaOV3 and RMUG-S) revealed miR-199a-3p as one of the miRNAs that are downregulated under hypoxia. In silico analyses indicated that MET is one of the target genes for miR-199a-3p; subsequently, miR-199a-3p expression was found to be inversely correlated with c-Met expression in ovarian cancer. Transfection of precursor miR-199a-3p into ovarian cancer cells reduced c-Met expression and inhibited the phosphorylation of c-Met, extracellular signal-regulated kinase, and AKT; in addition, proliferation, adhesion, and invasiveness were inhibited. Moreover, overexpression of miR-199a-3p in cancer cells significantly suppressed peritoneal dissemination in a xenograft model. In summary, the hypoxia-related microRNA miR-199a-3p drastically inhibits ovarian cancer progression through the downregulation of c-Met expression. Therefore, miR-199a-3p is a potential target for treating ovarian cancer dissemination.
| S-EPMC4484460 | biostudies-literature
Project description:microRNA-200c-3p (miR-200c-3p) has emerged as an important tumor growth regulator. However, its function in papillary thyroid carcinoma (PTC) is poorly understood. This study was conducted to investigate the role of miR-200c-3p in the progression of human PTC. The miR-200c-3p expression in human PTC tissues and cell lines was evaluated. The target relationship between miR-200c-3p and candidate genes was predicted through bioinformatic analysis and confirmed with a luciferase reporter assay. miRNA or gene expression was altered using transfection, and cell behavior was analyzed using CCK-8, wound healing, Transwell, and colony formation assays. The tumor-promoting effects of miR-200c-3p were evaluated by xenografting tumors with K1 cells in nude mice. The expression level of miR-200c-3p in human PTC tissues and cell lines markedly increased, and this increased expression was significantly associated with a worse overall survival. When inactivated, miR-200c-3p suppressed K1 cells' malignant behaviors, including decreasing proliferation and attenuating colony formation, migration, and invasion. Its inactivation also attenuated the development of xenografted K1 cells in nude mice. The effects of miR-200c-3p mimics on promoting the malignant behaviors of PTC cells were remarkably reversed by the overexpression of ATP2A2, as a downstream target of miR-200c-3p. miR-200c-3p acts as an oncogenic gene and promotes the malignant biological behaviors of human PTC cells, thereby directly targeting ATP2A2. This regulated axis may be used as a potential therapy of PTC.
| S-EPMC8788908 | biostudies-literature
Project description:BackgroundPapillary thyroid carcinoma (PTC) is the most prevalent histotype of thyroid cancer and the presence of BRAFV600E mutation in these tumors is related to the malignancy and prognosis of the disease. In recent years attention has been focused on the role of microRNAs in the biology of PTC cells, especially in their role in the modulation of pathways related to tumorigenesis. DLK1-DIO3-derived miRNAs have been shown to play important roles in tumor context and are globally downregulated in PTC.MethodsBased on a previous in silico target prediction and gene enrichment analysis, we identified miR-495-3p as the candidate with the highest tumor suppressor potential role in PTC among DLK1-DIO3-derived miRNAs. We used bioinformatics and an in vitro model of miR-495-3p overexpression to further understand the influence of this molecule on the tumorigenic processes of PTC.ResultsOverexpression of miR-495-3p impaired cell migration and invasion of PTC cells harboring the BRAFV600E mutation and affected the expression of targets predicted in the bioinformatic analysis, such as TGFB2, EREG and CCND1.ConclusionOverall, our results indicate that the loss of miR-495-3p expression during PTC development might play an important role in its progression.
| S-EPMC9911110 | biostudies-literature
Project description:ObjectiveThere is no effective and reliable biomarker to distinguish benign thyroid nodules from papillary thyroid carcinomas (PTC). This study aimed at examining the levels of plasma miRNAs in patients with PTC or benign nodules to explore the potential miRNA biomarkers for PTC.Patients and methodsGenome-wide plasma miRNA expression profiles were determined by the miRNA Microarray and the significantly higher levels of miRNAs were validated in plasma and tissues by quantitative RT-PCR. The levels of two miRNAs were further tested in seven patients before and after tumor excision and the potential values for the diagnosis of PTC were evaluated by receiver operating characteristic curve (ROC).ResultsIn comparison with that in the patients with benign nodules, eight significantly higher and three lower levels of plasma miRNAs were detected in the PTC patients. Further validation indicated that the levels of plasma miR-25-3p, miR-451a, miR-140-3p and let-7i were significantly higher in the PTC cases than in those with benign nodules or the healthy controls. Significantly higher levels of miR-25-3p and miR-451a were detected in the thyroid tissues from the PTC patients. The levels of plasma miR-25-3p and miR-451a in seven patients significantly decreased after tumor excision. ROC analyses revealed that the levels of plasma miR-25-3p at cut-off 1.41 and miR-451a at 1.38 had sensitivity of 92.8% and 88.9%, and specificity of 68.8% and 66.7% for distinguishing PTC from benign nodules, respectively.ConclusionOur findings suggest that the levels of plasma miR-25-3p and miR-451a may be valuable for the diagnosis of PTC.
| S-EPMC4500410 | biostudies-literature