Impaired microRNA processing by DICER1 downregulation endows thyroid cancer with increased aggressiveness.
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ABSTRACT:
SUBMITTER: Ramirez-Moya J
PROVIDER: S-EPMC6755984 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by targeting messenger RNA (mRNA) transcripts. Recently, a miRNA expression profile of human tumors has been characterized by an overall miRNA downregulation. Explanations for this observation include a failure of miRNA post-transcriptional regulation, transcriptional silencing associated with hypermethylation of CpG island promoters and miRNA transcriptional repression by oncogenic factors. Another possibility is that the enzymes and cofactors involved in miRNA processing pathways may themselves be targets of genetic disruption, further enhancing cellular transformation. However, no loss-of-function genetic alterations in the genes encoding these proteins have been reported. Here we have identified truncating mutations in TARBP2 (TAR RNA-binding protein 2), encoding an integral component of a DICER1-containing complex, in sporadic and hereditary carcinomas with microsatellite instability. The presence of TARBP2 frameshift mutations causes diminished TRBP protein expression and a defect in the processing of miRNAs. The reintroduction of TRBP in the deficient cells restores the efficient production of miRNAs and inhibits tumor growth. Most important, the TRBP impairment is associated with a destabilization of the DICER1 protein. These results provide, for a subset of human tumors, an explanation for the observed defects in the expression of mature miRNAs.
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Project description:Recent evidence indicates that long non-coding RNAs play important roles in tumorigenesis and cancer progression. BRAF-activated non-protein coding RNA (BANCR) is a novel and potential regulator of cancer cell proliferation and migration. However, little is known regarding the role of BANCR in papillary thyroid cancer (PTC). The current study used quantitative PCR to demonstrate that BANCR was significantly downregulated in 60 paired PTC tissues compared with normal tissues. In addition, BANCR was significantly correlated with lymph node metastasis (p = 0.02). Furthermore, Cell Counting Kits and Transwell assays were used to demonstrate that knocking down BANCR with short hairpin RNA (shRNA) transfection significantly promoted the proliferation and invasion of PTC cell lines. The flow cytometric analysis of apoptosis and the cell cycle revealed that the overexpression of BANCR inhibited cancer cell proliferation and invasion, which was associated with the induction of cell-cycle G2/M phase arrest and increased apoptosis. Moreover, western blotting was used to show that the MAPK and PI3K-Akt pathways were aberrantly activated during BANCR-mediated PTC cell proliferation and migration. These findings revealed that BANCR functions as a tumor suppressor during thyroid carcinogenesis.
| S-EPMC5907680 | biostudies-literature
Project description:The alteration of miRNA processing is a driver event in several tumors including thyroid cancer. In particular, somatic DICER1 mutations, reported in follicular-patterned lesions, are shared by benign as well as malignant tumors. In the present study, we investigated the effects of alterations in the miRNA processing genes on the miRNA profile. The study included 19 follicular adenomas (FAs) and 22 follicular variant of papillary thyroid carcinomas (FVPTCs). The mutational status in the hot spot regions of DICER1, DROSHA, TARBP2, DGCR8 and the most commonly affected genes in thyroid tumors was investigated on both tumor and paired normal tissues. The miRNA profile and the mRNA expression levels of DICER1, DROSHA, TARBP2, DGCR8 and XPO5 were also evaluated. Two DICER1 RNase IIIb domain mutations were found in FAs. These lesions presented a considerable loss of 5p miRNAs. Fifteen miRNAs were specifically deregulated in DICER1-mutant lesions compared to FAs and FVPTCs. These miRNAs regulate crucial pathways in cancer such as Hippo, p53 and TGF-beta signalling. DICER1 somatic mutations in the RNase IIIb domain are not specific for malignancy, but the miRNA imbalance that they cause is remarkable, especially with regard to the loss of 5p miRNAs. DICER1-mutant lesions have a characteristic miRNA deregulation, which is different from that of FVPTCs; nevertheless, this impairment is consistent with malignant transformation. Further studies providing the real risk of malignancy associated with DICER1 mutations and the evolution of DICER1-mutant lesions are needed to make them useful in the clinical practice.
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Project description:Disruption of microRNA (miRNA) expression patterns is now being recognized as a hallmark of human cancer. The causes of these altered profiles are diverse, and, among them, we found the existence of defects in the miRNA processing machinery. However, little is known about how these alterations affect the biology of the underlying tumors. Herein, we show that colorectal cancer cells with an impairment in DICER1, a major miRNA biogenesis gene, undergo enrichment of tumor stemness features and an epithelial-to-mesenchymal transition. These phenotypes are associated with the downregulation of miRNAs, such as miR-34a, miR-126 and those of the miR-200 family, that target critical coding genes in these pathways. Most importantly, DICER1 impairment also induces the acquisition of a greater capacity for tumor initiation and metastasis, two properties associated with cancer stem cells.
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Project description:The tumor suppressor DAB2IP contributes to modulate the network of information established between cancer cells and tumor microenvironment. Epigenetic and post-transcriptional inactivation of this protein is commonly observed in multiple human malignancies, and can potentially favor progression of tumors driven by a variety of genetic mutations. Performing a high-throughput screening of a large collection of human microRNA mimics, we identified miR-149-3p as a negative post-transcriptional modulator of DAB2IP. By efficiently downregulating DAB2IP, this miRNA enhances cancer cell motility and invasiveness, facilitating activation of NF-kB signaling and promoting expression of pro-inflammatory and pro-angiogenic factors. In addition, we found that miR-149-3p secreted by prostate cancer cells induces DAB2IP downregulation in recipient vascular endothelial cells, stimulating their proliferation and motility, thus potentially remodeling the tumor microenvironment. Finally, we found that inhibition of endogenous miR-149-3p restores DAB2IP activity and efficiently reduces tumor growth and dissemination of malignant cells. These observations suggest that miR-149-3p can promote cancer progression via coordinated inhibition of DAB2IP in tumor cells and in stromal cells.
| S-EPMC6030048 | biostudies-literature
Project description:A widespread downregulated expression of microRNAs (miRNAs) is commonly observed in human cancers. Similarly, deregulated expression of miRNA-processing pathway components, which results in the reduction of global miRNA expression, may also be associated with tumorigenesis. Here, we show that specific ablation of Dicer1 in intestinal epithelial cells accelerates intestinal inflammation-associated tumorigenesis. This effect was apparent only when a single copy of Dicer1 was deleted, but not with complete Dicer1 ablation. DICER expression and subsequent mature miRNA levels were inversely correlated with the number of intact Dicer1 alleles. Because the expression levels of DICER were retained in tumors and its surrounding tissues even after induction of colitis-associated tumors, the effects of Dicer1 deletion were cell-autonomous. Although the expression levels of representative oncogenes and tumor suppressor genes were in most cases inversely correlated with the expression levels of DICER, some genes were not affected by Dicer1 deletion. Thus, deregulating the delicate balance between the expression levels of tumor-promoting and -suppressive genes may be crucial for tumorigenesis in this unique haploinsufficient case.
| S-EPMC3759383 | biostudies-other
Project description:Global mature microRNA (miRNA) expression is downregulated in cancers, and impaired miRNA processing enhances cancer cell proliferation. These findings indicate that the miRNA system generally serves as a negative regulator during cancer progression. In this study, we investigated the role of the miRNA system in cancer cell invasion by determining the effect of damaging miRNA processing on invasion-essential urokinase-type plasminogen activator (uPA) expression in breast cancer cells. Short hairpin RNAs specific for Drosha, DGCR8, and Dicer, key components of miRNA processing machinery, were introduced into 2 breast cancer cell lines with high uPA expression and 2 lines with poor uPA expression. Knockdown of Drosha, DGCR8, or Dicer led to even higher uPA expression in cells with high uPA expression, while it was unable to increase uPA level in cells with poor uPA expression, suggesting that the miRNA system most likely impacts uPA expression as a facilitator. In cells with high uPA expression, knockdown of Drosha, DGCR8, or Dicer substantially increased in vitro invasion, and depleting uPA abrogated enhanced invasion. These results thus link the augmented invasion conferred by impaired miRNA processing to upregulated uPA expression. uPA mRNA was a direct target of miR-193a/b and miR-181a, and a higher uPA level in cells with impaired miRNA processing resulted from less mature miR-193a/b and miR-181a processed from their respective primary miRNAs. Importantly, the levels of mature miR-193a, miR-193b, and miR-181a, but not their respective primary miRNAs, were lower in high uPA-expressing cells compared to cells with low uPA expression, and this apparently attributed to lower Drosha/DGCR8 expression in high uPA-expressing cells. This study suggests that less efficient miRNA processing can be a mechanism responsible for reduced levels of mature forms of tumor-suppressive miRNAs frequently detected in cancers.
| S-EPMC3111246 | biostudies-literature
Project description:PurposeLeucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a cancer stem cell marker and a down-stream target in Wnt/?-catenin signaling. In human papillary thyroid cancer (PTC), over activation of Wnt/?-catenin has been associated with tumor aggressiveness.Patients and methodsUsing established human cell lines (TPC-1, KTC-1, Nthy-ori-3-1), we report LGR5 and R-spondin (RSPO1-3) overexpression in PTC and manipulate LGR5 and Wnt/?-catenin signaling via both pharmacologic and genetic interventions. We test the association of LGR5 tumor expression with markers of PTC aggressiveness using a Discovery Cohort (n = 26 patients) and a Validation Cohort (n = 157 patients). Lastly, we explore the association between LGR5 and the BRAFV600E mutation (n = 33 patients).ResultsOur results reveal that LGR5 and its ligand, RSPO, are overexpressed in human PTC, whereby Wnt/?-catenin signaling regulates LGR5 expression and promotes cellular migration. In two separate cohorts of patients, LGR5 and RSPO2 were associated with markers of tumor aggressiveness including: lymph node metastases, vascular invasion, increased tumor size, aggressive histology, advanced AJCC TNM stage, microscopic extra thyroidal extension, capsular invasion, and macroscopic invasion. As a biomarker, LGR5 positivity predicts lymph node metastasis with 95.5% sensitivity (95% CI 88.8%-98.7%) and 61% specificity (95% CI: 48.4%-72.4%) and has a negative predictive value (NPV) of 91.3% (95% CI 79.2%-97.5%) for lymph node metastatic disease. In human PTC, LGR5 is also strongly associated with the BRAFV600E mutation (p = 0.005).ConclusionWe conclude that overexpression of LGR5 is associated with markers of tumor aggressiveness in human PTC. LGR5 may serve as a future potential biomarker for patient risk stratification and loco regional metastases in PTC.
| S-EPMC4741472 | biostudies-literature
Project description:BackgroundPyruvate carboxylase (PC) is an important anaplerotic enzyme in the tricarboxylic acid cycle (TCA) in cancer cells. Although PC overexpression has been observed in thyroid cancer (TC), the mechanisms involved in the carcinogenic effects of PC are still unclear.MethodsBioinformatics analysis and clinical specimens were used to analyze the relationship of PC expression with clinicopathological variables in TC. Fatty acid synthesis was monitored by LC/MS, Nile red staining, and triglyceride analysis. Mitochondrial oxygen consumption was evaluated by the Seahorse XF Mito Cell Stress Test. The correlation of PC with FASN and SREBP1c was assessed by qRT-PCR and IHC in 38 human TC tissues. Western blotting was used to evaluate the protein expression of PC, FASN, and SREBP1c and members of the AKT/mTOR and EMT pathways in TC cell lines. Wound-healing, CCK-8, and Transwell assays and a nude mouse xenograft model were used to verify the regulatory effects of PC and SREBP1c on thyroid tumor cell proliferation, migration and invasion.ResultsWe demonstrated that PC increased fatty acid synthesis, which then promoted TC progression and metastasis. Analysis of GEO data showed that the overexpression of PC in papillary thyroid cancer (PTC) was associated with PTC invasion and the fatty acid synthesis pathway. Analysis of clinical tissue specimens from PTC patients revealed that PC was more highly expressed in specimens from PTC patients with lymph node metastasis than in those from patients without metastasis. Multiple genes in the fatty acid synthesis signaling pathway, including FASN and SREBP1c, were downregulated in PC-knockdown TC cells compared to control cells. Lipid levels were also decreased in the PC-knockdown TC cells. Moreover, the ability of cells to grow, invade, and metastasize was also suppressed upon PC knockdown, suggesting that PC-mediated lipogenesis activation increases the aggressiveness of TC cells. In addition, PC was found to activate the AKT/mTOR pathway, thus improving FASN-mediated de novo lipogenesis in TC cells by upregulating SREBP1c expression. Studies in a nude mouse xenograft model showed that PC knockdown decreased tumor weight, but this effect was attenuated by forced expression of SREBP1c.ConclusionsOur results demonstrate that PC is strongly involved in the tumor aggressiveness of TC via its stimulation of fatty acid synthesis.
| S-EPMC8220755 | biostudies-literature
Project description:Increasing evidence demonstrate that dysregulated microRNAs (miRNAs) are involved in carcinogenesis and tumor progression in papillary thyroid cancer (PTC). However, the specific miR-761 in cancer remains largely unknown. In this study, we reported for the first that miR-761 expression was down-regulated in PTC tissues and cell lines, and its decrease was associated with tumor size and TNM stage. Gain- and loss-of function experiments revealed that miR-761 inhibited cell proliferation, colony formation and cell cycle progression in vitro and in vivo. Moreover, TRIM29 was identified as a direct downstream target of miR-761 in PTC cells and mediated the functional effects of miR-761 in PTC. Restoration of TRIM29 expression at least partially abolished the biological effects of miR-761 on PTC cells. Furthermore, overexpression of lncRNA HOXA11-AS was inversely correlated with miR-761 expression in PTC tissues. LncRNA HOXA11-AS could modulate the miR-761 expression and regulate cellular behaviors. Taken together, this research supports the first evidence that lncRNA HOXA11-AS-reguated miR-761 plays a functional role in inhibiting PTC progression by targeting TRIM29 and represent a promising therapeutic strategy for patients with PTC.
| S-EPMC6895523 | biostudies-literature