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Journal ArticleDOI

miR-145, miR-133a and miR-133b: Tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma

15 Dec 2010-International Journal of Cancer (Wiley Subscription Services, Inc., A Wiley Company)-Vol. 127, Iss: 12, pp 2804-2814
TL;DR: The identification of tumor‐suppressive miRNAs,miR‐145, miR‐133a and miR-133b, directly control oncogenic FSCN1 gene, and could provide new insights into potential mechanisms of ESCC carcinogenesis.
Abstract: MicroRNAs (miRNAs), noncoding RNAs 21–25 nucleotides in length, regulate gene expression primarily at the posttranscriptional level. Growing evidence suggests that miRNAs are aberrantly expressed in many human cancers, and that they play significant roles in carcinogenesis and cancer progression. A search for miRNAs with a tumor-suppressive function in esophageal squamous cell carcinoma (ESCC) was performed using the miRNA expression signatures obtained from ESCC clinical specimens. A subset of 15 miRNAs was significantly downregulated in ESCC. A comparison of miRNA signatures from ESCC and our previous report identified 4 miRNAs that are downregulated in common (miR-145, miR-30a-3p, miR-133a and miR-133b), suggesting that these miRNAs are candidate tumor suppressors. Gain-of-function analysis revealed that 3 transfectants (miR-145, miR-133a and miR-133b) inhibit cell proliferation and cell invasion in ESCC cells. These miRNAs (miR-145, miR-133a and miR-133b), which have conserved sequences in the 3′UTR of FSCN1 (actin-binding protein, Fascin homolog 1), inhibited FSCN1 expression. The signal from a luciferase reporter assay was significantly decreased at 2 miR-145 target sites and 1 miR-133a/b site, suggesting both miRNAs directly regulate FSCN1. An FSCN1 loss-of-function assay found significant cell growth and invasion inhibition, implying an FSCN1 is associated with ESCC carcinogenesis. The identification of tumor-suppressive miRNAs, miR-145, miR-133a and miR-133b, directly control oncogenic FSCN1 gene. These signal pathways of ESCC could provide new insights into potential mechanisms of ESCC carcinogenesis.
Citations
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Journal ArticleDOI
TL;DR: It is found that MSC treatment of rats subjected to middle cerebral artery occlusion significantly increased microRNA 133b (miR‐133b) level in the ipsilateral hemisphere and this study provides the first demonstration that M SCs communicate with brain parenchymal cells and may regulate neurite outgrowth by transfer of miR‐ 133b to neural cells via exosomes.
Abstract: Multipotent mesenchymal stromal cells (MSCs) have potential therapeutic benefit for the treatment of neurological diseases and injury. MSCs interact with and alter brain parenchymal cells by direct cell-cell communication and/or by indirect secretion of factors and thereby promote functional recovery. In this study, we found that MSC treatment of rats subjected to middle cerebral artery occlusion (MCAo) significantly increased microRNA 133b (miR-133b) level in the ipsilateral hemisphere. In vitro, miR-133b levels in MSCs and in their exosomes increased after MSCs were exposed to ipsilateral ischemic tissue extracts from rats subjected to MCAo. miR-133b levels were also increased in primary cultured neurons and astrocytes treated with the exosome-enriched fractions released from these MSCs. Knockdown of miR-133b in MSCs confirmed that the increased miR-133b level in astrocytes is attributed to their transfer from MSCs. Further verification of this exosome-mediated intercellular communication was performed using a cel-miR-67 luciferase reporter system and an MSC-astrocyte coculture model. Cel-miR-67 in MSCs was transferred to astrocytes via exosomes between 50 and 100 nm in diameter. Our data suggest that the cel-miR-67 released from MSCs was primarily contained in exosomes. A gap junction intercellular communication inhibitor arrested the exosomal microRNA communication by inhibiting exosome release. Cultured neurons treated with exosome-enriched fractions from MSCs exposed to 72 hours post-MCAo brain extracts significantly increased the neurite branch number and total neurite length. This study provides the first demonstration that MSCs communicate with brain parenchymal cells and may regulate neurite outgrowth by transfer of miR-133b to neural cells via exosomes.

738 citations

Journal ArticleDOI
Caleb F. Davis1, Christopher J. Ricketts, Min Wang1, Lixing Yang2  +222 moreInstitutions (18)
TL;DR: Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations.

658 citations


Cites background from "miR-145, miR-133a and miR-133b: Tum..."

  • ...Cluster analysis of microRNA (miRNA) profiles also indicated heterogeneity (Figure S2C), and we could identify anticorrelations between miRNAs and their predicted mRNA targets (Table S4), including an anticorrelation (false discovery rate [FDR] 0.01) involving miR145 (low in ChRCC versus normal) and the complex I-associated NDUFA4 gene (Figure S2D) (Kano et al., 2010)....

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  • ...…(Figure S2C), and we could identify anticorrelations between miRNAs and their predicted mRNA targets (Table S4), including an anticorrelation (false discovery rate [FDR] 0.01) involving miR145 (low in ChRCC versus normal) and the complex I-associated NDUFA4 gene (Figure S2D) (Kano et al., 2010)....

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Journal ArticleDOI
TL;DR: In this article, the role of miR-145 in pulmonary arterial hypertension (PAH) was evaluated in mice treated with anti-miRs via measurement of systolic right ventricular pressure, right ventriches hypertrophy, and percentage of remodeled pulmonary arteries.
Abstract: Rationale: Despite improved understanding of the underlying genetics, pulmonary arterial hypertension (PAH) remains a severe disease. Extensive remodeling of small pulmonary arteries, including proliferation of pulmonary artery smooth muscle cells (PASMCs), characterizes PAH. MicroRNAs (miRNAs) are noncoding RNAs that have been shown to play a role in vascular remodeling. Objective: We assessed the role of miR-145 in PAH. Methods and Results: We localized miR-145 in mouse lung to smooth muscle. Using quantitative PCR, we demonstrated increased expression of miR-145 in wild-type mice exposed to hypoxia. PAH was evaluated in miR-145 knockout and mice treated with anti-miRs via measurement of systolic right ventricular pressure, right ventricular hypertrophy, and percentage of remodeled pulmonary arteries. miR-145 deficiency and anti-miR–mediated reduction resulted in significant protection from the development of PAH. In contrast, miR-143 anti-miR had no effect. Furthermore, we observed upregulation of miR-145 in lung tissue of patients with idiopathic and heritable PAH compared with unaffected control subjects and demonstrated expression of miR-145 in SMC of remodeled vessels from such patients. Finally, we show elevated levels of miR-145 expression in primary PASMCs cultured from patients with BMPR2 mutations and also in the lungs of BMPR2 -deficient mice. Conclusions: miR-145 is dysregulated in mouse models of PAH. Downregulation of miR-145 protects against the development of PAH. In patient samples of heritable PAH and idiopathic PAH, miR-145 is expressed in remodeled vessels and mutations in BMPR2 lead to upregulation of miR-145 in mice and PAH patients. Manipulation of miR-145 may represent a novel strategy in PAH treatment.

252 citations

Journal ArticleDOI
TL;DR: The downregulation ofmiR-1 and miR-133a was a frequent event in BC, and these miRNAs were recognised as tumour suppressive and TAGLN2 may be a target of both mi RNAs and had a potential oncogenic function.
Abstract: The tumour-suppressive function of miR-1 and miR-133a targeting TAGLN2 in bladder cancer

247 citations


Cites background from "miR-145, miR-133a and miR-133b: Tum..."

  • ...…was downregulated in pancreatic ductal adenocarcinoma, oesophageal squamous cell carcinoma, rhabdomyosarcoma, colorectal cancer, and squamous cell carcinoma of the tongue (Bandrés et al, 2006; Szafranska et al, 2007; Wong et al, 2008a, b; Arndt et al, 2009; Yan et al, 2009; Kano et al, 2010)....

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Journal ArticleDOI
TL;DR: Data implicated that several different filopodia inducing genes may contribute in a collective manner to cancer progression and the high metastasis rates associated with basal-type breast carcinomas.
Abstract: Slender bundled actin containing plasma membrane protrusions, called filopodia, are important for many essential cellular processes like cell adhesion, migration, angiogenesis and the formation of cell-cell contacts. In migrating cells, filopodia are the pioneers at the leading edge which probe the environment for cues. Integrins are cell surface adhesion receptors critically implicated in cell migration and they are transported actively to filopodia tips by an unconventional myosin, myosin-X. Integrin mediated adhesion stabilizes filopodia and promotes cell migration even though integrins are not essential for filopodia initiation. Myosin-X binds also PIP3 and this regulates its activation and localization to filopodia. Filopodia stimulate cell migration in many cell types and increased filopodia density has been described in cancer. Furthermore, several proteins implicated in filopodia formation, like fascin, are also relevant for cancer progression. To investigate this further, we performed a meta-analysis of the expression profiles of 10 filopodia-linked genes in human breast cancer. These data implicated that several different filopodia inducing genes may contribute in a collective manner to cancer progression and the high metastasis rates associated with basal-type breast carcinomas.

234 citations

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TL;DR: I MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators as discussed by the authors, and have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer.
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