ACVR1, a Therapeutic Target of Fibrodysplasia Ossificans Progressiva, Is Negatively Regulated by miR-148a

Song, Hongjiang; Wang, Qi; Wen, Jun-ge; Liu, Shunai; Gao, Xuesong; Cheng, Jun; Zhang, Deli

doi:10.3390/ijms13022063

Cited by 36 publications

(33 citation statements)

References 65 publications

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“…ACVR1 is normally inactive until it binds to extracellular BMP (Song et al, 2012). BMPs interact with specific BMP receptors (BMPRs) that phosphorylate downstream effector molecules.…”

Section: How the Acvr1-bmps Signaling Is Associated With Fop?mentioning

confidence: 99%

“…Subsequently, these form heteromeric complexes with the co-regulatory Smad4 and accumulate in the nucleus. Once phosphorylated, by directly binding to DNA and interacting with different transcriptional coactivators or co-repressors, Smads regulate target gene transcription (Song et al, 2012). The mutant ACVR1-p.R206H sensitizes mesenchymal cells to BMP-induced osteoblast differentiation, and stimulates new bone formation, i.e., the mutant p.R206H ACVR1 activates BMP signaling in the absence of BMP ligand and mediates BMP-independent chondrogenesis (Shen et al, 2009) (Fig.…”

Section: How the Acvr1-bmps Signaling Is Associated With Fop?mentioning

confidence: 99%

“…1). Song et al (2012) investigated whether miR-148a directly targets ACVR1 mRNA by reporter gene assays and mutational analysis at the miRNA binding sites, and inhibited ACVR1 both at the protein level and mRNA level. They suggested that miR-148a is an important mediator of ACVR1, thus offering a new potential target for the development of therapeutic agents against FOP (Song et al, 2012).…”

Section: How the Acvr1-bmps Signaling Is Associated With Fop?mentioning

confidence: 99%

“…Song et al (2012) investigated whether miR-148a directly targets ACVR1 mRNA by reporter gene assays and mutational analysis at the miRNA binding sites, and inhibited ACVR1 both at the protein level and mRNA level. They suggested that miR-148a is an important mediator of ACVR1, thus offering a new potential target for the development of therapeutic agents against FOP (Song et al, 2012). According to Song et al (2010), the p.R206H mutant showed a decreased binding affinity for FKBP1A/FKBP12, a known safeguard molecule against the leakage of transforming growth factor (TGF)-beta or BMP signaling.…”

Section: How the Acvr1-bmps Signaling Is Associated With Fop?mentioning

confidence: 99%

“…ACVR1 gene belonging to the transforming growth factor (TGF)-β superfamily (Song et al, 2012), consists of 139.417 kb, and was mapped to chromosome 2q23-24 (NCBI GenBank, 2012). Nakajima et al (2007) reported the c.617G>A; p.R206H mutation in the ACVR1 gene in individuals with FOP of various ethnic groups, and they suggested that mutation in the ACVR1 gene is common and recurrent in the global population.…”

Section: Acvr1/alk2mentioning

confidence: 99%

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Genetic abnormalities in Fibrodysplasia Ossificans Progressiva

Zhang

Peng

et al. 2012

Genes Genet. Syst.

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Fibrodysplasia ossificans progressiva (FOP), characterized by congenital malformation of bones, is an autosomal dominant disorder. This is a rare genetic disorder and its worldwide prevalence is approximately 1/2,000,000. There is no ethnic, racial, gender, or geographic predilection to FOP. It is regarded as one of the intractable disorders, which is not only an extremely disabling disease but also a condition of considerably shortened lifespan. Although the genetic defects of FOP are not completely known, several clinical and animal model studies have implicated that mutations in bone morphogenetic proteins, their receptors, and activin receptor type IA (ACVR1) genes are associated with FOP primarily. The noggin (NOG) gene has also been reported in some studies. In most of the cases of FOP, the mutation was found as 'de novo' however there is paternal age effect on mutations. Unfortunately, at present there is no efficient treatment for FOP. The recent discoveries of genetic basis of FOP provide a clue to the underlying pathophysiology and potential therapy. This review article focuses on the genetic mutations in FOP, their usage as diagnostic markers, and possible target specific drug development to treat FOP patients.

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“…ACVR1 is normally inactive until it binds to extracellular BMP (Song et al, 2012). BMPs interact with specific BMP receptors (BMPRs) that phosphorylate downstream effector molecules.…”

Section: How the Acvr1-bmps Signaling Is Associated With Fop?mentioning

confidence: 99%

Section: How the Acvr1-bmps Signaling Is Associated With Fop?mentioning

confidence: 99%

Section: How the Acvr1-bmps Signaling Is Associated With Fop?mentioning

confidence: 99%

Section: How the Acvr1-bmps Signaling Is Associated With Fop?mentioning

confidence: 99%

Section: Acvr1/alk2mentioning

confidence: 99%

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Genetic abnormalities in Fibrodysplasia Ossificans Progressiva

Zhang

Peng

et al. 2012

Genes Genet. Syst.

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Regulatory MiR‐148a‐ACVR1/BMP circuit defines a cancer stem cell‐like aggressive subtype of hepatocellular carcinoma

Liu

Guo

et al. 2015

Hepatology

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Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third most common cancer in Asia. HCC has heterogeneous etiologic and molecular profiles and a varied response to therapeutics. The high recurrence rate and curtailed survival in this cancer are attributed to its resistance to therapy. The ultimate goal is to develop a more effective personalized therapeutic strategy for HCC, but the first step is to develop a system for classifying the disease on the basis of molecular biomarkers. To that end, we performed mRNA and microRNA (miRNA) expression profiling in 100 HCC tissues. Clustering analysis of informative genes identified two robust subtypes, which were validated by an independent dataset. The subtype characterized by a cancer stem cell‐like signature was clinically aggressive and associated with poor survival. Integrated analysis of miRNA and mRNA expression in this subtype showed that miR‐148a was expressed at a significantly lower level in these tumors than in the other subtype. MiR‐148a has been shown to directly suppress the expression of activin A receptor type 1 (ACVR1), a key receptor in the signaling pathway of the bone morphogenetic proteins (BMPs), which regulate many stem cell markers as well as the clinically important cytokine interleukin‐8 (IL‐8). Increased expression of ACVR1 and its downstream genes EPCAM, CD24, CD90, and IL‐8 was associated with shorter survival in a larger cohort of 227 HCC cases. Introduction of miR‐148a resulted in suppressed tumor phenotypes both in vitro and in vivo. Conclusion: We identified a clinically aggressive stem cell‐like subtype of HCC that is characterized by an miR‐148a‐ACVR1‐BMP‐Wnt circuit. We propose that miR‐148a may serve as a prognostic biomarker and therapeutic target for this subtype of HCC. (Hepatology 2015;61:574‐584)

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MicroRNAs Provide Feedback Regulation of Epithelial‐Mesenchymal Transition Induced by Growth Factors

Qin

Tang

et al. 2015

Journal Cellular Physiology

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As regulators in gene expression, microRNAs take part in most biological processes including cell differentiation, apoptosis, cell cycle, and epithelial-to-mesenchymal transition (EMT). In order to evaluate their roles in EMT process, microRNA expression profile changes induced by EGF or TGF-β treatment on nasopharyngeal carcinoma cell HK-1 were analyzed, and miR-21, miR-148a, miR-505, and miR-1207-5p were found to be upregulated in growth factors-induced EMT process. miR-21 is already known as an oncogenic miRNA to promote metastasis, however, the exact functions of other three miRNAs in EMT are unclear. To our surprise, we found that miR-148a, miR-505, and miR-1207-5p can suppress EMT and metastasis phenotypes in HK-1 cells both in vitro and in vivo, which may relate to their inhibition on EMT and Wnt signaling molecules. MiRNAs confer robustness to biological processes by posttranscriptional repression of key transcriptional programs that are related to previous developmental stages or to alternative cell fates. Our findings indicate that miRNA feedback circuit is tuned to respond to growth factors-induced EMT, and we suggested a new negative feedback loop which may be an important element of the EMT process and confer biological robustness.

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ACVR1, a Therapeutic Target of Fibrodysplasia Ossificans Progressiva, Is Negatively Regulated by miR-148a

Cited by 36 publications

References 65 publications

Genetic abnormalities in Fibrodysplasia Ossificans Progressiva

Genetic abnormalities in Fibrodysplasia Ossificans Progressiva

Regulatory MiR‐148a‐ACVR1/BMP circuit defines a cancer stem cell‐like aggressive subtype of hepatocellular carcinoma

MicroRNAs Provide Feedback Regulation of Epithelial‐Mesenchymal Transition Induced by Growth Factors

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