Dataset Information

Mycotoxin ochratoxin A disrupts renal development via a miR-731/prolactin receptor axis in zebrafish.

ABSTRACT: Mycotoxin ochratoxin A (OTA) frequently contaminates various food and feed products, including cereals, coffee and wine. While the nephrotoxicity and teratogenicity of OTA have been extensively documented, the molecular mechanisms associated with OTA toxicity remained poorly understood in a developing organism. We showed that zebrafish embryos exposed to OTA demonstrated incorrect heart looping and small heart chambers. OTA also impaired the renal morphology and reduced the glomerular filtration rate of the embryonic zebrafish. The treatment of embryos with OTA attenuated the expression of the prolactin receptor, a gene (PRLRa) that has a key role in organogenesis and osmoregulation in vertebrates. OTA not only inhibited the phosphorylation of STAT5 and AKT, but also down-regulated the level of serpina1 mRNA in a dose-dependent manner. On the other hand, the microRNA profiling based on RNA sequencing revealed the up-regulation of microRNA-731 (miR-731) in the OTA-treated embryos. Further in silico analysis predicted that PRLRa was a target gene of miR-731. AntagomiR-731 restored PRLRa levels that had been reduced by OTA and also recovered the pronephros morphology that was damaged by OTA. These observations suggest that the exposure to OTA adversely affected the organogenesis of zebrafish, and the modulation of miR-731 and the PRLR signaling cascade contributed to the abnormal renal development mediated by OTA.

SUBMITTER: Wu TS

PROVIDER: S-EPMC6062247 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Mycotoxin ochratoxin A disrupts renal development <i>via</i> a miR-731/prolactin receptor axis in zebrafish.

Wu Ting-Shuan TS Yang Jiann-Jou JJ Wang Yan-Wei YW Yu Feng-Yih FY Liu Biing-Hui BH

Toxicology research 20160104 2

Mycotoxin ochratoxin A (OTA) frequently contaminates various food and feed products, including cereals, coffee and wine. While the nephrotoxicity and teratogenicity of OTA have been extensively documented, the molecular mechanisms associated with OTA toxicity remained poorly understood in a developing organism. We showed that zebrafish embryos exposed to OTA demonstrated incorrect heart looping and small heart chambers. OTA also impaired the renal morphology and reduced the glomerular filtration ...[more]

PMID: 30090366

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Project description:MicroRNAs (miRNAs) play significant roles in both embryonic hematopoiesis and hematological malignancy. Zebrafish miR-462-731 cluster is orthologous of miR-191-425 in human which regulates proliferation and tumorigenesis. In our previous work, miR-462-731 was found highly and ubiquitously expressed during early embryogenesis. In this study, by loss-of-function analysis (morpholino knockdown combined with CRISRP/Cas9 knockout) and mRNA profiling, we suggest that miR-462-731 is required for normal embryonic development by regulating cell survival. We found that loss of miR-462/miR-731 caused a remarkable decrease in the number of erythroid cells as well as an ectopic myeloid cell expansion at 48 hpf, suggesting a skewing of myeloid-erythroid lineage differentiation. Mechanistically, miR-462-731 provides an instructive input for pu.1-dependent primitive myelopoiesis through regulating etsrp/scl signaling combined with a novel pu.1/miR-462-731 feedback loop. On the other hand, morpholino (MO) knockdown of miR-462/miR-731 resulted in an expansion of posterior blood islands at 24 hpf, which is a mild ventralization phenotype resulted from elevation of BMP signaling. Rescue experiments with both BMP type I receptor inhibitor dorsomorphin and alk8 MO indicate that miR-462-731 acts upstream of alk8 within the BMP/Smad signaling pathway and functions as a novel endogenous BMP antagonist. Besides, an impairment of angiogenesis was observed in miR-462/miR-731 morphants. The specification of arteries and veins was also perturbed, as characterized by the irregular patterning of efnb2a and flt4 expression. Our study unveils a previously unrecognized role of miR-462-731 in BMP/Smad signaling mediated hematopoietic specification of mesodermal progenitors and demonstrates a miR-462-731 mediated regulatory mechanism driving primitive myelopoiesis in the ALPM. We also show a requirement for miR-462-731 in regulating arterial-venous specification and definitive hematopoietic stem cell (HSC) production. The current findings might provide further insights into the molecular mechanistic basis of miRNA regulation of embryonic hematopoiesis and hematological malignancy.

Project description:BACKGROUND:Recent evidence indicates that metformin inhibits mammalian cancer growth and metastasis through the regulation of microRNAs. Metformin regulates miR-381 stability, which plays a vital role in tumor progression. Moreover, increased YAP expression and activity induce non-small cell lung cancer (NSCLC) tumor growth and metastasis. However, the molecular mechanism underpinning how metformin-induced upregulation of miR-381 directly targets YAP or its interactions with the epithelial-mesenchymal transition (EMT) marker protein Snail in NSCLC is still unknown. METHODS:Levels of RNA and protein were analyzed using qPCR, western blotting and immunofluorescence staining. Cellular proliferation was detected using a CCK8 assay. Cell migration and invasion were analyzed using wound healing and transwell assays. Promoter activity and transcription were investigated using the luciferase reporter assay. Chromatin immunoprecipitation was used to detect the binding of YAP to the promoter of Snail. The interaction between miR-381 and the 3'UTR of YAP mRNA was analyzed using the MS2 expression system and co-immunoprecipitation with biotin. RESULTS:We observed that miR-381 expression is negatively correlated with YAP expression and plays an opposite role to YAP in the regulation of cellular proliferation, invasion, migration, and EMT of NSCLC cells. The miR-381 function as a tumor suppressor was significantly downregulated in lung cancer tissue specimens and cell lines, which decreased the expression of its direct target YAP. In addition, metformin decreased cell growth, migration, invasion, and EMT via up-regulation of miR-381. Moreover, YAP, which functions as a co-transcription factor, enhanced NSCLC progression and metastasis by upregulation of Snail. Snail knockdown downregulated the mesenchymal marker vimentin and upregulated the epithelial marker E-cadherin in lung cancer cells. Furthermore, miR-381, YAP, and Snail constitute the miR-381-YAP-Snail signal axis, which is repressed by metformin, and enhances cancer cell invasiveness by directly regulating EMT. CONCLUSIONS:Metformin-induced repression of miR-381-YAP-Snail axis activity disrupts NSCLC growth and metastasis. Thus, we believe that the miR-381-YAP-Snail signal axis may be a suitable diagnostic marker and a potential therapeutic target for lung cancer.

Dataset Information

Mycotoxin ochratoxin A disrupts renal development via a miR-731/prolactin receptor axis in zebrafish.

Publications

Mycotoxin ochratoxin A disrupts renal development <i>via</i> a miR-731/prolactin receptor axis in zebrafish.

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Dataset Information

Mycotoxin ochratoxin A disrupts renal development via a miR-731/prolactin receptor axis in zebrafish.

Publications

Mycotoxin ochratoxin A disrupts renal development &lt;i&gt;via&lt;/i&gt; a miR-731/prolactin receptor axis in zebrafish.

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OmicsDI is part of the ELIXIR infrastructure

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Mycotoxin ochratoxin A disrupts renal development <i>via</i> a miR-731/prolactin receptor axis in zebrafish.