scholarly journals MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid

2021 ◽  
Vol 9 ◽  
Author(s):  
Hiroki Yoshioka ◽  
Yurie Mikami ◽  
Sai Shankar Ramakrishnan ◽  
Akiko Suzuki ◽  
Junichi Iwata
Keyword(s):  
Cell Proliferation ◽  
Retinoic Acid ◽  
Cleft Palate ◽  
Cleft Lip ◽  
Specific Inhibitor ◽  
Mouse Embryos ◽  
Congenital Birth Defects ◽  
Excessive Intake

Cleft lip with/without cleft palate (CL/P) is one of the most common congenital birth defects, showing the complexity of both genetic and environmental contributions [e.g., maternal exposure to alcohol, cigarette, and retinoic acid (RA)] in humans. Recent studies suggest that epigenetic factors, including microRNAs (miRs), are altered by various environmental factors. In this study, to investigate whether and how miRs are involved in cleft palate (CP) induced by excessive intake of all-trans RA (atRA), we evaluated top 10 candidate miRs, which were selected through our bioinformatic analyses, in mouse embryonic palatal mesenchymal (MEPM) cells as well as in mouse embryos treated with atRA. Among them, overexpression of miR-27a-3p, miR-27b-3p, and miR-124-3p resulted in the significant reduction of cell proliferation in MEPM cells through the downregulation of CP-associated genes. Notably, we found that excessive atRA upregulated the expression of miR-124-3p, but not of miR-27a-3p and miR-27b-3p, in both in vivo and in vitro. Importantly, treatment with a specific inhibitor for miR-124-3p restored decreased cell proliferation through the normalization of target gene expression in atRA-treated MEPM cells and atRA-exposed mouse embryos, resulting in the rescue of CP in mice. Taken together, our results indicate that atRA causes CP through the induction of miR-124-3p in mice.

Deficient Cell Proliferation in Palatal Shelf Mesenchyme of CL/Fr Mouse Embryos

2004 ◽  
Vol 83 (10) ◽  
pp. 797-801 ◽  
Author(s):  
Y. Sasaki ◽  
S. Tanaka ◽  
T. Hamachi ◽  
Y. Taya
Keyword(s):  
Cell Proliferation ◽  
Cleft Lip ◽  
Absolute Number ◽  
Culture Cell ◽  
Mouse Embryos ◽  
Group Differences ◽  
Regional Patterns ◽  
Secondary Palate

How secondary palate formation is affected in the cleft lip genotype remains poorly understood. The purpose of this study was to analyze regional patterns of cell proliferation in CL/Fr mouse embryos with or without cleft lip. Pairs of palatal shelves were dissected at E13.5 from CL/Fr normal embryos (CL/Fr-N), CL/Fr embryos with bilateral cleft lip (CL/Fr-BCL), and a control strain of C57BL embryos (C57BL). The explants were examined histologically after 48 hrs of organ culture. Cell kinetics for proliferation in the palatal shelves was examined at E13.5 by the bromodeoxyuridine method in vivo. The CL/Fr-BCL palates fused as well as the CL/Fr-N palates in vitro. There were inter-group differences in the absolute number of BrdU-positive cells and the ratio of positive/(positive+negative) cells in the palate’s mesenchyme (C57BL > CL/Fr-N > CL/Fr-BCL) and epithelium (C57BL > CL/Fr-N = CL/Fr-BCL). These findings indicate that a cleft palate follows reduced cell proliferation of secondary palatal mesenchyme in CL/Fr mice.

Effects of retinoic acid steroidal analogs on human leukemic HL60 cell proliferation in vitro and on angiogenesis in vivo

2005 ◽  
Vol 16 (2) ◽  
pp. 151-158 ◽  
Author(s):  
Evaggelia S. Arsenou ◽  
Evangelia P. Papadimitriou ◽  
Eleni Kliafa ◽  
Maria Hountala ◽  
Sotiris S. Nikolaropoulos
Keyword(s):  
Cell Proliferation ◽  
Retinoic Acid ◽  
Hl60 Cell ◽  
Proliferation In Vitro

scholarly journals SP1-Mediated Upregulation of Long Noncoding RNA ZFAS1 Involved in Non-syndromic Cleft Lip and Palate via Inactivating WNT/β-Catenin Signaling Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Shiyu Chen ◽  
Zhonglin Jia ◽  
Ming Cai ◽  
Mujie Ye ◽  
Dandan Wu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Noncoding Rna ◽  
Chondrogenic Differentiation ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Tissue Sample ◽  
Human Umbilical Cord

Non-syndromic cleft lip and palate (NSCLP) is one of the most common congenital malformations with multifactorial etiology. Although long non-coding RNAs (lncRNAs) have been implicated in the development of lip and palate, their roles in NSCLP are not fully elucidated. This study aimed to investigate how dysregulated lncRNAs contribute to NSCLP. Using lncRNA sequencing, bioinformatics analysis, and clinical tissue sample detection, we identified that lncRNA ZFAS1 was significantly upregulated in NSCLP. The upregulation of ZFAS1 mediated by SP1 transcription factor (SP1) inhibited expression levels of Wnt family member 4 (WNT4) through the binding with CCCTC-binding factor (CTCF), subsequently inactivating the WNT/β-catenin signaling pathway, which has been reported to play a significant role on the development of lip and palate. Moreover, in vitro, the overexpression of ZFAS1 inhibited cell proliferation and migration in human oral keratinocytes and human umbilical cord mesenchymal stem cells (HUC-MSCs) and also repressed chondrogenic differentiation of HUC-MSCs. In vivo, ZFAS1 suppressed cell proliferation and numbers of chondrocyte in the zebrafish ethmoid plate. In summary, these results indicated that ZFAS1 may be involved in NSCLP by affecting cell proliferation, migration, and chondrogenic differentiation through inactivating the WNT/β-catenin signaling pathway.

scholarly journals Identification of New miRNA-mRNA Networks in the Development of Non-syndromic Cleft Lip With or Without Cleft Palate

2021 ◽  
Vol 9 ◽  
Author(s):  
Chengyi Fu ◽  
Shu Lou ◽  
Guirong Zhu ◽  
Liwen Fan ◽  
Xin Yu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cleft Palate ◽  
Negative Correlation ◽  
Cell Apoptosis ◽  
Cleft Lip ◽  
Target Genes ◽  
Craniofacial Development ◽  
Differentially Expressed ◽  
Differentially Expressed Mirnas

Objective: To identify new microRNA (miRNA)-mRNA networks in non-syndromic cleft lip with or without cleft palate (NSCL/P).Materials and Methods: Overlapping differentially expressed miRNAs (DEMs) were selected from cleft palate patients (GSE47939) and murine embryonic orofacial tissues (GSE20880). Next, the target genes of DEMs were predicted by Targetscan, miRDB, and FUNRICH, and further filtered through differentially expressed genes (DEGs) from NSCL/P patients and controls (GSE42589), MGI, MalaCards, and DECIPHER databases. The results were then confirmed by in vitro experiments. NSCL/P lip tissues were obtained to explore the expression of miRNAs and their target genes.Results: Let-7c-5p and miR-193a-3p were identified as DEMs, and their overexpression inhibited cell proliferation and promoted cell apoptosis. PIGA and TGFB2 were confirmed as targets of let-7c-5p and miR-193a-3p, respectively, and were involved in craniofacial development in mice. Negative correlation between miRNA and mRNA expression was detected in the NSCL/P lip tissues. They were also associated with the occurrence of NSCL/P based on the MGI, MalaCards, and DECIPHER databases.Conclusions: Let-7c-5p-PIGA and miR-193a-3p-TGFB2 networks may be involved in the development of NSCL/P.

scholarly journals Retinoic acid decreases fetal lung mesenchymal cell proliferation in vivo and in vitro

2004 ◽  
Vol 46 (3) ◽  
pp. 275-282 ◽  
Author(s):  
Sussie Dalvin ◽  
Katsumi Komatsuzaki ◽  
Mark A. Anselmo ◽  
David E. Kling ◽  
Jay J. Schnitzer ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Retinoic Acid ◽  
Mesenchymal Cell ◽  
Fetal Lung

scholarly journals Exploiting GRK2 Inhibition as a Therapeutic Option in Experimental Cancer Treatment: Role of p53-Induced Mitochondrial Apoptosis

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3530
Author(s):  
Jessica Gambardella ◽  
Antonella Fiordelisi ◽  
Gaetano Santulli ◽  
Michele Ciccarelli ◽  
Federica Andrea Cerasuolo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Cell ◽  
Nude Mice ◽  
Specific Inhibitor ◽  
Cancer Cell Proliferation ◽  
In Vivo Models ◽  
P53 Expression

The involvement of GRK2 in cancer cell proliferation and its counter-regulation of p53 have been suggested in breast cancer even if the underlying mechanism has not yet been elucidated. Furthermore, the possibility to pharmacologically inhibit GRK2 to delay cancer cell proliferation has never been explored. We investigated this possibility by setting up a study that combined in vitro and in vivo models to underpin the crosstalk between GRK2 and p53. To reach this aim, we took advantage of the different expression of p53 in cell lines of thyroid cancer (BHT 101 expressing p53 and FRO cells, which are p53-null) in which we overexpressed or silenced GRK2. The pharmacological inhibition of GRK2 was achieved using the specific inhibitor KRX-C7. The in vivo study was performed in Balb/c nude mice, where we treated BHT-101 or FRO-derived tumors with KRX-C7. In our in vitro model, FRO cells were unaffected by GRK2 expression levels, whereas BHT-101 cells were sensitive, thus suggesting a role for p53. The regulation of p53 by GRK2 is due to phosphorylative events in Thr-55, which induce the degradation of p53. In BHT-101 cells, the pharmacologic inhibition of GRK2 by KRX-C7 increased p53 levels and activated apoptosis through the mitochondrial release of cytochrome c. These KRX-C7-mediated events were also confirmed in cancer allograft models in nude mice. In conclusion, our data showed that GRK2 counter-regulates p53 expression in cancer cells through a kinase-dependent activity. Our results further corroborate the anti-proliferative role of GRK2 inhibitors in p53-sensitive tumors and propose GRK2 as a therapeutic target in selected cancers.

scholarly journals Dexamethasone Suppresses Palatal Cell Proliferation through miR-130a-3p

2021 ◽  
Vol 22 (22) ◽  
pp. 12453
Author(s):  
Hiroki Yoshioka ◽  
Goo Jun ◽  
Akiko Suzuki ◽  
Junichi Iwata
Keyword(s):  
Cell Proliferation ◽  
Cleft Palate ◽  
Birth Defects ◽  
Cleft Lip ◽  
Neural Crest Cell ◽  
Congenital Birth Defects ◽  
Cranial Neural Crest Cell ◽  
Primary Mouse ◽  
Mirna Sequencing ◽  
Crest Cell

Cleft lip with or without cleft palate (CL/P) is one of the most common congenital birth defects. This study aims to identify novel pathogenic microRNAs associated with cleft palate (CP). Through data analyses of miRNA-sequencing for developing palatal shelves of C57BL/6J mice, we found that miR-449a-3p, miR-449a-5p, miR-449b, miR-449c-3p, and miR-449c-5p were significantly upregulated, and that miR-19a-3p, miR-130a-3p, miR-301a-3p, and miR-486b-5p were significantly downregulated, at embryonic day E14.5 compared to E13.5. Among them, overexpression of the miR-449 family (miR-449a-3p, miR-449a-5p, miR-449b, miR-449c-3p, and miR-449c-5p) and miR-486b-5p resulted in reduced cell proliferation in primary mouse embryonic palatal mesenchymal (MEPM) cells and mouse cranial neural crest cell line O9-1. On the other hand, inhibitors of miR-130a-3p and miR-301a-3p significantly reduced cell proliferation in MEPM and O9-1 cells. Notably, we found that treatment with dexamethasone, a glucocorticoid known to induce CP in mice, suppressed miR-130a-3p expression in both MEPM and O9-1 cells. Moreover, a miR-130a-3p mimic could ameliorate the cell proliferation defect induced by dexamethasone through normalization of Slc24a2 expression. Taken together, our results suggest that miR-130-3p plays a crucial role in dexamethasone-induced CP in mice.

scholarly journals Excessive All-Trans Retinoic Acid Inhibits Cell Proliferation Through Upregulated MicroRNA-4680-3p in Cultured Human Palate Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Hiroki Yoshioka ◽  
Sai Shankar Ramakrishnan ◽  
Junbo Shim ◽  
Akiko Suzuki ◽  
Junichi Iwata
Keyword(s):  
Cell Proliferation ◽  
Retinoic Acid ◽  
Cleft Palate ◽  
Specific Inhibitor ◽  
Dependent Manner ◽  
Altered Expression ◽  
Expression Of Genes ◽  
All Trans Retinoic Acid ◽  
Congenital Birth Defect ◽  
Dose Dependent

Cleft palate is the second most common congenital birth defect, and both environmental and genetic factors are involved in the etiology of the disease. However, it remains largely unknown how environmental factors affect palate development. Our previous studies show that several microRNAs (miRs) suppress the expression of genes involved in cleft palate. Here we show that miR-4680-3p plays a crucial role in cleft palate pathogenesis. We found that all-trans retinoic acid (atRA) specifically induces miR-4680-3p in cultured human embryonic palatal mesenchymal (HEPM) cells. Overexpression of miR-4680-3p inhibited cell proliferation in a dose-dependent manner through the suppression of expression of ERBB2 and JADE1, which are known cleft palate-related genes. Importantly, a miR-4680-3p-specific inhibitor normalized cell proliferation and altered expression of ERBB2 and JADE1 in cells treated with atRA. Taken together, our results suggest that upregulation of miR-4680-3p induced by atRA may cause cleft palate through suppression of ERBB2 and JADE1. Thus, miRs may be potential targets for the prevention and diagnosis of cleft palate.

scholarly journals Accumulation of Retinoid X Receptor-α in Uterine Leiomyomas Is Associated with a Delayed Ligand-Dependent Proteasome-Mediated Degradation and an Alteration of Its Transcriptional Activity

2007 ◽  
Vol 21 (3) ◽  
pp. 602-612 ◽  
Author(s):  
Debora Lattuada ◽  
Paola Viganó ◽  
Silvia Mangioni ◽  
Jenny Sassone ◽  
Stefania Di Francesco ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Target Genes ◽  
Specific Inhibitor ◽  
Retinoid X Receptor ◽  
Uterine Leiomyomas ◽  
Full Length ◽  
Molecular Alteration ◽  
Ubiquitin Proteasome

Abstract An alteration of the retinoid pathway can influence the development of uterine leiomyomas in animal models, and retinoids have shown efficacy in inhibiting the growth of this benign tumor both in vitro and in vivo. However, the underlying mechanisms and biological implications are unclear. The present study was based on the demonstration of an accumulation of full-length retinoid X receptor α (RXRα) in leiomyomas that was not associated with a modification of its gene expression. This accumulation was shown to increase the transcription of the RXR-responsive gene cellular retinoic acid binding protein II (CRABP-II) and to be linked to the cellular redistribution of the receptor and to its retarded degradation via the ubiquitin/proteasome pathway. Accordingly, treatment with a specific proteasome inhibitor but not with protease inhibitors strongly inhibited the degradation of full-length RXRα in cells deriving from both myometrium and leiomyoma, but the formation of RXRα/ubiquitin conjugates was differentially regulated between the two cell types. Moreover, full-length RXRα accumulated in leiomyomas was abnormally phosphorylated at serine/threonine residues relative to myometrial tissue. The ligand to RXRα, 9-cis-retinoic acid, induced the receptor breakdown in smooth muscle cells deriving from both normal and tumor tissue, whereas a MAPK-specific inhibitor was able to reduce RXRα levels only in leiomyoma cells. These results suggest that switching of the ubiquitin/proteasome-dependent degradation of RXRα by phosphorylation in leiomyomas may be responsible for the accumulation of the receptor and the consequent dysregulation of retinoic acid target genes. The ability of retinoids to modify this molecular alteration may be the rationale for their use in the treatment of leiomyomas.

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