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Epigenetic inactivation of miR-203 as a key step in neural crest epithelial-to-mesenchymal transition.

ABSTRACT: miR-203 is a tumor-suppressor microRNA with known functions in cancer metastasis. Here, we explore its normal developmental role in the context of neural crest development. During the epithelial-to-mesenchymal transition of neural crest cells to emigrate from the neural tube, miR-203 displays a reciprocal expression pattern with key regulators of neural crest delamination, Phf12 and Snail2, and interacts with their 3'UTRs. We show that ectopic maintenance of miR-203 inhibits neural crest migration in chick, whereas its functional inhibition using a 'sponge' vector or morpholinos promotes premature neural crest delamination. Bisulfite sequencing further shows that epigenetic repression of miR-203 is mediated by the de novo DNA methyltransferase DNMT3B, the recruitment of which to regulatory regions on the miR-203 locus is directed by SNAIL2 in a negative-feedback loop. These findings reveal an important role for miR-203 in an epigenetic-microRNA regulatory network that influences the timing of neural crest delamination.

SUBMITTER: Sanchez-Vasquez E

PROVIDER: S-EPMC6467475 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Epigenetic inactivation of miR-203 as a key step in neural crest epithelial-to-mesenchymal transition.

Sánchez-Vásquez Estefanía E Bronner Marianne E ME Strobl-Mazzulla Pablo H PH

Development (Cambridge, England) 20190411 7

miR-203 is a tumor-suppressor microRNA with known functions in cancer metastasis. Here, we explore its normal developmental role in the context of neural crest development. During the epithelial-to-mesenchymal transition of neural crest cells to emigrate from the neural tube, miR-203 displays a reciprocal expression pattern with key regulators of neural crest delamination, <i>Phf12</i> and <i>Snail2</i>, and interacts with their 3'UTRs. We show that ectopic maintenance of miR-203 inhibits neural ...[more]

PMID: 30910825

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Project description:The aim of the present study was to investigate whether miR‑203 can inhibit transforming growth factor‑β (TGF‑β)‑induced epithelial‑mesenchymal transition (EMT), and the migration and invasion ability of non‑small cell lung cancer (NSCLC) cells by targeting SMAD3. In the present study, the expression levels of miR‑203, SMAD3 mRNA and protein in NSCLC tissues were examined, as well as their corresponding paracancerous samples. The miR‑203 mimics and miR‑203 inhibitor were transfected into the H226 cell line. RT‑qPCR was used to assess the expression levels of E‑cadherin, Snail, N‑cadherin and vimentin mRNA, and western blotting was performed to detect the expression levels of p‑SMAD2, SMAD2, p‑SMAD3, SMAD3 and SMAD4. The cell migration and invasion abilities were detected by Transwell assays. The target site of SMAD3 was predicted by the combined action between miR‑203 and dual luciferase. The results revealed that the RNA levels of miR‑203, compared with paracancerous tissues, were decreased in NSCLC tissues, while SMAD3 mRNA and protein levels were upregulated, and miR‑203 inhibited SMAD3 expression. Induction of TGF‑β led to decreased E‑cadherin mRNA levels, upregulation of Snail, N‑cadherin and vimentin mRNA levels (P<0.05), and significant increase in cell migration and invasion, whereas transfection of miR‑203 mimics reversed the aforementioned results (P<0.05). Conversely, miR‑203 inhibitor could further aggravate the aforementioned results (P<0.05). Western blot results revealed that transfection of miR‑203 mimics significantly reduced the protein expression of SMAD3 and p‑SMAD3 (P<0.05). Furthermore, the results of the Dual‑Luciferase assay revealed that miR‑203 inhibited SMAD3 expression by interacting with specific regions of its 3'‑UTR. Overall, a novel mechanism is revealed, in which, miR‑203 can inhibit SMAD3 by interacting with specific regions of the 3'‑UTR of SMAD3, thereby restraining TGF‑β‑induced EMT progression and migration and invasion of NSCLC cells.

Dataset Information

Epigenetic inactivation of miR-203 as a key step in neural crest epithelial-to-mesenchymal transition.

Publications

Epigenetic inactivation of miR-203 as a key step in neural crest epithelial-to-mesenchymal transition.

Similar Datasets

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