Dataset Information

MiR-18a Contributes to Preeclampsia by Downregulating Smad2 (Full Length) and Reducing TGF-? Signaling.

ABSTRACT: The study investigated the regulation of Smad2 by miR-18a and its role in preeclampsia (PE). Bioinformatics analysis showed that both Smad2 and Smad3 were the predicted targets for miR-18a. Mass spectrum analysis showed that two mature Smad2 isoforms existed in human placenta: full length, Smad2(FL), and that lacking exon3, Smad2(?exon3). The protein level of Smad2(FL), but not Smad2(?exon3) or Smad3, was significantly increased in severe PE (sPE) placenta, which was inversely correlated with the level of miR-18a. Elevated Smad2(FL) phosphorylation level appeared in sPE placenta, and Smad2 was colocalized with miR-18a in various subtypes of trophoblasts in human placenta. Smad2(FL) was validated as the direct target of miR-18a in HTR8/SVneo cells. miR-18a enhanced trophoblast cell invasion, which was blocked by the overexpression of Smad2(FL). Furthermore, overexpression of miR-18a repressed Smad2 activation and the inhibition of trophoblast cell invasion by transforming growth factor-? (TGF-?). In conclusion, our results suggest that miR-18a inhibits the expression of Smad2(FL), but not Smad2(?exon3) or Smad3, which can reduce TGF-? signaling, leading to the enhancement of trophoblast cell invasion. A lack of miR-18a, which results in the upregulation of Smad2(FL), contributes to the development of PE.

SUBMITTER: Xu P

PROVIDER: S-EPMC7566009 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

miR-18a Contributes to Preeclampsia by Downregulating Smad2 (Full Length) and Reducing TGF-β Signaling.

Xu Peng P Li Zhilang Z Wang Yongqing Y Yu Xin X Shao Xuan X Li Yu-Xia YX Peng Chun C Zhao Yangyu Y Wang Yan-Ling YL

Molecular therapy. Nucleic acids 20200923

The study investigated the regulation of Smad2 by miR-18a and its role in preeclampsia (PE). Bioinformatics analysis showed that both Smad2 and Smad3 were the predicted targets for miR-18a. Mass spectrum analysis showed that two mature Smad2 isoforms existed in human placenta: full length, Smad2(FL), and that lacking exon3, Smad2(Δexon3). The protein level of Smad2(FL), but not Smad2(Δexon3) or Smad3, was significantly increased in severe PE (sPE) placenta, which was inversely correlated with th ...[more]

PMID: 33230456

Similar Datasets

Project description:Transforming growth factors beta (TGF-?) are multi-functional cytokines capable of inducing apoptosis in epithelial cells, including glomerular podocytes. We and others have previously shown that podocyte-selective genetic deletion of the microRNA (miR)-processing enzyme, Dicer, caused glomerulosclerosis that was associated with podocyte apoptosis, and the miR-30 family was implicated in the process. Here, we report that apoptosis-associated genes were highly enriched among the predicted targets of miR-30 when compared with randomly selected miRs (26% vs. 4.5 ± 2.1%) or with the known TGF-?-regulated miR-192 (6%), miR-216a (5.1%), and miR-217 (0%). miR-30 family members were abundantly expressed in podocytes in normal mice but were downregulated in albumin/TGF-? transgenic mice with podocyte apoptosis and glomerulosclerosis. In vitro, TGF-? downregulated miR-30s in wildtype and Smad3-deficient, but not Smad2- or Smad2/Smad3-deficient, podocytes. The TGF-?-induced activation of caspase 3 and an increase in TUNEL-positive nuclei were significantly inhibited by the lentivirus-mediated overexpression of miR-30d, but not by a scrambled control miR, in podocytes. TGF-? stimulated the phosphorylation of pro-apoptotic p53 in podocytes with lentiviral expression of a scrambled miR, but not in podocytes expressing miR-30d. In contrast, miR-30d had no effect on the phosphorylation of pro-apoptotic p38 MAP kinase induced by TGF-?. Thus, we report that Smad2-dependent inhibition of miR-30s in podocytes is required for the activation of p53 and the induction of apoptosis by TGF-?. These results demonstrate a novel functional role for miR-30 in podocyte survival and indicate that the loss of miR-30 survival signaling is a novel and specific mechanism of TGF-?-induced podocyte apoptosis during glomerulosclerosis. We propose the therapeutic replacement of miR-30 as a novel strategy to prevent the podocyte apoptosis that is characteristic of progressive glomerular diseases.

Project description:BackgroundSorafenib can prolong the survival of patients with advanced hepatocellular carcinoma (HCC). However, drug resistance remains the main obstacle to improving its efficiency. This study aimed to explore the likely molecular mechanism of sorafenib resistance.MethodsDifferentially expressed microRNAs (miRNAs) related to sorafenib response were analyzed with the Limma package in R software. The expression levels of miR-126-3p and sprouty-related EVH1 domain-containing protein 1 (SPRED1) in HCC cells were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell viability and proliferation were detected with Cell Counting Kit-8 (CCK-8), EdU proliferation, and clone formation assays. Transwell assays were performed to measure cell migration and invasion. TargetScan, MicroRNA Target Prediction Database (miRDB), and StarBase v2.0 were used to predict the targets of miR-126-3p. SPRED1 was confirmed as a target gene of miR-126-3p by dual-luciferase reporter assay and Western blotting. Finally, the in vivo anti-tumor effect of LV-miR-126-3p inhibitor combined with sorafenib was evaluated via subcutaneous tumor models.ResultsHCC cells with high expression of miR-126-3p exhibited increased resistance to sorafenib. The results of bioinformatics analysis and the dual-luciferase reporter assay showed that miR-126-3p directly targeted SPRED1. The sensitivity of HCC cells to sorafenib was markedly enhanced by SPRED1 upregulation. Gain- and loss-of function experiments verified that miR-126-3p induced sorafenib resistance in HCC through downregulating SPRED1. Furthermore, the inhibition of miR-126-3p markedly increased the effectiveness of sorafenib against HCC in vivo. Mechanistically, our results suggested that miR-126-3p promoted sorafenib resistance via targeting SPRED1 and activating the ERK signaling pathway.ConclusionsOur study demonstrates that regulating the miR-126-3p/SPRED1 axis might be a promising strategy for enhancing the antitumor effect of sorafenib in the treatment of HCC.

Dataset Information

MiR-18a Contributes to Preeclampsia by Downregulating Smad2 (Full Length) and Reducing TGF-? Signaling.

Publications

miR-18a Contributes to Preeclampsia by Downregulating Smad2 (Full Length) and Reducing TGF-β Signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets