eLife
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2025
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IF 0
Chong Zhang,Zuoyan Zhang,Yueyi Wu,Yuchen Wu,Jing Cheng,Kaizhi Luo,Zhidi Li,Manman Zhang,Jian Wang,Xuesen Zhang,Yangling Li
Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, and the prognosis is poor due to distant metastasis. Thus, there is an urgent need to discover novel therapeutic targets and strategies to overcome metastasis. A series of in vitro and in vivo phenotype experiments were performed to investigate the role of phosphodiesterase 1A (PDE1A) in NSCLC. The RNA binding protein immunoprecipitation (RIP) assay, messenger RNA (mRNA) stability assay, and LC-MS/MS were performed to investigate the molecular mechanisms of PDE1A in NSCLC progression. PDE1A has been shown to promote metastasis and epithelial-mesenchymal transition (EMT) progression of NSCLC. In addition, NSCLC cells overexpressing PDE1A promoted angiogenesis by regulating exosome release. IL-6/JAK/STAT3 signaling pathway was highly enriched in PDE1A-coexpressed genes, and PDE1A promoted NSCLC metastasis by activating the STAT3 pathway. GO enrichment analysis of PDE1A-interacting genes showed that PDE1A might interact with YTHDF2 and participate in m6A-containing RNA binding. The binding between PDE1A and YTHDF2 was verified, and PDE1A regulated the STAT3 pathway by interacting with YTHDF2. The mechanism of the YTHDF2/PDE1A complex in regulating the STAT3 pathway was predicted by overlapping YTHDF2-interacting RNAs and genes coexpressed with YTHDF2 and STAT3. The interactions between YTHDF2 and target mRNAs were predicted, and there were three predicted targets of YTHDF2 with high scores: NRF2, SOCS2, and MET. Indeed, PDE1A interacted with YTHDF2, destabilized SOCS2, and activated the STAT3 pathway. Mechanistic data uncover a novel PDE1A/YTHDF2/STAT3 axis driving NSCLC metastasis and suggest potential therapeutic strategies for metastatic disease.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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生物化学
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信号转导
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RNA生物学
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肿瘤学
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产品关联
DOI
PubMed
JOURNAL OF HAZARDOUS MATERIALS
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2023
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IF 13.6
Weiwei Wang,Xin Li,Qiuhui Qian,Jin Yan,Haishan Huang,Xuedong Wang,Huili Wang
Because triclosan (TCS) has been confirmed to cause severe neurotoxicity, it is urgent to disclose the underlying toxicity mechanisms at varying levels. TCS exposure resulted in a series of malformations in larval zebrafish, including reduced neurons, blood-vessel ablation and abnormal neurobehavior. Apoptosis staining and the upregulated expression of proapoptotic genes demonstrated that TCS induced neuronal apoptosis and neurotransmitter disorders. By integrating RT-qPCR analysis with the effects of pathway inhibitors and agonists, we found that TCS triggered abnormal regulation of neuron development-related functional genes, and suppressed the BDNF/TrkB signaling pathway. TCS inhibited total m 6 A-RNA modification level by activating the demethylase ALKBH5, and induced neurodevelopmental toxicity based on the knockdown experiments of alkbh5 and molecular docking . The main novelties of this study lies in: (1) based on specific staining and transgenic lines, the differential neurotoxicity effects of TCS were unravelled at individual, physiological, biochemical and molecular levels in vivo ; (2) from a epigenetics viewpoint, the decreasing m 6 A methylation level was confirmed to be mediated by alkbh5 upregulation; and (3) both homology modeling and molecular docking evidenced the targeting action of TCS on ALKBH5 enzyme. These findings open a novel avene for TCS’s risk assessment and early intervention of the contaminant-sourcing diseases.
研究领域:
毒理学
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神经科学
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分子生物学
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表观遗传学
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发育生物学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
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2020
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IF 6.793
Tian-Xin Zhao,Jun-Ke Wang,Lian-Ju Shen,Chun-Lan Long,Bin Liu,Yi Wei,Lin-Dong Han,Yue-Xin Wei,Sheng-De Wu,Guang-Hui Wei
Di-(2-ethylhexyl) phthalate (DEHP) is a common environmental endocrine disrupting chemical that may induce male reproductive disorders. Exposure to DEHP at a prepubertal stage could lead to prepubertal testicular injury, but the underlying mechanisms remain unclear. In this study, we exposed Sprague-Dawley rats to 0, 250, and 500 mg DEHP per kg body weight per day at the prepuberty stage from postnatal day 22 (PND 22) to PND 35 by oral gavage. Testicular injury and oxidative stress were evaluated, and the levels of 6-methyladenosine (m6A) modification and expression of modulator genes for RNA methylation were measured in testes . Furthermore, m6A modification of the important antioxidant transcription factor Nrf2 was analyzed using methylated RNA immunoprecipitation qPCR. Our results show that DEHP worsened testicular histology, decreased testosterone concentrations, downregulated expression of spermatogenesis inducers, enhanced oxidative stress, inhibited the Nrf2-mediated antioxidant pathway, and increased apoptosis in testes. Additionally, DEHP increased global levels of m6A RNA modification and altered the expression of two important RNA methylation modulator genes, FTO and YTHDC2 . Moreover, m6A modification of Nrf2 mRNA increased upon DEHP exposure. Overall, these findings link oxidative stress imbalance with epigenetic effects of DEHP toxicity and provide insight into the testicular toxicity of DEHP from the new perspective of m6A modification.
研究领域:
毒理学
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生殖生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）