Pub Date : 2024-04-05DOI: 10.1007/s10565-024-09858-5
Ye-Ji Lee, Minsuk Kim, Hee-Sun Kim, Jihee Lee Kang
The epithelial-mesenchymal transition (EMT) and fibroblast activation are major events in idiopathic pulmonary fibrosis pathogenesis. Here, we investigated whether growth arrest-specific protein 6 (Gas6) plays a protective role in lung fibrosis via suppression of the EMT and fibroblast activation. rGas6 administration inhibited the EMT in isolated mouse ATII cells 14 days post-BLM treatment based on morphologic cellular alterations, changes in mRNA and protein expression profiles of EMT markers, and induction of EMT-activating transcription factors. BLM-induced increases in gene expression of fibroblast activation-related markers and the invasive capacity of primary lung fibroblasts in primary lung fibroblasts were reversed by rGas6 administration. Furthermore, the hydroxyproline content and collagen accumulation in interstitial areas with damaged alveolar structures in lung tissue were reduced by rGas6 administration. Targeting Gas6/Axl signaling events with specific inhibitors of Axl (BGB324), COX-2 (NS-398), EP1/EP2 receptor (AH-6809), or PGD2 DP2 receptor (BAY-u3405) reversed the inhibitory effects of rGas6 on EMT and fibroblast activation. Finally, we confirmed the antifibrotic effects of Gas6 using Gas6−/− mice. Therefore, Gas6/Axl signaling events play a potential role in inhibition of EMT process and fibroblast activation via COX-2-derived PGE2 and PGD2 production, ultimately preventing the development of pulmonary fibrosis.
{"title":"Administration of Gas6 attenuates lung fibrosis via inhibition of the epithelial-mesenchymal transition and fibroblast activation","authors":"Ye-Ji Lee, Minsuk Kim, Hee-Sun Kim, Jihee Lee Kang","doi":"10.1007/s10565-024-09858-5","DOIUrl":"https://doi.org/10.1007/s10565-024-09858-5","url":null,"abstract":"<p>The epithelial-mesenchymal transition (EMT) and fibroblast activation are major events in idiopathic pulmonary fibrosis pathogenesis. Here, we investigated whether growth arrest-specific protein 6 (Gas6) plays a protective role in lung fibrosis via suppression of the EMT and fibroblast activation. rGas6 administration inhibited the EMT in isolated mouse ATII cells 14 days post-BLM treatment based on morphologic cellular alterations, changes in mRNA and protein expression profiles of EMT markers, and induction of EMT-activating transcription factors. BLM-induced increases in gene expression of fibroblast activation-related markers and the invasive capacity of primary lung fibroblasts in primary lung fibroblasts were reversed by rGas6 administration. Furthermore, the hydroxyproline content and collagen accumulation in interstitial areas with damaged alveolar structures in lung tissue were reduced by rGas6 administration. Targeting Gas6/Axl signaling events with specific inhibitors of Axl (BGB324), COX-2 (NS-398), EP1/EP2 receptor (AH-6809), or PGD2 DP2 receptor (BAY-u3405) reversed the inhibitory effects of rGas6 on EMT and fibroblast activation. Finally, we confirmed the antifibrotic effects of Gas6 using Gas6<sup>−/−</sup> mice. Therefore, Gas6/Axl signaling events play a potential role in inhibition of EMT process and fibroblast activation via COX-2-derived PGE<sub>2</sub> and PGD<sub>2</sub> production, ultimately preventing the development of pulmonary fibrosis.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140559989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-04DOI: 10.1007/s10565-024-09859-4
Danhong Dong, Jiangpeng Wei, Weidong Wang, Haikun Zhou, Liu Hong, Gang Ji, Xisheng Yang
RNA-binding proteins (RBPs) make vital impacts on tumor progression and are important potential targets for tumor treatment. Previous studies have shown that RBP regulator of differentiation 1 (ROD1), enriched in the nucleus, is abnormally expressed and functions as a splicing factor in tumors; however, the mechanism underlying its involvement in gastric cancer (GC) is unknown. In this study, ROD1 is found to stimulate GC cell proliferation and metastasis and is related to poor patient prognosis. In vitro experiments showed that ROD1 influences GC proliferation and metastasis through modulating the imbalance of the level of the oncogenic gene OIP5 and the tumor suppressor gene GPD1L. Further studies showed that the N6-methyladenosine (m6A) “reader” protein YTHDC1 can interact with ROD1 and regulate the balance of the expression of the downstream molecules OIP5/GPD1L by promoting the nuclear enrichment of ROD1. Therefore, YTHDC1 stimulates GC development and progression through modulating nuclear enrichment of the splicing factor ROD1.