Abstract
Acute pancreatitis (AP) is an inflammatory, complicated pancreatic disease, carrying significant morbidity and mortality. However, the molecular and cellular mechanisms involved in AP pathogenesis remain to be elucidated. Here, we explore the role of FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR) in AP progression. Caerulein with or without LPS- induced or taurolithocholic acid 3-sulfate (TLC-S)-induced AP mouse models and cell models were performed for the validation of FENDRR expression in vivo and in vitro, respectively. Histopathological examinations of pancreatic tissues were performed to evaluate the severity of AP. Transmission electron microscopy was utilized to visualize the autophagic vacuoles. siRNA specifically targeting FENDRR was further applied. Flow cytometry was employed to assess cell apoptosis. ELISA, immunoflureoscence, and western blotting analysis were also performed to determine the levels of inflammatory cytokines and autophagy activity. RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays were carried out to reveal the epigenetic regulation of FENDRR on ATG7. Additionally, silencing FENDRR was also verified in AP mouse models. Higher FENDRR and impaired autophagy were displayed in both AP mouse models and cell models. FENDRR knockdown dramatically attenuated caerulein- or TLC-S-induced AR42J cells apoptosis and autophagy suppression. Further mechanistic experiments implied that the action of FENDRR is moderately attributable to its repression of ATG7 via direct interaction with the epigenetic repressor PRC2. Moreover, the silencing of FENDRR significantly induced the promotion of ATG7, thus alleviating the development of AP in vivo. Our study highlights FENDRR as a novel target that may contribute to AP progression, suggesting a therapeutic target for AP treatment.
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This work was supported by Natural Science Foundation of Hunan Province (grant no: 2019JJ40472).
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Guarantor of integrity of the entire study: Shang-Ping Zhao
Study concepts: Shang-Ping Zhao
Study design: Shang-Ping Zhao and Xue-Fei Xiao
Definition of intellectual content: Ming-Shi Yang
Literature research: Zuo-Liang Liu
Experimental studies: Can Yu
Data acquisition: Can Yu
Data analysis: Shang-Ping Zhao and Can Yu
Statistical analysis: Zuo-Liang Liu
Manuscript preparation: Zuo-Liang Liu
Manuscript editing: Can Yu
Manuscript review: Bing-Chang Yang and Xue-Fei Xiao
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Zhao, SP., Yu, C., Yang, MS. et al. Long Non-coding RNA FENDRR Modulates Autophagy Through Epigenetic Suppression of ATG7 via Binding PRC2 in Acute Pancreatitis. Inflammation 44, 999–1013 (2021). https://doi.org/10.1007/s10753-020-01395-7
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DOI: https://doi.org/10.1007/s10753-020-01395-7