2. Academic Validation
  3. A microRNA checkpoint for Ca2+ signaling and overload in acute pancreatitis

A microRNA checkpoint for Ca2+ signaling and overload in acute pancreatitis

  • Mol Ther. 2022 Apr 6;30(4):1754-1774. doi: 10.1016/j.ymthe.2022.01.033.
Wenya Du 1,  Geng Liu 1,  Na Shi 2,  Dongmei Tang 1,  Pawel E Ferdek 3,  Monika A Jakubowska 4,  Shiyu Liu 5,  Xinyue Zhu 1,  Jiayu Zhang 1,  Linbo Yao 5,  Xiongbo Sang 1,  Sailan Zou 1,  Tingting Liu 5,  Rajarshi Mukherjee 6,  David N Criddle 7,  Xiaofeng Zheng 8,  Qing Xia 5,  Per-Olof Berggren 9,  Wendong Huang 10,  Robert Sutton 11,  Yan Tian 12,  Wei Huang 13,  Xianghui Fu 14
Affiliations

Affiliations

  • 1 Division of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 Sichuan, China.
  • 2 Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China; Institutes for Systems Genetics & Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.
  • 3 Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
  • 4 Malopolska Centre of Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
  • 5 Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.
  • 6 Liverpool Pancreatitis Research Group, Liverpool University Hospitals NHS Foundation Trust and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK.
  • 7 Department of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK.
  • 8 Center for Diabetes and Metabolism Research, Division of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.
  • 9 Center for Diabetes and Metabolism Research, Division of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China; The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, 17176 Stockholm, Sweden.
  • 10 Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
  • 11 Liverpool Pancreatitis Research Group, Liverpool University Hospitals NHS Foundation Trust and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK. Electronic address: r.sutton@liverpool.ac.uk.
  • 12 Division of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 Sichuan, China. Electronic address: tyfxh@163.com.
  • 13 Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China; Institutes for Systems Genetics & Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China; West China Biobanks, Department of Clinical Research Management, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China. Electronic address: dr_wei_huang@scu.edu.cn.
  • 14 Division of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 Sichuan, China. Electronic address: xfu@scu.edu.cn.
PMID: 35077860 DOI: 10.1016/j.ymthe.2022.01.033
Abstract

Acute pancreatitis (AP) is a common digestive disease without specific treatment, and its pathogenesis features multiple deleterious amplification loops dependent on translation, triggered by cytosolic CA2+ ([CA2+]i) overload; however, the underlying mechanisms in CA2+ overload of AP remains incompletely understood. Here we show that microRNA-26a (miR-26a) inhibits pancreatic acinar cell (PAC) store-operated CA2+ entry (SOCE) channel expression, CA2+ overload, and AP. We find that major SOCE channels are post-transcriptionally induced in PACs during AP, whereas miR-26a expression is reduced in experimental and human AP and correlated with AP severity. Mechanistically, miR-26a simultaneously targets Trpc3 and Trpc6 SOCE channels and attenuates physiological oscillations and pathological elevations of [CA2+]i in PACs. MiR-26a deficiency increases SOCE channel expression and [CA2+]i overload, and significantly exacerbates AP. Conversely, global or PAC-specific overexpression of miR-26a in mice ameliorates pancreatic edema, neutrophil infiltration, acinar necrosis, and systemic inflammation, accompanied with remarkable improvements on pathological determinants related with [CA2+]i overload. Moreover, pancreatic or systemic administration of an miR-26a mimic to mice significantly alleviates experimental AP. These findings reveal a previously unknown mechanism underlying AP pathogenesis, establish a critical role for miR-26a in CA2+ signaling in the exocrine pancreas, and identify a potential target for the treatment of AP.

Keywords

autophagy; endoplasmic reticulum stress; inflammation; mouse models; noncoding RNA; pancreatic acinar cell; store-operated calcium entry channels; targeted therapy; transient receptor potential canonical channels.

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