1. Academic Validation
  2. Neutrophil-derived serine proteases induce FOXA2-mediated autophagy dysfunction and exacerbate colitis-associated carcinogenesis via protease activated receptor 2

Neutrophil-derived serine proteases induce FOXA2-mediated autophagy dysfunction and exacerbate colitis-associated carcinogenesis via protease activated receptor 2

  • Autophagy. 2025 Apr 17:1-18. doi: 10.1080/15548627.2025.2489335.
Junhu Yuan 1 Jianhui Ma 1 Fanyu Zhang 1 Tan Wang 2 Xiaxiang Jian 3 Bingzhi Wang 4 Weiwei Li 5 Xiaoli Zhang 6 Yubin Cao 7 Hong Yang 7 Yiming Ma 1 Hongying Wang 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 2 State Key Lab of Molecular Oncology, Laboratory of Cell and Molecular Biology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 3 Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
  • 4 Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 5 Zhejiang Key Laboratory of Radiation Oncology, Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
  • 6 Department of Injury and Repair, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
  • 7 Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Abstract

Autophagy plays a critical role in colitis-associated colorectal Cancer (CAC). However, non-autonomous regulation of macroautophagic/autophagic flux during inflammation remains largely unexplored. Here, we show that F2rl1/PAR2 deficiency (F2rl1[ΔIEC]) aggravated azoxymethane-dextran sulfate sodium-induced CAC based on tumor number and burden, promoted Autophagy dysfunction characterized by SQSTM1/p62 accumulation and autophagosome-lysosome fusion inhibition in IECs, and reduced lysosomal acidification by suppressing FOXA2-induced V-ATPase ATP6V0E1 transcription. FOXA2 or ATP6V0E1 overexpression rescued Autophagy impairment, Reactive Oxygen Species accumulation, and DNA damage induced by F2RL1 deficiency in vitro and in vivo. Neutrophil-derived serine proteases suppressed FOXA2 expression, causing Autophagy dysfunction. F2RL1 knockout completely blocked the effects of neutrophil proteases on FOXA2 and ATP6V0E1. The correlation between neutrophil and FOXA2-ATP6V0E1 activities was validated in ulcerative colitis and colorectal carcinoma. Therefore, F2RL1 deficiency in intestinal epithelial cells suppressed FOXA2 expression, leading to V-ATPase-mediated autophagic dysfunction and exacerbating CAC. Neutrophils may contribute to impaired Autophagy and promote CAC by inactivating canonical F2RL1/PAR2 signaling via its derived proteases. F2RL1/PAR2 signaling may participate in maintaining intestinal homeostasis via Autophagy. These findings provide useful insights into F2RL1/PAR2 and its cleaving serine proteases in CAC and would help in developing new therapeutic strategies for this malignancy.Abbreviations: AOM: azoxymethane; ATP6V0C: ATPase H+ transporting V0 subunit c; ATP6V0E1: ATPase H+ transporting V0 subunit e1; ATP6V1C2: ATPase H+ transporting V1 subunit C2; ATP6V1F: ATPase H+ transporting V1 subunit F; CAC: colitis-associated colorectal cancer; CRC: colorectal cancer; CTSB: Cathepsin B; CTSG: Cathepsin G; DEGs: differentially expressed genes; DSS: dextran sulfate sodium; FOXA2: forkhead box protein A2; F2RL1: F2R like trypsin receptor 1; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TFs: transcription factors; UC: ulcerative colitis.

Keywords

Autophagy; F2RL1/PAR2; forkhead box protein A2; gut homeostasis; innate immunity; intestinal epithelium.

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