Yuan Junhu, Ma Jianhui, Zhang Fanyu, Wang Tan, Jian Xiaxiang, Wang Bingzhi, Li Weiwei, Zhang Xiaoli, Cao Yubin, Yang Hong, Ma Yiming, Wang Hongying
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.
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.
Autophagy. 2025 Apr 17:1-18. doi: 10.1080/15548627.2025.2489335.
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 deficiency ([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 transcription. or overexpression rescued autophagy impairment, reactive oxygen species accumulation, and DNA damage induced by deficiency and . Neutrophil-derived serine proteases suppressed expression, causing autophagy dysfunction. knockout completely blocked the effects of neutrophil proteases on and . The correlation between neutrophil and activities was validated in ulcerative colitis and colorectal carcinoma. Therefore, deficiency in intestinal epithelial cells suppressed 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.: 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.
自噬在结肠炎相关结直肠癌（CAC）中起着关键作用。然而，炎症期间巨自噬/自噬通量的非自主性调节在很大程度上仍未得到探索。在此，我们表明，基于肿瘤数量和负担，[ΔIEC]缺陷加剧了氧化偶氮甲烷-葡聚糖硫酸钠诱导的CAC，促进了以IECs中SQSTM1/p62积累和自噬体-溶酶体融合抑制为特征的自噬功能障碍，并通过抑制FOXA2诱导的V-ATPase转录降低了溶酶体酸化。[具体物质]或过表达挽救了由[具体物质]缺陷和[具体物质]诱导的自噬损伤、活性氧积累和DNA损伤。中性粒细胞衍生的丝氨酸蛋白酶抑制[具体物质]表达，导致自噬功能障碍。[具体物质]敲除完全阻断了中性粒细胞蛋白酶对[具体物质]和[具体物质]的影响。在溃疡性结肠炎和结直肠癌中验证了中性粒细胞与[具体物质]活性之间的相关性。因此，肠上皮细胞中的[具体物质]缺陷抑制了[具体物质]表达，导致V-ATPase介导的自噬功能障碍并加剧了CAC。中性粒细胞可能通过其衍生的蛋白酶使经典的F2RL1/PAR2信号失活，从而导致自噬受损并促进CAC。F2RL1/PAR2信号可能通过自噬参与维持肠道稳态。这些发现为F2RL1/PAR2及其切割丝氨酸蛋白酶在CAC中的作用提供了有用的见解，并将有助于开发针对这种恶性肿瘤的新治疗策略。：AOM：氧化偶氮甲烷；ATP6V0C：ATP酶H+转运V0亚基c；ATP6V0E1：ATP酶H+转运V0亚基e1；ATP6V1C2：ATP酶H+转运V1亚基C2；ATP6V1F：ATP酶H+转运V1亚基F；CAC：结肠炎相关结直肠癌；CRC：结直肠癌；CTSB：组织蛋白酶B；CTSG：组织蛋白酶G；DEGs：差异表达基因；DSS：葡聚糖硫酸钠；FOXA2：叉头框蛋白A2；F2RL1：F2R样胰蛋白酶受体1；IBD：炎症性肠病；IECs：肠上皮细胞；LAMP1：溶酶体相关膜蛋白1；MAP1LC3/LC3：微管相关蛋白1轻链3；ROS：活性氧；SQSTM1/p62：聚集体蛋白1；TFs：转录因子；UC：溃疡性结肠炎
