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作者

Weichun Zhu Zehao Chen Yunqian Gao Chungang Zhai Xia Li Ning Wang Kang Fu Wentao Chen Jieqiong Peng Dan Xu Lei Qiao Wenqiang Chen

作者单位

Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province ⁶https://orcid.org/0000-0002-6374-386X ¹State Key Laboratory for Innovation and Transformation of Luobing Theory ⁴Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China ³Department of gastroenterology, Shandong Second Provincial General Hospital, Jinan, Shandong ⁷https://orcid.org/0000-0002-0350-1383 Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China, 250012 ⁵Department of General Practice, Qilu Hospital of Shandong University, Jinan, China ²https://orcid.org/0009-0001-8847-5558

刊名

Molecules and Cells

年份

2025

页码

100298

ISSN

1016-8478

关键词

Colorectal cancer Tumor-associated macrophages Chaperone-mediated autophagy Angiogenesis HIF-1α

摘要

Chaperone-mediated autophagy is a highly selective form of autophagy re-sponsible for the degradation of specific cytosolic proteins within lysosomes. Recent research has established a significant correlation between CMA and colorectal cancer . However, the majority of current research focuses on tumor parenchymal cells, with limited attention paid to the expression and role of CMA in tumor stromal cells, particularly in tumor-associated macro-phages . In this study, we generated myeloid-specif...更多

Chaperone-mediated autophagy is a highly selective form of autophagy re-sponsible for the degradation of specific cytosolic proteins within lysosomes. Recent research has established a significant correlation between CMA and colorectal cancer . However, the majority of current research focuses on tumor parenchymal cells, with limited attention paid to the expression and role of CMA in tumor stromal cells, particularly in tumor-associated macro-phages . In this study, we generated myeloid-specific LAMP2A-knockout and knock-in mice to investigate the role of macrophage CMA in dextran sodium sulfate -induced colitis and azoxymethane /DSS-induced CRC. Our findings indicated that the expression of LAMP2A, the rate-limiting component of CMA, was reduced in TAMs of both human and mouse CRC tissues. The knockout of LAMP2A in macrophages exacerbated experimentally induced colitis and colitis-related CRC, whereas its overexpression in macrophages alleviated the progression of colitis and CRC in mice. Notably, we observed increased angiogenesis within the tumor mass of CRC tissues from LAMP2A-mØKO mice. Mechanistically, LAMP2A deficiency elevated the protein levels of HIF-1α, thereby enhancing the secretion of its target genes, vascular endothelial growth factor A and IL-1β, which are two important proangiogenic cytokines. Our study suggests that the activation of CMA in macrophages may represent a promising therapeutic strategy for the treatment of CRC.收起

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