Intestinal epithelial cell autophagy deficiency suppresses inflammation-associated colon tumorigenesis

Hao Liu; Jun Lou; Yunlong Liu; Zhen Liu; Jiansheng Xie; Jiachun Sun; Hongming Pan; Weidong Han

doi:10.1016/j.omtn.2022.02.012

Intestinal epithelial cell autophagy deficiency suppresses inflammation-associated colon tumorigenesis

Mol Ther Nucleic Acids. 2022 Feb 20:28:35-46. doi: 10.1016/j.omtn.2022.02.012. eCollection 2022 Jun 14.

Authors

Hao Liu^{1

2}, Jun Lou¹, Yunlong Liu¹, Zhen Liu¹, Jiansheng Xie^{1

2}, Jiachun Sun³, Hongming Pan¹, Weidong Han¹

Affiliations

¹ Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qingchun Road, Hangzhou, Zhejiang, China.
² Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
³ The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, China.

Abstract

Colitis-associated cancer (CAC) is closely related to chronic inflammation, whose underlying molecular mechanism, however, has not been elaborated comprehensively. In the current study, an investigation was conducted on the role of autophagy in the initiation and progression of azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colon tumors, a mouse model for CAC in humans. Mice with the intestinal epithelial cell (IEC)-specific deletion of the autophagy-related gene 7 (Atg7) saw a significant decrease in tumor number, burden, and risk of high-grade dysplasia. The autophagy deficiency of IECs resulted in the accumulation of T cells, especially CD8⁺ T lymphocytes in colon lamina propria. Furthermore, it was found that autophagy protects against DSS-induced intestinal injury through maintaining epithelial barrier function and promoting the survival and proliferation of IECs. Mechanistically, autophagy in IECs enhanced the activation of epithelial STAT3/ERK to promote the survival and proliferation of colonic epithelial cells during the development of CAC. Therefore, the findings unveil the essential role of autophagy in activating the processes of colonic protection, regeneration, and tumorigenesis.

Keywords: STAT3/ERK; autophagy; colitis-associated colorectal cancer; inflammation; intestinal epithelial cells.