KLHL21 suppresses gastric tumourigenesis via maintaining STAT3 signalling equilibrium in stomach homoeostasis

作者：Xiaobo Huang, Qiang Huang, Mei-Chen Jiang, Qing Zhong, Hua-Long Zheng, Jia‐Bin Wang, Ze-Ning Huang, Hua‐Gen Wang, Zhiyu Liu, Yifan Li, Kai-Xiang Xu, Mi Lin, Ping Li, Zhihong Huang, Jian‐Wei Xie, Jian-Xian Lin, Jun Lü, Jianwen Que, Chao-Hui Zheng, Qi‐Yue Chen, Chang‐Ming Huang · 发表于：Gut · 年份：2024 · DOI：10.1136/gutjnl-2023-331111 · 被引用次数：17 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Helicobacter pylori-related gastroenterology studies、Genetic factors in colorectal cancer

Objective Precancerous metaplasia transition to dysplasia poses a risk for subsequent intestinal-type gastric adenocarcinoma. However, the molecular basis underlying the transformation from metaplastic to cancerous cells remains poorly understood. Design An integrated analysis of genes associated with metaplasia, dysplasia was conducted, verified and characterised in the gastric tissues of patients by single-cell RNA sequencing and immunostaining. Multiple mouse models, including homozygous conditional knockout Klhl21 -floxed mice, were generated to investigate the role of Klhl21 deletion in stemness, DNA damage and tumour formation. Mass-spectrometry-based proteomics and ribosome sequencing were used to elucidate the underlying molecular mechanisms. Results Kelch-like protein 21 (KLHL21) expression progressively decreased in metaplasia, dysplasia and cancer. Genetic deletion of Klhl21 enhances the rapid proliferation of Mist1 + cells and their descendant cells. Klhl21 loss during metaplasia facilitates the recruitment of damaged cells into the cell cycle via STAT3 signalling. Increased STAT3 activity was confirmed in cancer cells lacking KLHL21, boosting self-renewal and tumourigenicity. Mechanistically, the loss of KLHL21 promotes PIK3CB mRNA translation by stabilising the PABPC1-eIF4G complex, subsequently causing STAT3 activation. Pharmacological STAT3 inhibition by TTI-101 elicited anticancer effects, effectively impeding the transition from metaplasia to dysplasia. In p...