癌前化生转变为不典型增生会带来随后发生肠型胃腺癌的风险。然而，化生细胞向癌细胞转化的分子基础仍然知之甚少。通过单细胞RNA测序和免疫染色，对患者胃组织中与化生、不典型增生相关的基因进行了综合分析、验证和表征。建立了多种小鼠模型，包括纯合条件敲除 Klhl21-floxed 小鼠，以研究 Klhl21 缺失在干性、DNA 损伤和肿瘤形成中的作用。基于质谱的蛋白质组学和核糖体测序被用来阐明潜在的分子机制。Kelch 样蛋白 21 (KLHL21) 的表达在化生、不典型增生和癌症中逐渐降低。 Klhl21 的基因缺失增强了 Mist1 细胞及其后代细胞的快速增殖。化生过程中 Klhl21 的丢失有助于通过 STAT3 信号传导将受损细胞招募到细胞周期中。在缺乏 KLHL21 的癌细胞中证实了 STAT3 活性增加，从而促进自我更新和致瘤性。从机制上讲，KLHL21 的缺失通过稳定 PABPC1-eIF4G 复合物来促进 PIK3CB mRNA 翻译，随后引起 STAT3 激活。 TTI-101 药理学 STAT3 抑制可引发抗癌作用，有效阻止化生向异型增生的转变。在胃癌患者中，低水平的 KLHL21 生存率较短，对辅助化疗的反应较差。我们的研究结果强调，KLHL21 缺失会通过 PABPC1 介导的 PIK3CB 翻译激活触发 STAT3 重新激活，而靶向 STAT3 可以逆转 KLHL21 的癌前化生。胃部缺陷。© 作者（或其雇主）2024。禁止商业重复使用。请参阅权利和权限。由英国医学杂志出版。

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.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.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 patients with gastric cancer, low levels of KLHL21 had a shorter survival rate and a worse response to adjuvant chemotherapy.Our findings highlighted that KLHL21 loss triggers STAT3 reactivation through PABPC1-mediated PIK3CB translational activation, and targeting STAT3 can reverse preneoplastic metaplasia in KLHL21-deficient stomachs.© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.