Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
Gut. 2024 Oct 7;73(11):1785-1798. doi: 10.1136/gutjnl-2023-331111.
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 -floxed mice, were generated to investigate the role of 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 enhances the rapid proliferation of cells and their descendant cells. 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 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.
癌前化生向异型增生的转变会增加随后发生肠型胃腺癌的风险。然而，化生细胞向癌变细胞转化的分子基础仍知之甚少。
通过单细胞 RNA 测序和免疫染色，对与化生、异型增生相关的基因进行了综合分析，并在患者的胃组织中进行了验证和特征分析。生成了多种小鼠模型，包括纯合条件性敲除 -floxed 小鼠，以研究缺失对干细胞特性、DNA 损伤和肿瘤形成的作用。基于质谱的蛋白质组学和核糖体测序用于阐明潜在的分子机制。
Kelch-like 蛋白 21（KLHL21）在化生、异型增生和癌症中的表达逐渐降低。KLHL21 的遗传缺失增强了 细胞及其后代细胞的快速增殖。化生过程中 KLHL21 的缺失通过 STAT3 信号促进受损细胞进入细胞周期。在缺乏 KLHL21 的癌细胞中证实了 STAT3 活性增加，从而增强了自我更新和致瘤性。在机制上，KLHL21 的缺失通过稳定 PABPC1-eIF4G 复合物促进 KLHL21 缺失的 mRNA 翻译，随后导致 STAT3 激活。通过 TTI-101 抑制 STAT3 可发挥抗癌作用，有效阻止化生向异型增生的转变。在胃癌患者中，KLHL21 水平低的患者生存率更短，对辅助化疗的反应更差。
我们的研究结果表明，KLHL21 的缺失通过 PABPC1 介导的 PIK3CB 翻译激活触发 STAT3 重新激活，靶向 STAT3 可以逆转 KLHL21 缺陷胃中的癌前化生。
