Journal Article

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

Huang, Ze-Ning, Huang, Qiang, Wang, Hua-Gen, Zheng, Chao-Hui, Li, Ping, Lin, Mi, Que, Jian-Wen, Xu, Kai-Xiang, Huang, Zhi-Hong, Chen, Qi-Yue, Huang, Chang-Ming, Li, Yi-Fan, Wang, Jia-Bin, Zhong, Qing, Lin, Jian-Xian, Lu, Jun, Xie, Jian-Wei, Huang, Xiao-Bo, Jiang, Mei-Chen, Zheng, Hua-Long, Liu, Zhi-Yu

2024

Overview

ObjectivePrecancerous 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.DesignAn 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.ResultsKelch-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.ConclusionsOur 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.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD
• Subject: Adenocarcinoma / Adenocarcinoma - genetics / Adenocarcinoma - metabolism / Adenocarcinoma - pathology / Animal models / Animals / Carcinogenesis - genetics / Carcinogenesis - metabolism / Cell culture / Cell cycle / Cell proliferation / Cell self-renewal / CELL SIGNALLING / Cell Transformation, Neoplastic - genetics / Cell Transformation, Neoplastic - metabolism / CHEMOTHERAPY / Clonal deletion / DNA DAMAGE / DNA sequencing / Drug dosages / Dysplasia / GASTRIC CANCER / Gastric Mucosa - metabolism / Gastric Mucosa - pathology / Gene deletion / Genetic transformation / Homeostasis / Humans / Initiation factor eIF-4G / Laboratory animals / Medical prognosis / Metaplasia / Metaplasia - metabolism / Mice / Mice, Knockout / Molecular modelling / mRNA / Polypeptides / Precancerous Conditions - genetics / Precancerous Conditions - metabolism / Precancerous Conditions - pathology / Proteins / Proteomics / Signal Transduction / Stat3 protein / STAT3 Transcription Factor - metabolism / STEM CELLS / Stomach / Stomach - pathology / Stomach Neoplasms - genetics / Stomach Neoplasms - metabolism / Stomach Neoplasms - pathology / Tumorigenesis