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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.

Tumor cells have developed multiple mechanisms to escape immune recognition mediated by T cells. Indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme inducing immune tolerance, is involved in tumor escape from host immune systems. Feiji Recipe, a Chinese herbal recipe that composed of 12 traditional Chinese medicines, has been used to recover immuno-surveillance and to interven immune escape in lung cancer patients. To elucidate the biological role of IDO in the tumorigenesis of lung cancer, and the intervention of Feiji Recipe on tumor immune escape, we established a mouse lung cancer cell line (2LL-EGFP-IDO) with overexpression of IDO. IDO expression did not affect cell proliferation. 2LL-EGFP-IDO cells were effective in reducing the level of tryptophan and increasing the level of its downstream metabolites, kynurenines, in culture medium as assessed by HPLC. Feiji Recipe could up-regulate the percentage of CD8+ T cells by inhibits the expression of IDO in co-culture system. The results of these studies indicate that Feiji Recipe can enhance the immune response and reverses tumor immune escape by induce the activity of CD8+ T cells, which might be related to the inhibition of IDO expression.