Molecular medicine (Cambridge, Mass.) · 2026
A TRIM15-CDX2 loop drives bile acid-induced gastric intestinal metaplasia.
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Wang Dan, Chen Jian, Xu Wei, Shrestha Sachin Mulmi, Lu Qin, Ren Lihua, Ji Qinghua, Wu Hailu, Shi Ruihua
Аннотация
BACKGROUND: Gastric intestinal metaplasia (GIM), a precancerous lesion and risk factor for gastric cancer, is closely associated with chronic bile acid (BA) exposure; however, its molecular mechanisms remain unclear. This study aimed to identify key regulators involved in BA-associated GIM and to elucidate their functional roles.
METHODS: TRIM15 and GIM markers (CDX2, MUC2, KLF4, and VIL1) were assessed in human GIM and paired normal tissues by RNA-seq, RT‒qPCR, Western blotting (WB), and immunofluorescence (IF). BA profiles were analyzed using UHPLC‒MS/MS. In vitro, GES-1 cells were treated with CDCA and subjected to TRIM15 gain- and loss-of-function assays. CDX2-mediated transcriptional regulation of TRIM15 was evaluated by dual-luciferase reporter and ChIP assays. NF-κB signaling and related proteins were assessed by WB and IF. The interaction between TRIM15 and IκBα and the levels of ubiquitination were investigated by coimmunoprecipitation, LC-MS/MS and protein-protein docking analysis. Functional assays were used to assess proliferation and apoptosis. In vivo validation was performed using an AAV9-mediated TRIM15 knockdown rat model.
RESULTS: TRIM15 expression was consistently upregulated in GIM and increased stepwise with disease severity, accompanied by a positive association with CDX2 expression. BA profiling revealed the selective enrichment of cholic acid (CA) and chenodeoxycholic acid (CDCA), which induced GIM-associated phenotypes in vitro. Mechanistically, CDX2 directly bound to the TRIM15 promoter to increase its transcription, whereas TRIM15 promoted CDX2 expression via the NF-κB pathway, resulting in the formation of a regulatory loop. Further mechanistic analyses revealed that TRIM15 promoted K48-linked ubiquitination and subsequent proteasomal degradation of IκBα, thereby enhancing p65 phosphorylation. Notably, this effect was abolished by expression of the degradation-resistant IκBα S32A/S36A mutant. In vivo, TRIM15 knockdown attenuated gastric mucosal injury and intestinal metaplasia and reduced NF-κB signaling and CDX2 expression.
CONCLUSION: These findings suggest the involvement of a TRIM15-NF-κB-CDX2 regulatory loop in BA-associated GIM. TRIM15 may contribute to epithelial reprogramming under BA exposure and could be a potential biomarker and therapeutic target for GIM progression.
METHODS: TRIM15 and GIM markers (CDX2, MUC2, KLF4, and VIL1) were assessed in human GIM and paired normal tissues by RNA-seq, RT‒qPCR, Western blotting (WB), and immunofluorescence (IF). BA profiles were analyzed using UHPLC‒MS/MS. In vitro, GES-1 cells were treated with CDCA and subjected to TRIM15 gain- and loss-of-function assays. CDX2-mediated transcriptional regulation of TRIM15 was evaluated by dual-luciferase reporter and ChIP assays. NF-κB signaling and related proteins were assessed by WB and IF. The interaction between TRIM15 and IκBα and the levels of ubiquitination were investigated by coimmunoprecipitation, LC-MS/MS and protein-protein docking analysis. Functional assays were used to assess proliferation and apoptosis. In vivo validation was performed using an AAV9-mediated TRIM15 knockdown rat model.
RESULTS: TRIM15 expression was consistently upregulated in GIM and increased stepwise with disease severity, accompanied by a positive association with CDX2 expression. BA profiling revealed the selective enrichment of cholic acid (CA) and chenodeoxycholic acid (CDCA), which induced GIM-associated phenotypes in vitro. Mechanistically, CDX2 directly bound to the TRIM15 promoter to increase its transcription, whereas TRIM15 promoted CDX2 expression via the NF-κB pathway, resulting in the formation of a regulatory loop. Further mechanistic analyses revealed that TRIM15 promoted K48-linked ubiquitination and subsequent proteasomal degradation of IκBα, thereby enhancing p65 phosphorylation. Notably, this effect was abolished by expression of the degradation-resistant IκBα S32A/S36A mutant. In vivo, TRIM15 knockdown attenuated gastric mucosal injury and intestinal metaplasia and reduced NF-κB signaling and CDX2 expression.
CONCLUSION: These findings suggest the involvement of a TRIM15-NF-κB-CDX2 regulatory loop in BA-associated GIM. TRIM15 may contribute to epithelial reprogramming under BA exposure and could be a potential biomarker and therapeutic target for GIM progression.