Pancreas · 2026
The Transcription Factor TFAP2A Induces M2 Macrophage Polarization by Upregulating EPS8L3 Expression, Thereby Accelerating the Malignant Progression of Pancreatic Ductal Adenocarcinoma.
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Maimaiti Yilihamu, Abuduwaili Zaiyinuer, Yan Dong, Dong Xiaogang, Tong Qing, Yang Huan, Kong Panpan, Abula Yimamumaimaitijiang
Аннотация
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), the main pancreatic cancer type, was highly aggressive and lethal. Studies showed that the epidermal growth factor receptor pathway substrate 8-Like protein 3 (EPS8L3) was significantly upregulated in PDAC. This study aimed to explore how EPS8L3 promoted PDAC progression.
METHODS: First, bioinformatics analysis, qRT-PCR, and western blot (WB) techniques were utilized to ascertain the expression profile of EPS8L3 in clinical samples and cells of PDAC. Subsequently, EdU proliferation assays, cell apoptosis detection, glycolysis assay kits, in vivo xenograft tumor experiments, and immunohistochemical (IHC) staining were conducted to explore the impact of EPS8L3 silencing on PDAC cell proliferation, apoptosis, glycolytic pathway, and tumor growth in vivo. Meanwhile, flow cytometry was employed to analyze the expression of CD163, a marker of macrophage M2 polarization. Furthermore, with the aid of JASPAR and GEPIA websites, combined with chromatin immunoprecipitation (Ch-IP) experiments and dual luciferase reporter gene experiments, the interaction between transcription factor AP-2α (TFAP2A) and EPS8L3 was further confirmed. Finally, a rescue experiment was performed with EPS8L3 overexpression in TFAP2A-knockdown cells to validate the potential impact of EPS8L3 on TFAP2A function.
RESULTS: EPS8L3 was highly expressed in PDAC tumors and PDAC cells, and its silencing effectively inhibited the proliferation of PDAC cells and promoted their apoptosis. Furthermore, the glycolytic pathway in PDAC cells, tumor growth in vivo, and M2 polarization of macrophages were also blocked by EPS8L3 knockdown. TFAP2A interacted with EPS8L3 and positively regulated its expression. Overexpression of EPS8L3 restored the effects of TFAP2A knockdown on PDAC cell progression.
CONCLUSIONS: TFAP2A positively regulated EPS8L3 to facilitate M2 polarization of macrophages and the malignant progression of PDAC cells.
METHODS: First, bioinformatics analysis, qRT-PCR, and western blot (WB) techniques were utilized to ascertain the expression profile of EPS8L3 in clinical samples and cells of PDAC. Subsequently, EdU proliferation assays, cell apoptosis detection, glycolysis assay kits, in vivo xenograft tumor experiments, and immunohistochemical (IHC) staining were conducted to explore the impact of EPS8L3 silencing on PDAC cell proliferation, apoptosis, glycolytic pathway, and tumor growth in vivo. Meanwhile, flow cytometry was employed to analyze the expression of CD163, a marker of macrophage M2 polarization. Furthermore, with the aid of JASPAR and GEPIA websites, combined with chromatin immunoprecipitation (Ch-IP) experiments and dual luciferase reporter gene experiments, the interaction between transcription factor AP-2α (TFAP2A) and EPS8L3 was further confirmed. Finally, a rescue experiment was performed with EPS8L3 overexpression in TFAP2A-knockdown cells to validate the potential impact of EPS8L3 on TFAP2A function.
RESULTS: EPS8L3 was highly expressed in PDAC tumors and PDAC cells, and its silencing effectively inhibited the proliferation of PDAC cells and promoted their apoptosis. Furthermore, the glycolytic pathway in PDAC cells, tumor growth in vivo, and M2 polarization of macrophages were also blocked by EPS8L3 knockdown. TFAP2A interacted with EPS8L3 and positively regulated its expression. Overexpression of EPS8L3 restored the effects of TFAP2A knockdown on PDAC cell progression.
CONCLUSIONS: TFAP2A positively regulated EPS8L3 to facilitate M2 polarization of macrophages and the malignant progression of PDAC cells.