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The RBP2–BECN1–VEGF Axis Orchestrates a Self-Amplifying Circuit to Drive Malignant Progression in Gastric Cancer

ABSTRACT: Gastric cancer remains one of the leading causes of cancer-related mortality worldwide, with its progression governed by aberrant epigenetic modification and dysregulated signaling networks. Retinoblastoma-binding protein 2 (RBP2, also termed KDM5A/JARID1A), a histone H3K4me2/3 demethylase, is frequently overexpressed in multiple human malignancies. However, the molecular mechanism by which RBP2 regulates autophagy and angiogenesis signaling networks in gastric cancer remains poorly elucidated. The present study aimed to explore the functional role and underlying mechanism of RBP2 in facilitating gastric cancer progression via constructing an autophagy-angiogenesis positive feedback loop.A series of clinical specimen analyses, cellular functional experiments, and xenograft tumor models were performed in this study. The results demonstrated that RBP2 was significantly upregulated in gastric cancer tissues and positively correlated with the expression of the core autophagy gene BECN1. Mechanistically, RBP2 directly bound to the promoter region of BECN1 and transcriptionally activated its expression, thereby triggering protective autophagy in gastric cancer cells. RBP2-induced autophagy further promoted the secretion of vascular endothelial growth factor (VEGF), a pivotal pro-angiogenic factor in tumors. Notably, secreted VEGF exerted a positive feedback regulatory effect on RBP2 expression. Further mechanistic investigation revealed that VEGF inhibited JNK phosphorylation, subsequently downregulating the p53/miR-212 signaling axis. Suppression of miR-212 expression abrogated its post-transcriptional inhibitory effect on RBP2, leading to a significant increase in RBP2 expression.Collectively, this study firstly identifies a novel positive feedback loop termed RBP2-BECN1-autophagy-VEGF-JNK/p53/miR-212-RBP2 in gastric cancer. This self-amplifying signaling cascade integrates epigenetic regulation, cellular autophagy, and pro-angiogenic signaling, continuously driving gastric cancer cell proliferation, invasion, and tumor growth. These findings provide novel mechanistic insights into gastric cancer pathogenesis and offer promising combinatorial therapeutic targets for clinical gastric cancer treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE334190 | GEO | 2026/09/09

REPOSITORIES: GEO

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Project description:A major contributor to cancer mortality is recurrence and subsequent metastatic transformation following therapeutic intervention. In order to develop new treatment modalities or improve the efficacy of current ones it is important to understand the molecular mechanisms that promote therapy-resistance to cancer cells. One pathway that has been demonstrated to therapy resistance is autophagy, a self-digestive process that can eliminate unnecessary or damaged organelles to protect cancer cells from necrosis. Effective targeting of this pathway could lead to the development of new therapies. In our studies, we found that the VEGF-C/NRP-2 axis is involved in the activation of autophagy, which is essential for the survival of cancer cells following chemotherapy treatment. Furthermore, we identified two VEGF-C/NRP-2-regulated genes, LAMP-2 and WDFY-1 that have previously been suggested to participate in autophagy and vesicular trafficking. The upregulation of WDFY-1 upon depleted level of VEGF-C contributed to cytotoxic drug-mediated cell death. Altogether, these data suggest a link between VEGF-C/neuropilin-2 axis and cancer cell survival despite the presence of chemotherapy-induced stress. Human prostate cancer cell lines PC3, Du145 and pancreatic cancer cell line CaPan1 were cultured at 37οC either in RPMI 1640 with L-glutamine or in DMEM media with 10% fetal bovine serum and supplemented with penicillin/streptomycin. PC3 stable transfected cell line was growing in presence of 1µg/ml puromycin selection pressure. Cells were transfected with SmartPool cocktail siRNA for NRP-2, VEGF-C, LAMP-2, and WDFY-1, using DharmaFECT 1-4. siRNA transfection was allowed to proceed 72 h before collection of whole-cell extract or total RNA.To identify potential pathways involved in this VEGF-C-mediated cell survival, we performed a microarray study comparing cells depleted in either VEGF-C or NRP-2 using SmartPool siRNA to PC-3 cells treated with scrambled siRNA. Upon comparison of the two data sets, we found 34 gene-tags that were commonly up- or down-regulated in both NRP-2- and VEGF-C-depleted cells.

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The RBP2–BECN1–VEGF Axis Orchestrates a Self-Amplifying Circuit to Drive Malignant Progression in Gastric Cancer

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