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<p>Gastric adenocarcinoma (GA), a major contributor to cancer-related mortality worldwide, is characterized by malignant progression driven by complex gene regulatory networks. However, the biological functions and N6-methyladenosine (m<sup>6</sup>A)-dependent regulatory mechanisms of RNA-binding motif protein 15 (RBM15), immunoglobulin-like domain-containing receptor 1 (ILDR1), and insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) in GA remain unclear. This study investigated their expression patterns, correlations, and regulatory mechanisms. Bioinformatics analyses were performed using TIMER, GEPIA, and TNMplot databases to predict the key regulatory axis in GA. RBM15-overexpression and ILDR1/IGF2BP3 knockdown models were established in two GA cell lines (AGS and SNU638) <i>via</i> transfection. Quantitative reverse transcription polymerase chain reaction and western blotting were used to assess gene and protein expression levels. Methylated RNA immunoprecipitation, RNA immunoprecipitation, and dual-luciferase reporter assay were performed to evaluate m<sup>6</sup>A modification and RNA-protein interactions. Messenger RNA stability was assessed using actinomycin D treatment, while Cell Counting Kit-8 and Transwell assays were employed to evaluate cell proliferation, migration, and invasion. In vivo xenograft experiments were conducted to investigate the effects of the RBM15/ILDR1 axis on tumor growth. RBM15 was significantly upregulated in GA tissues and positively correlated with ILDR1 expression. ILDR1 silencing markedly suppressed the cell proliferation, migration, and invasive capacity of GA. Mechanistically, RBM15 overexpression increased the m<sup>6</sup>A methylation level of ILDR1 mRNA. Furthermore, this methylation relied on the interaction between the m<sup>6</sup>A reader protein IGF2BP3 and ILDR1 mRNA. Notably, RBM15 overexpression effectively reversed the suppressive effects of ILDR1 depletion on malignant cellular phenotypes. Overall, RBM15 induced ILDR1 m<sup>6</sup>A methylation to enhance its stability in an IGF2BP3-dependent manner, thereby promoting GA progression. These findings provide novel mechanistic insights into GA pathogenesis and establish theoretical foundations for developing potential diagnostic biomarkers and targeted therapeutic strategies.</p>

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RBM15 enhances ILDR1 n6-methyladenosine methylation to accelerate gastric adenocarcinoma progression via an IGF2BP3-dependent manner

  • 期刊论文

  • 发表日期：

    2026年7月2日

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  • Wei Hu,
  • Xin Zhou,
  • Bin Jiang,
  • Jun Liu,
  • Zi-Wei Li,
  • Ming Song,
  • Xin Zheng

摘要

Gastric adenocarcinoma (GA), a major contributor to cancer-related mortality worldwide, is characterized by malignant progression driven by complex gene regulatory networks. However, the biological functions and N6-methyladenosine (m6A)-dependent regulatory mechanisms of RNA-binding motif protein 15 (RBM15), immunoglobulin-like domain-containing receptor 1 (ILDR1), and insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) in GA remain unclear. This study investigated their expression patterns, correlations, and regulatory mechanisms. Bioinformatics analyses were performed using TIMER, GEPIA, and TNMplot databases to predict the key regulatory axis in GA. RBM15-overexpression and ILDR1/IGF2BP3 knockdown models were established in two GA cell lines (AGS and SNU638) via transfection. Quantitative reverse transcription polymerase chain reaction and western blotting were used to assess gene and protein expression levels. Methylated RNA immunoprecipitation, RNA immunoprecipitation, and dual-luciferase reporter assay were performed to evaluate m6A modification and RNA-protein interactions. Messenger RNA stability was assessed using actinomycin D treatment, while Cell Counting Kit-8 and Transwell assays were employed to evaluate cell proliferation, migration, and invasion. In vivo xenograft experiments were conducted to investigate the effects of the RBM15/ILDR1 axis on tumor growth. RBM15 was significantly upregulated in GA tissues and positively correlated with ILDR1 expression. ILDR1 silencing markedly suppressed the cell proliferation, migration, and invasive capacity of GA. Mechanistically, RBM15 overexpression increased the m6A methylation level of ILDR1 mRNA. Furthermore, this methylation relied on the interaction between the m6A reader protein IGF2BP3 and ILDR1 mRNA. Notably, RBM15 overexpression effectively reversed the suppressive effects of ILDR1 depletion on malignant cellular phenotypes. Overall, RBM15 induced ILDR1 m6A methylation to enhance its stability in an IGF2BP3-dependent manner, thereby promoting GA progression. These findings provide novel mechanistic insights into GA pathogenesis and establish theoretical foundations for developing potential diagnostic biomarkers and targeted therapeutic strategies.