MAO B抑制与贝伐珠单抗协同作用在结直肠癌模型中的转录组学见解

Background : Monoamine oxidase B (MAO B) plays a critical role in colorectal cancer (CRC) by influencing oxidative stress, angiogenesis, and therapy resistance. Building on preclinical evidence of MAO B inhibition in CRC, this study aimed to characterize transcriptomic alterations following treatment with MAO B inhibitors-Deprenyl, Rasagiline, and Safinamide alone and in combination with the anti-angiogenic agent Bevacizumab (Bev), to elucidate potential mechanisms underlying their antitumor synergy. Methods : RNA sequencing was performed on HT29 CRC xenograft model tumor samples treated with MAO B inhibitors as single agents and in combination with Bev. Differential gene expression (DEG) analysis (|log2FC| > 2; adjusted p < 0.05) identified distinct gene signatures across treatment groups. DEGs were clustered using Gene Ontology (GO), and enrichment was assessed using Fisher's exact test. Canonical pathway analysis was performed to characterize major signaling changes. To assess clinical relevance, DEGs were evaluated for correlation with MAO B expression in TCGA CRC datasets. Results: Distinct and overlapping transcriptional signatures were observed across treatment groups. Tumor-suppressive genes: VSIG1, GLIPR1, GUCY2C, SMPD3, CDX1, CDX2 , and GJA1 were strongly upregulated with MAO B inhibitor treatment, indicating enhanced apoptotic and anti-angiogenic signaling. Oncogenic drivers: MAGEA12, SOX5, OXCT1, VCAM1 , and TNC were significantly downregulated, in combination therapy groups, suggesting suppression of epithelial mesenchymal transition and metastatic potential. Long non-coding RNA (lnc) TPTEP1 and anti-inflammatory mediator LYPD8 were upregulated in Rasagiline-treated tumors, while oncogenic lncRNA XIST was downregulated in Safinamide-treated samples. When compared with TCGA CRC datasets, these treatment-responsive genes showed significant correlation with MAO B expression. Upregulated genes: GUCY2C, CDX1, BTNL3, and SMPD3 showed negative correlation with MAO B, whereas downregulated genes including SOX5, OCT1, VCAM1 , and TNC exhibited a positive correlation, further supporting the clinical relevance of MAO B associated gene expression patterns. GO analysis showed enrichment of oxidation reduction and neural signaling pathways in the Deprenyl group, whereas Bev combinations were associated with inhibited Wnt signaling and activation of the CDX pathway which is associated with the upregulation of CDX1/2 gene that plays a crucial role in the development and maintenance of the intestinal epithelium. Conclusion: MAO B inhibition modulates key oncogenic, apoptotic, and angiogenic pathways in CRC tumors. Combination treatment with Bev amplifies tumor-suppressive gene expression and attenuates pro-angiogenic signaling, highlighting the therapeutic potential of MAO B inhibitors as complementary agents in CRC treatment strategies.