張榮善Ochirbat Sonjid2026-05-062026-05-062024-12-24https://203.71.86.71/handle/123456789/9175學位別：博士 口試委員：黃錦前; 陳玉華; 楊沂淵; 林峰輝; 楊瀅臻; 張榮善 關鍵字：nicotine、nicotinic acetylcholine receptors α9、bispecific antibody、angiogenesis、microtube array membrane murine modelNicotine has been increasingly identified as a factor that promotes angiogenesis through the activation of endogenous cholinergic pathways. Various subtypes of nicotinic acetylcholine receptors (nAChRs) have been closely linked to the initiation and progression of multiple cancers. Recent research has shown that α9-nAChRs are significantly overexpressed in breast tumors, especially in patients diagnosed at advanced stages. In vitro studies have demonstrated that the activation of α9-nAChRs promotes greater proliferation and migration in breast cancer cells. To study the tumor-promoting role of α9-nAChRs in breast cancer, we designed a novel bispecific antibody (α9 BsAb) that targets both α9-nAChRs and methoxy-polyethylene glycol (mPEG), allowing us to examine the molecular mechanisms driving α9-nAChR-mediated tumor progression. Unexpectedly, we discovered a critical angiogenic function of α9-nAChR in promoting nicotine-induced neovascularization within tumor environments. Our results showed that α9 BsAbs significantly inhibited nicotine-induced endothelial cell tube formation, reduced blood vessel development in the Matrigel plug assay, and attenuated angiogenesis in a murine microtube array membrane (MTAM) model. Further investigations revealed that α9 BsAbs effectively suppressed the nicotine-induced upregulation of HIF-2α, VEGF-A, p-VEGFR2, VEGFR2, and MMP9 in MDA-MB-231 cells, suggesting a substantial role of α9-nAChRs in driving nicotine-related angiogenic pathways. To validate our findings, we used shRNA to silence α9-nAChR expression, which similarly resulted in the suppression of nicotine-induced angiogenic signaling. In conclusion, α9-nAChR plays a critical role in nicotine-induced angiogenesis, and α9 BsAb may serve as a potential therapeutic candidate.系所名稱：國際醫學研究博士學位學程thesis