The angiogenic role of the alpha 9-nicotinic acetylcholine receptor in triple-negative breast cancers

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE
Sonjid Ochirbat, Tzu-Chun Kan, Chun-Chun Hsu, Tzu-Hsuan Huang, Kuo-Hsiang Chuang, Michael Chen, Chun-Chia Cheng, Chun-Chao Chang, Sri Rahayu, Jungshan Chang
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引用次数: 0

Abstract

Nicotine acts as an angiogenic factor by stimulating endogenous cholinergic pathways. Several subtypes of nicotinic acetylcholine receptors (nAChRs) have been demonstrated to be closely correlated to the formation and progression of different types of cancers. Recently, several studies have found that nicotinic acetylcholine receptors α9 (α9-nAChRs) are highly expressed in breast tumors, especially in tumors derived from patients diagnosed at advanced stages. In vitro studies have demonstrated that activation of α9-nAChRs is associated with increased proliferation and migration of breast cancer. To study the tumor-promoting role of α9-nAChRs in breast cancers, we generated a novel anti-α9-nAChR and methoxy-polyethylene glycol (mPEG) bispecific antibody (α9 BsAb) for dissecting the molecular mechanism on α9-nAChR-mediated tumor progression. Unexpectedly, we discovered the angiogenic role of α9-nAChR in nicotine-induced neovascularization of tumors. It revealed α9 BsAbs reduced nicotine-induced endothelial cell tube formation, blood vessel development in Matrigel plug assay and angiogenesis in microtube array membrane murine model (MTAMs). To unbraid the molecular mechanism of α9-nAChR in nicotine-mediated angiogenesis, the α9 BsAbs were applied and revealed the inhibitory roles in nicotine-induced production of hypoxia-inducible factor-2 alpha (HIF-2α), vascular endothelial growth factor A (VEGF-A), phosphorylated vascular endothelial growth factor receptor 2 (p-VEGFR2), vascular endothelial growth factor receptor 2 (VEGFR2) and matrix metalloproteinase-9 (MMP9) from triple-negative breast cancer cells (MDA-MB-231), suggesting α9-nAChRs played an important role in nicotine-induced angiogenesis. To confirm our results, the shRNA targeting α9-nAChRs was designed and used to silence α9-nAChR expression and then evaluated the angiogenic role of α9-nAChRs. The results showed α9 shRNA also played an inhibitory effect in blocking the nicotine-induced angiogenic signaling. Taken together, α9-nAChR played a critical role in nicotine-induced angiogenesis and this bispecific antibody (α9 BsAb) may serve as a potential therapeutic candidate for treatments of the α9 positive cancers.

Abstract Image

Abstract Image

α-9-烟碱乙酰胆碱受体在三阴性乳腺癌中的血管生成作用。
尼古丁通过刺激内源性胆碱能通路起到血管生成因子的作用。尼古丁乙酰胆碱受体(nAChRs)的几种亚型已被证实与不同类型癌症的形成和发展密切相关。最近,一些研究发现,烟碱乙酰胆碱受体α9(α9-nAChRs)在乳腺肿瘤中高度表达,尤其是在晚期患者的肿瘤中。体外研究表明,α9-nAChRs 的激活与乳腺癌的增殖和迁移增加有关。为了研究α9-nAChRs在乳腺癌中的促瘤作用,我们制备了一种新型抗α9-nAChR和甲氧基聚乙二醇(mPEG)双特异性抗体(α9 BsAb),用于剖析α9-nAChR介导的肿瘤进展的分子机制。我们意外地发现了α9-nAChR在尼古丁诱导的肿瘤新生血管中的血管生成作用。研究发现,α9 BsAbs能减少尼古丁诱导的内皮细胞管形成、Matrigel塞试验中的血管发育以及微管阵列膜小鼠模型(MTAMs)中的血管生成。为了解开α9-nAChR在尼古丁介导的血管生成中的分子机制,应用α9 BsAbs揭示了其在尼古丁诱导的缺氧诱导因子-2α(HIF-2α)、血管内皮生长因子A(VEGF-A)生成中的抑制作用、这表明α9-nAChRs 在烟碱诱导的血管生成中发挥了重要作用。为了证实我们的研究结果,研究人员设计了靶向α9-nAChRs的shRNA,并利用它沉默了α9-nAChRs的表达,然后评估了α9-nAChRs的血管生成作用。结果表明,α9 shRNA 在阻断尼古丁诱导的血管生成信号方面也起到了抑制作用。综上所述,α9-nAChR在尼古丁诱导的血管生成中起着关键作用,这种双特异性抗体(α9 BsAb)可作为治疗α9阳性癌症的潜在候选疗法。
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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
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