Gemmill Robert M, Nasarre Patrick, Nair-Menon Joyce, Cappuzzo Federico, Landi Lorenza, D'Incecco Armida, Uramoto Hidetaka, Yoshida Takeshi, Haura Eric B, Armeson Kent, Drabkin Harry A
Division of Hematology/Oncology, Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
Azienda Unità Sanitaria Locale della Romagna, Ravenna 48100, Italy.
Sci Signal. 2017 Jan 17;10(462):eaag0528. doi: 10.1126/scisignal.aag0528.
Neuropilins (NRP1 and NRP2) are co-receptors for heparin-binding growth factors and class 3 semaphorins. Different isoforms of NRP1 and NRP2 are produced by alternative splicing. We found that in non-small cell lung cancer (NSCLC) cell lines, transforming growth factor-β (TGFβ) signaling preferentially increased the abundance of NRP2b. NRP2b and NRP2a differ only in their carboxyl-terminal regions. Although the presence of NRP2b inhibited cultured cell proliferation and primary tumor growth, NRP2b enhanced cellular migration, invasion into Matrigel, and tumorsphere formation in cultured cells in response to TGFβ signaling and promoted metastasis in xenograft mouse models. These effects of overexpressed NRP2b contrast with the effects of overexpressed NRP2a. Hepatocyte growth factor (HGF)-induced phosphorylation of the kinase AKT was specifically promoted by NRP2b, whereas inhibiting the HGF receptor MET attenuated NRP2b-dependent cell migration. Unlike NRP2a, NRP2b did not bind the PDZ domain scaffolding protein GAIP carboxyl terminus-interacting protein (GIPC1) and only weakly recruited phosphatase and tensin homolog (PTEN), potentially explaining the difference between NRP2b-mediated and NRP2a-mediated effects. Analysis of NSCLC patient tumors showed that NRP2b abundance correlated with that of the immune cell checkpoint receptor ligand PD-L1 as well as with epithelial-to-mesenchymal transition (EMT) phenotypes in the tumors, acquired resistance to epidermal growth factor receptor (EGFR) inhibitors, disease progression, and poor survival in patients. NRP2b knockdown attenuated the acquisition of resistance to the EGFR inhibitor gefitinib in cultured NSCLC cells. Thus, in NSCLC, NRP2b contributed to the oncogenic response to TGFβ and correlated with tumor progression in patients.
神经纤毛蛋白（NRP1和NRP2）是肝素结合生长因子和3类信号素的共受体。NRP1和NRP2的不同异构体通过可变剪接产生。我们发现，在非小细胞肺癌（NSCLC）细胞系中，转化生长因子-β（TGFβ）信号传导优先增加NRP2b的丰度。NRP2b和NRP2a仅在其羧基末端区域有所不同。尽管NRP2b的存在抑制了培养细胞的增殖和原发性肿瘤的生长，但NRP2b增强了细胞迁移、向基质胶中的侵袭以及培养细胞中肿瘤球的形成，以响应TGFβ信号传导，并促进了异种移植小鼠模型中的转移。过表达的NRP2b的这些作用与过表达的NRP2a的作用形成对比。肝细胞生长因子（HGF）诱导的激酶AKT磷酸化由NRP2b特异性促进，而抑制HGF受体MET减弱了NRP2b依赖性细胞迁移。与NRP2a不同，NRP2b不结合PDZ结构域支架蛋白GAIP羧基末端相互作用蛋白（GIPC1），并且仅微弱地募集磷酸酶和张力蛋白同源物（PTEN），这可能解释了NRP2b介导的和NRP2a介导的作用之间的差异。对NSCLC患者肿瘤的分析表明，NRP2b丰度与免疫细胞检查点受体配体PD-L1的丰度以及肿瘤中的上皮-间质转化（EMT）表型、对表皮生长因子受体（EGFR）抑制剂的获得性耐药、疾病进展和患者的不良生存相关。NRP2b敲低减弱了培养的NSCLC细胞对EGFR抑制剂吉非替尼的耐药性获得。因此，在NSCLC中，NRP2b促成了对TGFβ的致癌反应，并与患者的肿瘤进展相关。
