Neurokinin-1 activation affects EGFR related signal transduction in triple negative breast cancer
Neurokinin-1 activation affects EGFR related signal transduction in triple negative breast cancer
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Neurokinin-1 激活影响三阴性乳腺癌中 EGFR 相关信号转导
DOI：
10.1016/j.cellsig.2015.03.015
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发表时间：
2015
影响因子：
4.8
通讯作者：
Liu Xiu-Ping
中科院分区：
文献类型：
--
作者：
Wang Ji-Gang;Yang Wen-Lin;Ding Di;Zhang Lei;Liu Xiu-Ping;Yu Juan;Hu Ji-Lin;Ren Hong;Liu Xiu-Ping
乳腺癌过度表达神经激肽-1 （NK-1）。本研究的目的是探讨NK-1和EGFR在三阴性乳腺癌（tnbc）中的关系。免疫组化检测NK-1和EGFR在tnbc中的表达。[Sar9, \Met(O2)11]用P （SMSP）物质激活MDA-MB-231和MDA-MB-468两种TNBC细胞株中的NK-1。用L-733060和抗NK-1的siRNA抑制NK-1。采用CCK-8增殖试验检测NK-1的体外调节作用。采用western blot和实时定量PCR分析NK-1激活和抑制对EGFR及其下行通路的影响。我们发现EGFR阳性病例的比例随着NK-1水平的升高而增加。SMSP能促进TNBC细胞增殖，L-733060和siRNA能抑制细胞增殖，诱导细胞凋亡。此外，SMSP还能增强磷酸化(p)-EGFR和EGFR的表达，激活p- akt和p- erk。NK1-siRNA可降低p-EGFR、p-Akt和p-Erk。在西妥昔单抗（0.2 mg/mL）存在的情况下，SMSP仍能刺激细胞增殖，激活p-EGFR。然而，在厄洛替尼（10 μM）存在下，SMSP不能刺激细胞增殖，也不能激活p-EGFR。我们的研究表明NK-1和EGFR在tnbc中存在相互作用。这些结果提示NK-1可能通过磷酸化EGFR调控TNBC增殖，而NK-1的活化可能影响EGFR单克隆抗体的疗效。
Breast cancers bear overexpression of neurokinin-1 (NK-1). The aim of this study was to investigate the relationship between NK-1 and EGFR in triple negative breast cancers (TNBCs). Immunohistochemistry was performed to investigate NK-1 and EGFR expressions in TNBCs. [Sar9, \Met(O2)11] substance P (SMSP) was used to activate NK-1 in two TNBC cell lines, MDA-MB-231 and MDA-MB-468. L-733060 and siRNA against NK-1 were used to inhibit NK-1. Thein vitroregulatory effect of NK-1 was determined using CCK-8 proliferation assay. The effects of NK-1 activation and inhibition on EGFR and its downstreaming pathway were analyzed using western blot and real-time quantitative PCR. We found that the proportion of EGFR positive cases was increased with the increasement of NK-1 levels. SMSP could promote the proliferation of TNBC cells, while L-733060 and siRNA could inhibit cell proliferation and induce apoptosis. Moreover, SMSP could enhance expressions of phosphorylation (p)-EGFR and EGFR, and activate p-Akt and p-Erk. NK1-siRNA could decrease p-EGFR, p-Akt and p-Erk. In the presence of cetuximab (0.2 mg/mL), SMSP still could stimulate cell proliferation, and activate p-EGFR. However, in the presence of erlotinib (10 μM), SMSP could not stimulate cell proliferation and could not activate p-EGFR. Our study showed the interaction between NK-1 and EGFR in TNBCs. These results suggested that NK-1 may regulate TNBC proliferation through EGFR phosphorylation, and the curative effect of EGFR monoclonal antibodies may be affected by NK-1 activation.