Neurokinin-1 receptor promotes non-small cell lung cancer progression through transactivation of EGFR.
Neurokinin-1 receptor promotes non-small cell lung cancer progression through transactivation of EGFR.
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Neurokinin-1 受体通过 EGFR 反式激活促进非小细胞肺癌进展。
DOI：
10.1038/s41419-021-04485-y
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发表时间：
2022-01-10
影响因子：
9
通讯作者：
Mou LY
中科院分区：
文献类型：
--
作者：
Zhang XW;Li L;Hu WQ;Hu MN;Tao Y;Hu H;Miao XK;Yang WL;Zhu Q;Mou LY
尽管靶向治疗取得了巨大进展，但肺癌仍然是全球癌症相关死亡的首要原因。G蛋白偶联受体神经激肽-1（NK 1 R）在多种癌症中发挥多种作用，但其在肺癌中的病理作用和临床意义尚不清楚。在这里，我们将NK 1 R鉴定为在人类肺癌样品的转录组和组织阵列中显著上调的GPCR，其与晚期临床阶段和不良预后相关。值得注意的是，NK 1 R在NSCLC患者的组织中与表皮生长因子受体（EGFR）共表达，并且共定位于肿瘤细胞中。NK 1 R可通过与EGFR相互作用、反式激活EGFR磷酸化以及调节ERK 1/2和Akt的细胞内信号传导而与EGFR发生串扰。NK 1 R的激活促进肺癌细胞的增殖、集落形成、EMT、MMP 2/14表达和迁移。选择性拮抗剂阿瑞匹坦抑制NK 1 R可抑制细胞增殖和迁移。NK 1 R的敲低显著减缓了裸鼠中肿瘤的生长。肺癌细胞对吉非替尼/奥希替尼的敏感性在存在选择性NK 1 R拮抗剂阿瑞匹坦的情况下高度增加。我们的数据表明，NK 1 R通过EGFR信号传导在肺癌的发展中起重要作用，NK 1 R和EGFR之间的串扰可能为肺癌治疗提供潜在的治疗靶点。
Despite the great advances in target therapy, lung cancer remains the top cause of cancer-related death worldwide. G protein-coupled receptor neurokinin-1 (NK1R) is shown to play multiple roles in various cancers; however, the pathological roles and clinical implication in lung cancer are unclarified. Here we identified NK1R as a significantly upregulated GPCR in the transcriptome and tissue array of human lung cancer samples, associated with advanced clinical stages and poor prognosis. Notably, NK1R is co-expressed with epidermal growth factor receptor (EGFR) in NSCLC patients’ tissues and co-localized in the tumor cells. NK1R can crosstalk with EGFR by interacting with EGFR, transactivating EGFR phosphorylation and regulating the intracellular signaling of ERK1/2 and Akt. Activation of NK1R promotes the proliferation, colony formation, EMT, MMP2/14 expression, and migration of lung cancer cells. The inhibition of NK1R by selective antagonist aprepitant repressed cell proliferation and migration in vitro. Knockdown of NK1R significantly slowed down the tumor growth in nude mice. The sensitivity of lung cancer cells to gefitinib/osimertinib is highly increased in the presence of the selective NK1R antagonist aprepitant. Our data suggest that NK1R plays an important role in lung cancer development through EGFR signaling and the crosstalk between NK1R and EGFR may provide a potential therapeutic target for lung cancer treatment.
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影响因子：
4.8
作者：
Koon, HW;Zhao, DZ;Pothoulakis, C
通讯作者：
Pothoulakis, C
影响因子：
4.8
作者：
McConalogue, K;Déry, O;Bunnett, NW
通讯作者：
Bunnett, NW
影响因子：
3
作者：
Moody TW;Ramos-Alvarez I;Moreno P;Mantey SA;Ridnour L;Wink D;Jensen RT
通讯作者：
Jensen RT
DOI：
10.1038/nrd.2017.178
发表时间：
2017-12
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Hauser AS;Attwood MM;Rask-Andersen M;Schiöth HB;Gloriam DE
通讯作者：
Gloriam DE
影响因子：
5
作者：
Bayati, Samaneh;Bashash, Davood;Ghaffari, Seyed H.
通讯作者：
Ghaffari, Seyed H.