Abstract
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.
Highlights
Lung cancer remains the top cause of cancer-related death in China and worldwide for years and non-small cell lung cancer (NSCLC) accounts for more than 80% of lung cancer cases [1, 2]
Upregulation of Neurokinin-1 receptor (NK1R) is associated with NSCLC development and poor prognosis To investigate its potential role in NSCLC, the expression of NK1R was detected in a tissue array consisting of 30 samples of human lung adenocarcinoma
We further analyzed NK1R expression in NSCLC and adjacent non-tumor tissues in two datasets GSE130779 and GSE2514 downloaded from Gene Expression Omnibus (GEO) databases [38, 39], revealing that expression of NK1R was significantly upregulated in NSCLC tumor tissues compared with the adjacent non-tumor tissues or normal tissues (Fig. 1C)
Summary
Lung cancer remains the top cause of cancer-related death in China and worldwide for years and non-small cell lung cancer (NSCLC) accounts for more than 80% of lung cancer cases [1, 2]. Tyrosine kinase inhibitors of EGF receptor (EGFR TKI) have dramatically changed the therapeutic paradigm of NSCLC [3], which are generated to bind and inhibit the intracellular kinase domain of EGFR with positive EGFR mutations [4]. The development of acquired resistance was almost inevitable and secondary EGFR mutations, commonly T790M, occurred in about half of the relapsed patients. Osimertinib, the third-generation EGFR TKI was approved to overcome the resistance of T790M mutation [7]; acquired resistance has already been detected in clinical treatment [8, 9]. All approved EGFR TKIs are gene-type specific and much less efficient in patients with wtEGFR amplification or other insensitive mutant EGFRs (such as Ex20ins); there is still a large part of NSCLC patients who cannot benefit from current EGFR-targeting therapeutic strategies. The failures highlight the unmet need to identify other targets serving to promote tumor progression, which may be developed into novel strategies for NSCLC therapy
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