Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China.
Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China.
Cell Oncol (Dordr). 2024 Jun;47(3):779-791. doi: 10.1007/s13402-023-00894-7. Epub 2023 Oct 30.
TRPV1 is a nonselective Ca channel protein that is widely expressed and plays an important role during the occurrence and development of many cancers. Activation of TRPV1 channels can affect tumour progression by regulating proliferation, apoptosis and migration. Some studies have also shown that activating TRPV1 can affect tumour progression by modulating tumour immunity. However, the effects of TRPV1 on the development of non-small cell lung cancer (NSCLC) have not been explored clearly.
The Cancer Genome Atlas (TCGA) database and spatial transcriptomics datasets from 10 × Genomics were used to analyze TRPV1 expression in various tumour tissues. Cell proliferation and apoptosis were examined by cell counting kit 8 (CCK8), colony formation, and flow cytometry. Immunohistochemistry, qPCR, and western blotting were used to determine the mRNA and protein expression levels of TRPV1 and other related molecules. Tumour xenografts in BALB/C and C57BL/6J mice were used to determine the effects of TRPV1 on NSCLC development in vivo. Neurotransmitter content was examined by LC-MS/MS, ELISA and Immunohistochemistry. Immune cell infiltration was assessed by flow cytometry.
In this study, we found that TRPV1 expression was significantly upregulated in NSCLC and that patients with high TRPV1 expression had a poor prognosis. TRPV1 knockdown can significantly inhibit NSCLC proliferation and induce cell apoptosis through Ca-IGF1R signaling. In addition, TRPV1 knockdown resulted in increased infiltration of CD4 T cells, CD8 T cells, GZMBCD8 T cells and DCs and decreased infiltration of immunosuppressive MDSCs in NSCLC. In addition, TRPV1 knockout effectively decreased the expression of M2 macrophage markers CD163 and increased the expression of M1-associated, costimulatory markers CD86. Knockdown or knockout of TRPV1 significantly inhibit tumour growth and promoted an antitumour immune response through supressing γ-aminobutyric acid (GABA) secretion in NSCLC.
Our study suggests that TRPV1 acts as a tumour promoter in NSCLC, mediating pro-proliferative and anti-apoptotic effects on NSCLC through IGF1R signaling and regulating GABA release to affect the tumour immune response.
TRPV1 是一种非选择性的钙通道蛋白，广泛表达，在许多癌症的发生和发展中发挥重要作用。TRPV1 通道的激活可以通过调节增殖、凋亡和迁移来影响肿瘤进展。一些研究还表明，激活 TRPV1 通过调节肿瘤免疫可以影响肿瘤进展。然而，TRPV1 对非小细胞肺癌（NSCLC）发展的影响尚未得到明确探讨。
利用癌症基因组图谱（TCGA）数据库和 10× Genomics 的空间转录组学数据集分析各种肿瘤组织中 TRPV1 的表达。通过细胞计数试剂盒 8（CCK8）、集落形成和流式细胞术检测细胞增殖和凋亡。免疫组织化学、qPCR 和 Western blot 用于测定 TRPV1 及其他相关分子的 mRNA 和蛋白表达水平。在 BALB/C 和 C57BL/6J 小鼠中建立肿瘤异种移植模型，以确定 TRPV1 对 NSCLC 体内发展的影响。通过 LC-MS/MS、ELISA 和免疫组织化学检测神经递质含量。通过流式细胞术评估免疫细胞浸润。
在这项研究中，我们发现 TRPV1 在 NSCLC 中表达显著上调，高 TRPV1 表达的患者预后不良。TRPV1 敲低可通过 Ca-IGF1R 信号显著抑制 NSCLC 增殖并诱导细胞凋亡。此外，TRPV1 敲低导致 NSCLC 中 CD4 T 细胞、CD8 T 细胞、GZMBCD8 T 细胞和 DC 浸润增加，而免疫抑制性 MDSC 浸润减少。此外，TRPV1 基因敲除有效降低了 NSCLC 中 M2 巨噬细胞标志物 CD163 的表达，增加了与 M1 相关的共刺激标志物 CD86 的表达。TRPV1 敲低或敲除通过抑制 NSCLC 中 γ-氨基丁酸（GABA）的释放，显著抑制肿瘤生长并促进抗肿瘤免疫反应。
我们的研究表明，TRPV1 在 NSCLC 中作为肿瘤促进剂发挥作用，通过 IGF1R 信号介导对 NSCLC 的促增殖和抗凋亡作用，并通过调节 GABA 释放来影响肿瘤免疫反应。
