5-HT₇ Receptor Contributes to Proliferation, Migration and Invasion in NSCLC Cells

Because only a small portion of NSCLC (non-small-cell lung cancer) patients benefit from molecular targeted therapy or immunotherapy and do not develop therapeutic resistance, continued research on new targets is warranted. Serotonin has recently emerged as a growth factor for tumor cells, and its receptors may be potential therapeutic targets. The mechanism related to the behavior of the 5-HT₇ receptor in NSCLC remains unknown.

Both gene expression analysis and immunohistochemical analysis were conducted to evaluate 5-HT₇ receptor expression in NSCLC tissues. The correlation between 5-HT₇ receptor expression and clinicopathological features was also examined. Cell proliferation was measured using a CCK8 (Cell Counting Kit-8) assay and colony formation, migration and invasion were evaluated by the Transwell assay. siRNA transfection and stimulation with the selective agonist LP211 were used to identify the involvement of molecules in proliferation, migration and invasion. Quantitative real-time chain reaction (qRT-PCR) and Western blotting were used to quantifiy mRNA and protein levels, respectively. Pathway inhibitors facilitated the exploration of possible signaling pathways regulated by the 5-HT₇ receptor in migration and invasion.

The 5-HT₇ receptor was overexpressed in NSCLC tumor tissues compared with adjacent normal lung tissues. High 5-HT₇ receptor expression levels were correlated with lymph node metastasis (P=0.007) and advanced TNM stage (P=0.000) in NSCLC patients. The 5-HT₇ receptor positively regulated cell proliferation, migration and invasion in NSCLC cells. The stimulatory effect of the 5-HT₇ receptor on A549 cell migration and invasion may occur through the P38 pathway. In H1299 cells, the 5-HT₇ receptor might positively regulate Src to promote cell migration and invasion.

Our findings suggest that the 5-HT₇ receptor, which mediates NSCLC progression, may be a potential therapeutic target.