HTR3A is correlated with unfavorable histology and promotes proliferation through ERK phosphorylation in lung adenocarcinoma

Lung cancer is the leading cause of cancer death around the world. Adenocarcinoma is the most common histological type and has various histologic subtypes: lepidic, acinar, papillary, solid, and invasive mucinous adenocarcinoma. Histologic subtypes are related to invasiveness of tumors; eg, lepidic subtype is less invasive than acinar/papillary subtype. HTR3A is the main subunit of 5‐hydroxytryptamine 3 (5‐HT3) receptors, which are the only ligand‐gated ion channels in seven families of 5‐HT receptors. Although 5‐HT3 receptor is expressed mainly throughout the central and peripheral nervous systems, some papers report the effect of 5‐HT3 receptors on tumor cells, including lung cancer. However, whether HTR3A correlates with histopathological findings such as the histologic subtypes or the distribution in an individual sample remains unclear. Immunohistochemically, we revealed that the higher expression level of HTR3A was detected in acinar, papillary, and solid adenocarcinoma than in adenocarcinoma in situ and lepidic adenocarcinoma; the former was a more aggressive subtype than the latter. We also showed the relationship between HTR3A expression and Ki‐67 positivity, widely used as a proliferation marker. Moreover, we generated HTR3A‐knockdown lung adenocarcinoma cells and showed that the HTR3A knockdown attenuated proliferation by ERK phosphorylation. Our results indicated that HTR3A expression was related to proliferation in lung adenocarcinoma, by means of both in vitro and immunohistochemical assays on clinical samples. We showed the therapeutic potential of a 5‐HT3 receptor antagonist, tropisetron, for the treatment of lung adenocarcinoma.