HTR3A is correlated with the unfavorable histology and promotes proliferation via 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; for example, 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 7 families of 5-HT receptors. Though 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, the higher expression level of HTR3A was detected in acinar, papillary, and solid adenocarcinoma than in lepidic adenocarcinoma; the former was more aggressive subtype than the latter. We also showed the relationship between the expression of HTR3A and Ki-67, widely used as a proliferation marker. Moreover, we generated HTR3A-knockdown lung adenocarcinoma cells and showed that the HTR3A knockdown attenuated proliferation via ERK phosphorylation. Our results demonstrated 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. Overall design: We divided 30 cases into 2 groups. The first group had 20 cases and was composed of relatively indolent histological subtype, such as lepidic, acinar, and papillary (good-prognosis group). The second group had 10 cases and was composed of relatively aggressive subtype, such as micropapillary and solid (poor-prognosis group). We compared the levels of gene expression profiles between 2 groups.