Abstract
Ion channels and pumps not only regulate membrane potential, ion homeostasis, and electric signaling in excitable cells but also contribute to cell proliferation, migration, apoptosis, and differentiation. Channel proteins and ion pumps can form macromolecular complexes with signaling molecules, including growth factors and cell adhesion molecules. Serotonin (5-hydroxytryptamine (5-HT)) promotes the proliferation of various cancer cell types mediated through the activation of the 5-HT receptor (HTR). Only HTR3 is a ligand-gated ion channel. However, the role of the HTR3 family of HTRs in lung cancer has not been adequately evaluated. We evaluated the relationship between the HTR3 family of HTRs and lung cancer patients' survival using Kaplan–Meier analyses and examined the expression levels of target proteins using immunohistochemistry. In this study, we found that HTR3C was amplified with high frequency in lung cancer patients, and HTR3C protein expression levels were significantly associated with lymph node metastasis and distant metastasis in lung cancer tissues. Survival analysis using the log-rank test demonstrated a decrease in disease-free survival (DFS) and overall survival (OS) rates among the high-level HTR3C expression group compared with the low-level HTR3C expression group. We also evaluated the risk factors associated with lung cancer. The univariate and multivariate analyses of DFS and OS showed that HTR3C expression was a significant predictor of patient outcomes. Taken together, these data demonstrated that HTR3C expression levels were associated with poor DFS and OS in lung cancer patients, indicating that HTR3C can serve as a useful predictive biomarker for lung cancer.
Highlights
Lung cancer is a malignant tumor type and is currently the leading cause of cancer-related deaths worldwide
We evaluated the genetic profiles of HTR3 family members (HTR3A–HTR3E) in non-small-cell lung cancer (NSCLC) patients using a publicly available dataset. e genetic profiles of HTR3 family members were obtained from 6,122 NSCLC samples, which revealed that HTR3C, HTR3D, and HTR3E were significantly amplified in NSCLC genetic profiles (Figure 1)
We analyzed the frequency of gene amplification co-occurrence within the same samples from lung cancer patients, which showed high frequencies of co-occurrence for some gene amplification pairs within the same patient, including HTR3C/HTR3D, HTR3C/HTR3E, and HTR3D/HTR3E, whereas the co-occurrence of gene amplification was not observed for other gene pairs (HTR3A/ HTR3B, HTR3B/HTR3D, and HTR3B/HTR3C) (Supplementary Table 1)
Summary
Lung cancer is a malignant tumor type and is currently the leading cause of cancer-related deaths worldwide. As high as 80% of lung cancer cases are categorized as non-small-cell lung cancer (NSCLC) [1, 2]. 70% of newly diagnosed lung cancer patients require systemic treatment due to locally advanced or metastatic disease. Lung cancer patients often have poor prognoses, low 5-year survival rates, and high mortality rates, most likely due to the high metastatic rate of lung cancer [2,3,4]. Ion channels contribute to the malignant behaviors of cancer cells, including migration, invasion, cell cycle control, and metastasis [5]. Ion channel upregulation and increased activity have been reported in response to mitogen exposure [6,7,8], and accumulating evidence supports the existence of a direct link between transmembrane ion flow and carcinogenesis [9, 10]
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