Expression of Na+-K+-2Cl- cotransporter isoform 1 (NKCC1) predicts poor prognosis in lung adenocarcinoma and EGFR-mutated adenocarcinoma patients

Abstract

Background: Sodium-potassium-chloride cotransporter isoform 1 (NKCC1) is an active ions cotransporter and modulates cellular volume and migration. NKCC1 blockers can inhibit cancer cell growth. Aim: We aimed to elucidate the expression and prognostic significance of NKCC1 in non-small cell lung cancer (NSCLC).Methods: We retrospectively analyzed 788 NSCLC patients with either adenocarcinoma (n=503) or squamous cell carcinoma (n=285) by immunohistochemistry to correlate NKCC1 expression with clinicopathologic and survival outcomes. Results: In adenocarcinoma, high NKCC1 expression was associated with larger tumor size (P=0.013), vascular invasion (P<0.001), lymphatic invasion (P<0.001), perineural invasion (P=0.019) and advanced pathologic stage (P<0.001), but there are no significant correlations between NKCC1 expression and clinicopathological parameters in squamous cell carcinoma. Patients with high NKCC1 expression had significantly shorter disease-free survival (DFS; P<0.001) and shorter overall survival (OS; P<0.001) than those with low NKCC1 expression in adenocarcinoma. In squamous cell carcinoma, NKCC1 expression was not associated with prognosis. Multivariate analysis revealed that high NKCC1 expression was an independent prognostic factor for DFS in lung adenocarcinomas (HR, 1.709; 95% CI 1.029-2.130; P=0.033) and for OS in EGFR-mutated adenocarcinoma patients (HR, 3.165; 95% CI 1.424-7.035; P=0.005). Conclusion: NKCC1 high expression predicted a bad clinical outcome for lung adenocarcinoma patients and EGFR-mutated subgroup. Therefore, NKCC1 may play a role in lung adenocarcinoma and novel therapeutic tactics could be developed by targeting NKCC1 protein.