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Na+/H+ exchanger 1 has tumor suppressive activity and prognostic value in esophageal squamous cell carcinoma.

ABSTRACT: Na+/H+ exchanger 1 (NHE1) is a plasma membrane transporter that controls intracellular pH and regulates apoptosis and invasion in various cancer cells. However, the function of NHE1 in esophageal squamous cell carcinoma (ESCC) cells and the relationship between the expression of NHE1 and prognosis of ESCC remain unclear. We found that the knockdown of NHE1 in ESCC cells inhibited apoptosis and promoted cell proliferation, migration, and invasion and showed increases in Snail, ?-catenin, and activation of PI3K-AKT signaling, which was consistent with the results obtained from microarrays. Microarrays results suggested that the knockdown of NHE1 suppressed Notch signaling pathway. An immunohistochemical investigation of 61 primary ESCC samples revealed that NHE1 was expressed at higher levels in well-differentiated tumors. The 5-year survival rate was poorer in the NHE1 low group (57.0%) than in the NHE1 high group (82.8%). Multivariate analyses revealed that the weak expression of NHE1 was associated with shorter postoperative survival (hazard ratio 3.570, 95% CI 1.291-11.484, p = 0.0135).We herein demonstrated that the suppression of NHE1 in ESCC may enhance malignant potential by mediating PI3K-AKT signaling and EMT via Notch signaling, and may be related to a poor prognosis in patients with ESCC.

SUBMITTER: Ariyoshi Y

PROVIDER: S-EPMC5356793 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Na+/H+ exchanger 1 has tumor suppressive activity and prognostic value in esophageal squamous cell carcinoma.

Ariyoshi Yosuke Y Shiozaki Atsushi A Ichikawa Daisuke D Shimizu Hiroki H Kosuga Toshiyuki T Konishi Hirotaka H Komatsu Shuhei S Fujiwara Hitoshi H Okamoto Kazuma K Kishimoto Mitsuo M Marunaka Yoshinori Y Otsuji Eigo E

Oncotarget 20170101 2

Na+/H+ exchanger 1 (NHE1) is a plasma membrane transporter that controls intracellular pH and regulates apoptosis and invasion in various cancer cells. However, the function of NHE1 in esophageal squamous cell carcinoma (ESCC) cells and the relationship between the expression of NHE1 and prognosis of ESCC remain unclear. We found that the knockdown of NHE1 in ESCC cells inhibited apoptosis and promoted cell proliferation, migration, and invasion and showed increases in Snail, β-catenin, and acti ...[more]

PMID: 27902974

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Project description:BackgroundThe current TNM classification system does not consider tumor length for patients with esophageal carcinoma (EC). This study explored the effect of tumor length, in addition to tumor depth and lymph node involvement, on survival in patients with esophageal squamous cell carcinoma (ESCC).MethodsA total of 498 ESCC patients who underwent surgical resection as the primary treatment were selected in the retrospective study. Pathological details were collected, which included tumor type, TNM stage, differentiation. Other collected information were: the types of esophageal resection, ABO blood group, family history and demographic and lifestyle factors. A time-dependent receiver operating characteristic (ROC) curve and a regression tree for survival were used to identify the cut-off point of tumor length, which was 3 cm. Univariate and multivariate Cox proportional hazard regression models were used to identify the prognostic factors to ESCC.Results & discussionThe 1-, 3-, 5-year overall survival rates were found to be 82.5%, 55.6%, and 35.1%, respectively. Patients who had larger tumor length (>3 cm) had a higher risk for death than the rest patients. From the univariate Cox proportional hazards regression model, the overall survival rate was significantly influenced by the depth of the tumor and lymph node involvement (either as dummy or continuous variables), Sex, and tumor length. Using these four variables in the multivariate Cox proportional hazard regression model, we found that the overall survival was significantly influenced by all variables except Sex. Therefore, in addition to the depth of the tumor and lymph node involvement (as either dummy or continuous variables), the tumor length is also an independent prognostic factor for ESCC. The overall survival rate was higher in a group with smaller tumor length (≤3 cm) than those patients with larger tumor length (>3 cm), no matter what the tumor stage was.ConclusionThe tumor length was found to be an important prognostic factor for ESCC patients without receiving neoadjuvant therapy. The modification of EC staging system may consider tumor length to better predict ESCC survival and identify higher risk patients for postoperative therapy.

Project description:BackgroundAbsent in melanoma 1-like (AIM1L), also known as crystalline beta gamma domain containing 2. The relationship between AIM1L and tumors has not been fully investigated, and the biological function of AIM1L in different tumors is unknown, so we bioinformatically explored a possible relationship between AIM1L and esophageal squamous cell carcinoma (ESCC).MethodsAIM1L mRNA expression was detected by the Gene Expression Omnibus database (GSE20347, GSE161533, and GSE53625), and protein level expression was detected by immunohistochemistry. The correlation between AIM1L expression and clinical pathological characteristics was evaluated by the Wilcoxon signed rank test or chi-square test. Kaplan-Meier analysis and Cox proportional risk regression model were used to determine the prognostic value of AIM1L in ESCC patients and establish and verify a nomogram. Find genes highly related to the expression of AIM1L, conduct GO and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis, and conduct GSEA analysis on the gene set. The "CIBERSORT" R package was used to explore the relationship between AIM1L and immune infiltration, and the "OncoPredict" R package was used to explore the relationship between AIM1L and drug sensitivity.ResultsCompared with the matched adjacent non-cancer tissues, the expression of AIM1L was down-regulated in ESCC tissues, and correlated with tumor grade. Kaplan-Meier survival analysis and Cox analysis showed that the low expression of AIM1L was related to the poor prognosis of ESCC patients. Enrichment analysis explained the possible function of AIM1L, GSEA determined the highly correlated signal pathway of AIM1L low expression phenotype, immune infiltration analysis determined that AIM1L was related to activated NK cells and macrophage M2, and drug sensitivity analysis determined that the low expression of AIM1L might be related to EGFR targeted drug resistance.ConclusionAIM1L may be a candidate tumor suppressor gene for ESCC and an independent molecular biomarker for the prognosis of ESCC patients.

Dataset Information

Na+/H+ exchanger 1 has tumor suppressive activity and prognostic value in esophageal squamous cell carcinoma.

Publications

Na+/H+ exchanger 1 has tumor suppressive activity and prognostic value in esophageal squamous cell carcinoma.

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