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Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer.

ABSTRACT: PURPOSE:The eukaryotic translation initiation factor complex 4E (eIF4E) is downstream in the mammalian target of rapamycin (mTOR) pathway. This study explored expression of eIF4E and its relationship with the PTEN/AKT and RAS/MEK/ERK pathways in non-small cell lung carcinoma (NSCLC). EXPERIMENTAL DESIGN:The status of phosphorylated eIF4E (p-eIF4E), phosphorylated AKT (p-AKT), PTEN, phosphorylated tuberin (p-TSC2), phosphorylated mTOR (p-mTOR), phosphorylated S6 (p-S6), and phosphorylated Erk1/2 (p-Erk1/2) was studied using immunohistochemical analysis applied to a tissue microarray containing 300 NSCLCs. Staining results for each antibody were compared with clinical and pathologic features, and the relationship between staining results was explored. RESULTS:Overexpression of p-eIF4E, p-AKT, p-TSC2, p-mTOR, p-S6, and p-Erk1/2 in NSCLC was found in 39.9%, 78.8%, 5.1%, 46.7%, 27.1%, and 16.6% of tumors, respectively. The phenotype of p-eIF4E correlated positively with that of p-AKT, p-TSC2, and p-S6 (P < 0.001). Overall survival in NSCLC patients was significantly shorter in cases with overexpression of p-eIF4E and p-AKT alone and in combination (log-rank P < 0.001, each). Cases with underexpression of PTEN were limited (6.4%), and this phenotype did not correlate with any clinical variable. In cluster analysis, the p-AKT/p-mTOR/p-eIF4E/p-S6-positive group had significantly shorter survival compared with the survival of all cases (P < 0.001). Multivariate analysis showed that p-eIF4E overexpression is an independent prognostic factor for NSCLC (P = 0.004). CONCLUSIONS:This study shows that p-eIF4E expression in addition to p-AKT predicts poor prognosis in NSCLC. Moreover, the correlation between expression of p-eIF4E with p-AKT, as well as p-TSC2 and p-S6, indicates that eIF4E activation through the AKT pathway plays an important role in the progression of NSCLC.

SUBMITTER: Yoshizawa A

PROVIDER: S-EPMC7581274 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer.

Yoshizawa Akihiko A Fukuoka Junya J Shimizu Shigeki S Shilo Konstantin K Franks Teri J TJ Hewitt Stephen M SM Fujii Takeshi T Cordon-Cardo Carlos C Jen Jin J Travis William D WD

Clinical cancer research : an official journal of the American Association for Cancer Research 20091215 1

<h4>Purpose</h4>The eukaryotic translation initiation factor complex 4E (eIF4E) is downstream in the mammalian target of rapamycin (mTOR) pathway. This study explored expression of eIF4E and its relationship with the PTEN/AKT and RAS/MEK/ERK pathways in non-small cell lung carcinoma (NSCLC).<h4>Experimental design</h4>The status of phosphorylated eIF4E (p-eIF4E), phosphorylated AKT (p-AKT), PTEN, phosphorylated tuberin (p-TSC2), phosphorylated mTOR (p-mTOR), phosphorylated S6 (p-S6), and phospho ...[more]

PMID: 20008839

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Project description:The Akt (protein kinase B)/mammalian target of rapamycin (mTOR) pathway, which is dysregulated in various cancers, controls the assembly of eukaryotic translation initiation factor 4F (eIF4E) complex. However, whether aberrant expression of phosphorylated Akt (p-Akt), phosphorylated mTOR (p-mTOR) and phosphorylated eIF4E (p-eIF4E) is associated with clinicopathological characteristics in surgically resected non-small cell lung cancer (NSCLC) has been rarely reported. Here, we investigated expression of p-Akt, p-mTOR and p-eIF4E proteins in NSCLC by immunohistochemistry and evaluated their correlation with clinicopathological characteristics and prognostic significance. The results showed that the positive percentage of p-Akt, p-mTOR and p-eIF4E was higher in NSCLC. Additionally, p-mTOR and p-eIF4E was dramatically higher in lung adenocarcinoma (both P<0.05). Most importantly, NSCLC patients with lymph node metastasis had significantly elevated expression of p-Akt, p-mTOR and p-eIF4E (all P<0.05). Positive expression of p-Akt, and any positive expression of p-Akt, p-mTOR and p-eIF4E proteins were positively correlated with clinical stages (both P<0.05). Spearman's rank correlation test revealed that expression of p-Akt was correlated with p-eIF4E and p-mTOR (r = 0.107, P = 0.047; r = 0.287, P<0.001, respectively). Also, p-eIF4E had positive correlation with p-mTOR (r = 0.265, P<0.001). Furthermore, NSCLC patients with increased expression of p-Akt, p-mTOR and p-eIF4E, and any positive expression of above three proteins had lower overall survival rates (all P<0.05). Multivariate Cox regression analysis further indicated thatp-eIF4E was an independent prognostic factor for NSCLC patients (P = 0.046). Taken together, overexpression of p-Akt, p-mTOR and p-eIF4E proteins is associated with metastasis and poor prognosis of NSCLC patients after surgical resection, and positive expression of p-eIF4E protein may act as an independent unfavorable prognostic biomarker for overall survival of NSCLC patients.

Dataset Information

Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer.

Publications

Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer.

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