Levels of 4EBP1/eIF4E Activation in Renal Cell Carcinoma Could Differentially Predict Its Early and Late Recurrence

Abstract

A subset of patients who undergo curative surgery for localized clear cell renal cell carcinoma (ccRCC) will experience early or late recurrence. Tumor viability depends on protein synthesis via the eukaryotic initiation factor (eIF)4E-binding protein 1 (4EBP1/eIF4E) axis. Activation levels of the axis in ccRCC tissues could differentially affect tumor recurrence and the timing of recurrence after curative nephrectomy. Background: The objective was to explore the predictive markers of late recurrence (LR) > 5 years after curative nephrectomy for renal cell carcinoma (RCC). Patients and Methods: We retrospectively examined the data from 303 patients with localized clear cell RCC treated surgically at our institution from 1993 to 2011. Activation of the eukaryotic initiation factor (eIF)4E-binding protein 1 (4EBP1)/eIF4E axis at the mammalian target of rapamycin complex 1 (mTORC1) was evaluated in the tumor specimens. Weak, intermediate, and strong immunohistochemistry staining grades were defined for 4EBP1, phosphorylated 4EBP1, and eIF4E. The effects of clinicopathologic factors and activation level grades on tumor recurrence were analyzed using multivariate Cox regression models. To validate the present findings, we investigated clinical data from The Cancer Genome Atlas and protein/phosphoprotein data from corresponding patients from The Cancer Proteome Atlas. Results: Of the 303 patients, 31 and 16 patients developed early recurrence (ER, 5 years) and LR, respectively. The activation levels were comparable among the subcategories of pathologic TN stage, Fuhrman grade, and microvascular and capsular invasion. Pathologic stage ! T1b, Fuhrman grade 3/4, and an intermediate or strong activation level correlated significantly with overall recurrence and ER. Strong activation of the axis and pathologic stage ! T1b were identified as independent predictors of LR. Only 2 patients with weak activation experienced recurrence (1 each with ER and LR). Similar results were confirmed by the analyses of The Cancer Genome Atlas and The Cancer Proteome Atlas data. Conclusion: The activation level of the axis in RCC tissues could independently predict for recurrence and differentially affect the timing of recurrence.

Impact of eIF4E phosphorylation at Ser209 via MNK2a on tumour recurrence after curative surgery in localized clear cell renal cell carcinoma

“…Conversely, MNK2 selectively interacts with mTORC1 in a kinaseindependent manner and inhibits S6K phosphorylation [25]. Recently, we demonstrated that the lower or higher expression of eIF4E reflected a weaker or stronger activation of the mTORC1/4EBP1/eIF4E signalling pathway, respectively [26]. In the present study, significantly lower eIF4E and higher p-eIF4E expressions were observed in ccRCC patients who did not experience tumour recurrence than in those who did.…”

Expression of total and phospho 4EBP1 in metastatic and non‑metastatic renal cell carcinoma

“…One supposed reason for the result is that phosphorylation of 4EBP1 promotes to dissociate 4EBP1/eIF4E assembly (7,8). Actually, we previously elucidated that high levels of 4EBP1/eIF4E activation predicts RCC recurrence (14). Another reason is the consequence of Akt/mTORC1 pathway activation.…”

“…Akt activation by low-density lipoprotein (LDL) addition in RCC cell lines counteracts the anti-tumor effects of the VEGF-targeted agents sunitinib and sorafenib (13). In adition, we have previously reported that high levels of 4EBP1/eIF4E activeation predict higher recurrence rate (14).…”

Integrative Radiogenomics Approach for Risk Assessment of Post-Operative Metastasis in Pathological T1 Renal Cell Carcinoma: A Pilot Retrospective Cohort Study

“…Hypoxia and necrosis determined as significant radiomic features played a central role in RCC progression by modulating critical signaling pathways including PI3K/AKT signaling, Notch signaling, Wnt signaling, and focal adhesion, governing stem-cell-like phenotype, cancer cell plasticity, metabolic reprogramming, epithelial-to-mesenchymal transition (EMT) closely associated with higher probability to escape the primary tumor and survive in an avascular metastatic site [2,5,21,[38][39][40]. The aberrant overexpression of key proteins via cap-dependent mRNA translation is known to be a requisite for tumor progression and metastasis via the strong activation of the eukaryotic initiation factor (eIF) 4E-binding protein 1 (4EBP1/eIF4E) axis in RCC [41]. Furthermore, an ECM remodeling program and an ECM-receptor interaction pathway facilitate cell survival, angiogenesis, EMT, and metastasis of RCC via the subsequent activation of the focal adhesion kinase (FAK)/c-Jun N-terminal kinase pathway and PI3K/AKT pathway [42][43][44].…”