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

Osamu Ichiyanagi,Masaki Ushijima,Hiromi Ito,Yuta Kurota,Hayato Nishida,Tomoyuki Kato,Takafumi Narisawa,Toshihiko Sakurai,Michinobu Ozawa,Hidenori Kanno,Norihiko Tsuchiya,Takanobu Kabasawa,Mitsunori Yamakawa,Sei Naito

doi:10.18632/oncotarget.27017

Osamu Ichiyanagi, Masaki Ushijima + Show 12 more

Open Access

https://doi.org/10.18632/oncotarget.27017

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Journal: Oncotarget	Publication Date: Jun 18, 2019
Citations: 2	License type: cc-by

Affiliation: Kihoku hospital, Yamagata University

Abstract

Background: We investigated the roles of eIF4E phosphorylation (Ser209) in tumour recurrence after curative nephrectomy for localized clear cell renal cell carcinoma (ccRCC).Methods: Expression of eIF4E, p eIF4E and MNKs (MAPK interacting kinases), was evaluated in surgical specimens obtained from consecutive non metastatic ccRCC patients (n = 290) by immunohistochemistry (IHC), immunoblotting, and qRT PCR at the protein and mRNA levels. In human RCC cell lines, the effects of eIF4E phosphorylation were examined using immunoblotting, proliferation, migration and invasion assays with pharmacological inhibitors (CGP57380 or ETP45835) and specific small interfering (si) RNAs against MNK1/2(a/b).Results: In postoperative follow-up (median, 7.9 y), 40 patients experienced metastatic recurrence. In multivariate Cox analyses, higher IHC expression of p eIF4E in ccRCC significantly predicted a longer recurrence-free interval. eIF4E is phosphorylated mainly by MNK2a in tumour specimens and cell lines. In 786-O and A-498 cell lines, pharmacological inhibition of MNKs decreased p-eIF4E and increased vimentin and N cadherin but did not influence proliferation. Similarly, MNK2 or MNK2a inhibition with siRNA reduced p-eIF4E and enhanced vimentin translation, cell migration and invasion in the cell lines.Conclusions: MNK2a-induced eIF4E phosphorylation may suppress metastatic recurrence of ccRCC, partially due to vimentin downregulation at the translational level, consequently leading to inhibition of epithelial–mesenchymal transition.

Highlights

Renal cell carcinoma (RCC) is one of the most common malignant tumours originating in the kidney
Consecutive patients (n = 290) who underwent curative surgery for localized clear cell renal cell carcinoma (ccRCC) were recruited in the present study
We examined the influence of MAP kinase interacting kinase (MNK) inhibition on eukaryotic initiation factor 4E (eIF4E) phosphorylation in 786-O and A498 using a smallmolecule MNK1/2 inhibitor CGP57380 [9] or ETP45835 [13] (Figure 3A)

Summary

Introduction

Renal cell carcinoma (RCC) is one of the most common malignant tumours originating in the kidney. The survival rates for metastatic RCC have been drastically www.oncotarget.com improved owing to the development of targeted drugs and immune checkpoint inhibitors [3]. The prognosis of patients with advanced-stage (T3-4, N+, M+) RCC remains extremely poor, with a 5-year overall survival (OS) rate of 10%–30% [1]. The 5-year recurrence-free and overall survival rates of RCC at stage I were around 95%, respectively [1]. Up to 30% of patients who undergo curative surgery for clinically-confined RCC suffer from disease recurrence [4]. We investigated the roles of eIF4E phosphorylation (Ser209) in tumour recurrence after curative nephrectomy for localized clear cell renal cell carcinoma (ccRCC)

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