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

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

doi:10.18632/oncotarget.27017

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Research Papers:

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

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

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Oncotarget. 2019; 10:4053-4068. https://doi.org/10.18632/oncotarget.27017

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Abstract

Osamu Ichiyanagi1^,2^,*, Hiromi Ito1^,*, Sei Naito1^,*, Takanobu Kabasawa3, Hidenori Kanno1, Takafumi Narisawa1, Masaki Ushijima1, Yuta Kurota1, Michinobu Ozawa1, Toshihiko Sakurai1, Hayato Nishida1, Tomoyuki Kato1, Mitsunori Yamakawa3 and Norihiko Tsuchiya1

1 Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan

2 Department of Urology, Yamagata Prefectural Kahoku Hospital, Kahoku, Japan

3 Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, Yamagata, Japan

* These authors contributed equally to this work

Correspondence to:

Sei Naito,

email:

[email protected]

Keywords: renal cell carcinoma; phospho-eIF4E (p-eIF4E); MNK (MAPK-interacting kinase); recurrence-free; epithelial−mesenchymal transition

Received: February 01, 2019 Accepted: May 20, 2019 Published: June 18, 2019

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.

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Research Papers:

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

Abstract