Mutual regulation between Raf/MEK/ERK signaling and Y-box-binding protein-1 promotes prostate cancer progression

Kenjiro Imada, Masaki Shiota, Kenichi Kohashi, Kentaro Kuroiwa, Yoo Hyun Song, Masaaki Sugimoto, Seiji Naito, Yoshinao Oda

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Purpose: Y-box-binding protein-1 (YB-1) is known to conduct various functions related to cell proliferation, anti-apoptosis, epithelial-mesenchymal transition, and castration resistance in prostate cancer. However, it is still unknown how YB-1 affects cancer biology, especially its correlations with the mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, we aimed to examine the interaction between YB-1 and the MAPK pathway in prostate cancer. Experimental Design: Quantitative real-time PCR, Western blotting, and co-immunoprecipitation assay were conducted in prostate cancer cells. YB-1, phosphorylated YB-1 (p-YB-1), and ERK2 protein expressions in 165 clinical specimens of prostate cancer were investigated by immunohistochemistry. YB-1, p-YB-1, and ERK2 nuclear expressions were compared with clinicopathologic characteristics and patient prognoses. Results: EGF upregulated p-YB-1, whereas MEK inhibitor (U0126, PD98059) decreased p-YB-1. Inversely, silencing of YB-1 using siRNA decreased the expression of ERK2 and phosphorylated MEK, ERK1/2, and RSK. Furthermore, YB-1 interacted with ERK2 and Raf-1 and regulated their expressions, through the proteasomal pathway. Immunohistochemical staining showed a significant correlation among the nuclear expressions of YB-1, p-YB-1, and ERK2. The Cox proportional hazards model revealed that high ERK2 expression was an independent prognostic factor [HR, 7.947; 95% confidence interval (CI), 3.527-20.508; P < 0.0001]. Conclusion: We revealed the functional relationship between YB-1 and MAPK signaling and its biochemical relevance to the progression of prostate cancer. In addition, ERK2 expression was an independent prognostic factor. These findings suggest that both the ERK pathway and YB-1 may be promising molecular targets for prostate cancer diagnosis and therapeutics.

Original languageEnglish
Pages (from-to)4638-4650
Number of pages13
JournalClinical Cancer Research
Volume19
Issue number17
DOIs
Publication statusPublished - Sep 1 2013

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Y-Box-Binding Protein 1
Mitogen-Activated Protein Kinase Kinases
Prostatic Neoplasms
Mitogen-Activated Protein Kinases
Epithelial-Mesenchymal Transition
MAP Kinase Signaling System
Castration
Proportional Hazards Models
Immunoprecipitation
Epidermal Growth Factor
Small Interfering RNA
Real-Time Polymerase Chain Reaction
Research Design
Western Blotting
Immunohistochemistry
Cell Proliferation
Confidence Intervals
Apoptosis
Staining and Labeling

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Mutual regulation between Raf/MEK/ERK signaling and Y-box-binding protein-1 promotes prostate cancer progression. / Imada, Kenjiro; Shiota, Masaki; Kohashi, Kenichi; Kuroiwa, Kentaro; Song, Yoo Hyun; Sugimoto, Masaaki; Naito, Seiji; Oda, Yoshinao.

In: Clinical Cancer Research, Vol. 19, No. 17, 01.09.2013, p. 4638-4650.

Research output: Contribution to journalArticle

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abstract = "Purpose: Y-box-binding protein-1 (YB-1) is known to conduct various functions related to cell proliferation, anti-apoptosis, epithelial-mesenchymal transition, and castration resistance in prostate cancer. However, it is still unknown how YB-1 affects cancer biology, especially its correlations with the mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, we aimed to examine the interaction between YB-1 and the MAPK pathway in prostate cancer. Experimental Design: Quantitative real-time PCR, Western blotting, and co-immunoprecipitation assay were conducted in prostate cancer cells. YB-1, phosphorylated YB-1 (p-YB-1), and ERK2 protein expressions in 165 clinical specimens of prostate cancer were investigated by immunohistochemistry. YB-1, p-YB-1, and ERK2 nuclear expressions were compared with clinicopathologic characteristics and patient prognoses. Results: EGF upregulated p-YB-1, whereas MEK inhibitor (U0126, PD98059) decreased p-YB-1. Inversely, silencing of YB-1 using siRNA decreased the expression of ERK2 and phosphorylated MEK, ERK1/2, and RSK. Furthermore, YB-1 interacted with ERK2 and Raf-1 and regulated their expressions, through the proteasomal pathway. Immunohistochemical staining showed a significant correlation among the nuclear expressions of YB-1, p-YB-1, and ERK2. The Cox proportional hazards model revealed that high ERK2 expression was an independent prognostic factor [HR, 7.947; 95{\%} confidence interval (CI), 3.527-20.508; P < 0.0001]. Conclusion: We revealed the functional relationship between YB-1 and MAPK signaling and its biochemical relevance to the progression of prostate cancer. In addition, ERK2 expression was an independent prognostic factor. These findings suggest that both the ERK pathway and YB-1 may be promising molecular targets for prostate cancer diagnosis and therapeutics.",
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AU - Imada, Kenjiro

AU - Shiota, Masaki

AU - Kohashi, Kenichi

AU - Kuroiwa, Kentaro

AU - Song, Yoo Hyun

AU - Sugimoto, Masaaki

AU - Naito, Seiji

AU - Oda, Yoshinao

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