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c-Jun N-terminal kinase activation has a prognostic implication and is negatively associated with FOXO1 activation in gastric cancer

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Authors
Choi, Youngsun; Park, Jinju; Choi, Yiseul; Ko, Young San; Yu, Da-Ae; Kim, Younghoon; Pyo, Jung-Soo; Jang, Bo Gun; Kim, Min A.; Kim, Woo Ho; Lee, Byung Lan
Issue Date
2016-06-06
Publisher
BioMed Central
Citation
BMC Gastroenterology, 16(1):59
Keywords
JNKGastric cancerClinical significanceProliferationFOXO1
Description
This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made.
Abstract
Abstract

Background
Since the biological function of c-Jun N-terminal kinase (JNK) in gastric cancer remains unclear, we investigated the clinical significance of JNK activation and its association with FOXO1 activation.


Methods
Immunohistochemical tissue array analysis of 483 human gastric cancer specimens was performed, and the results of the immunostaining were quantified. The correlation between JNK activation (nuclear staining for pJNK) and clinicopathological features, the proliferation index, prognosis or FOXO1 inactivation (cytoplasmic staining for pFOXO1) was analyzed. The SNU-638 gastric cancer cell line was used for in vitro analysis.


Results
Nuclear staining of pJNK was found in 38 % of the gastric carcinomas and was higher in the early stages of pTNM (P < 0.001). pJNK staining negatively correlated with lymphatic invasion (P = 0.034) and positively correlated with intestinal type by Lauren’s classification (P = 0.037), Ki-67-labeling index (P < 0.001), cyclin D1 (P = 0.045), cyclin E (P < 0.001) and pFOXO1 (P < 0.001). JNK activation correlated with a longer patients survival (P =0.008) and patients with a JNK-active and FOXO1-inactive tumor had a higher survival rate than the remainder of the population (P = 0.004). In vitro analysis showed that JNK inhibition by SP600125 in SNU-638 cells decreased cyclin D1 protein expression and increased FOXO1 activation. Further, JNK inhibition markedly suppressed colony formation, which was partially restored by FOXO1 shRNA expression.


Conclusions
Our results indicate that JNK activation may serve as a valuable prognostic factor in gastric cancer, and that it is implicated in gastric tumorigenesis, at least in part, through FOXO1 inhibition.
Language
English
URI
http://hdl.handle.net/10371/100557
DOI
https://doi.org/10.1186/s12876-016-0473-9
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College of Medicine/School of Medicine (의과대학/대학원)Anatomy (해부학전공)Journal Papers (저널논문_해부학전공)
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