c-Jun N-terminal kinase activation has a prognostic implication and is negatively associated with FOXO1 activation in gastric cancer.
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.
Department of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
Youngsun
Y
Choi
Department of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
Jinju
J
Park
Department of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
Yiseul
Y
Choi
Departments of Anatomy, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
Young San
YS
Ko
Departments of Anatomy, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
Da-Ae
DA
Yu
Department of Pathology, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
Younghoon
Y
Kim
Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea.
Jung-Soo
JS
Pyo
Department of Pathology, Jeju National University Hospital, Jeju, 690-767, South Korea.
Bo Gun
BG
Jang
Department of Pathology, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
Min A
MA
Kim
Department of Pathology, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
Woo Ho
WH
Kim
Department of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, South Korea. dslanat@snu.ac.kr.|Departments of Anatomy, Seoul National University College of Medicine, Seoul, 110-799, South Korea. dslanat@snu.ac.kr.|Ischemic/Hypoxic Disease Institute Medical Research Center, Seoul National University College of Medicine, Seoul, 110-799, South Korea. dslanat@snu.ac.kr.
Byung Lan
BL
Lee
D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate
D014408:Biomarkers, Tumor; D000071161:Forkhead Box Protein O1; D048031:JNK Mitogen-Activated Protein Kinases
Clinical significance; FOXO1; Gastric cancer; JNK; Proliferation