Background: Since the biological function of c-Jun N-terminal kinase (JNK) in gastric cancer remains unclear, we\ninvestigated the clinical significance of JNK activation and its association with FOXO1 activation.\nMethods: Immunohistochemical tissue array analysis of 483 human gastric cancer specimens was performed, and\nthe results of the immunostaining were quantified. The correlation between JNK activation (nuclear staining for\npJNK) and clinicopathological features, the proliferation index, prognosis or FOXO1 inactivation (cytoplasmic\nstaining for pFOXO1) was analyzed. The SNU-638 gastric cancer cell line was used for in vitro analysis.\nResults: Nuclear staining of pJNK was found in 38 % of the gastric carcinomas and was higher in the early stages\nof pTNM (P < 0.001). pJNK staining negatively correlated with lymphatic invasion (P = 0.034) and positively correlated\nwith intestinal type by Lauren�s classification (P = 0.037), Ki-67-labeling index (P < 0.001), cyclin D1 (P = 0.045), cyclin\nE (P < 0.001) and pFOXO1 (P < 0.001). JNK activation correlated with a longer patients survival (P =0.008) and\npatients with a JNK-active and FOXO1-inactive tumor had a higher survival rate than the remainder of the\npopulation (P = 0.004). In vitro analysis showed that JNK inhibition by SP600125 in SNU-638 cells decreased cyclin\nD1 protein expression and increased FOXO1 activation. Further, JNK inhibition markedly suppressed colony\nformation, which was partially restored by FOXO1 shRNA expression.\nConclusions: Our results indicate that JNK activation may serve as a valuable prognostic factor in gastric cancer,\nand that it is implicated in gastric tumorigenesis, at least in part, through FOXO1 inhibition
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