Abstract
BackgroundSince 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.MethodsImmunohistochemical 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.ResultsNuclear 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.ConclusionsOur 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.
Highlights
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
We evaluated the immunostaining for the active form of JNK phosphorylated at Thr183 and Tyr185 in 483 surgically resected human gastric carcinoma specimens and assessed its clinical significance
JNK activation is associated with the clinicopathological factors in gastric cancer In order to investigate the clinical significance of JNK activation in gastric cancer, the correlations between nuclear positive g h form of JNK (pJNK) staining and the clinicopathologic features in 483 gastric cancer cases were analyzed (Table 2)
Summary
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. Gastric cancer develops through the accumulation of genetic alterations, Choi et al BMC Gastroenterology (2016) 16:59 c-Jun N-terminal kinase (JNK) is a mitogen-activated protein kinase (MAPK), which regulates a wide range of cellular functions through both transcription-dependent and transcription-independent mechanisms [8]. Several in vitro studies have shown that JNK activation decreases gastric cancer cell survival [13,14,15,16,17,18]. JNK activation suppressed the apoptosis of gastric cancer cells in one study [19]. Shibata et al [20] reported that JNK increased the development of gastric tumor in mice. The role of JNK in gastric cancer remains elusive
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