Clinicopathological and prognostic significance of MKK4 and MKK7 in resectable pancreatic ductal adenocarcinoma

Abstract

Mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7) were shown to regulate biological behavior in many malignancies. In pancreatic ductal adenocarcinoma (PDAC), it remains controversial whether MKK4 and MKK7 have pro-oncogenic or tumor-suppressive activities. Furthermore, their clinicopathological and prognostic implications are unknown. In the present study, we detected MKK4 and MKK7 expressions in the nucleus and cytoplasm of resected PDAC tissues from 321 patients by tissue microarray-based immunohistochemistry. Cytoplasmic MKK4 and MKK7 expressions were significantly downregulated, whereas nuclear MKK4 expression was significantly upregulated in tumor tissues compared with nontumor tissues. Tumor cytoplasmic MKK4 and MKK7 expressions were significantly negatively associated with histologic grade. Cytoplasmic MKK4 expression was also negatively correlated with CA19-9 level. By univariate analysis, high cytoplasmic MKK4 expression was significantly associated with longer cancer-specific survival (hazard ratio [HR], 0.705; 95% confidence interval, 0.510-0.974), with a similar trend observed for MKK7 expression. High MKK4 and MKK7 messenger RNA expressions were significantly associated with longer overall survival in The Cancer Genome Atlas database. Although MKK4 expression was not significant in a multivariate Cox regression analysis, combination of MKK4/MKK7 and pN stage was identified as an independent prognostic indicator and had the lowest HR (HR, 0.308; 95% confidence interval, 0.126-0.752). Furthermore, combined analysis of MKK4 and MKK7 greatly increased the prognostic predictive power. In addition, downregulation of MKK4 or MKK7 increased proliferation of pancreatic cancer cells in vitro. In conclusion, high MKK4 expression and its combination with high MKK7 expression both predicted favorable prognosis in resectable PDAC.