Clinicopathologic and prognostic significance of MKK4 and MKK7 in resectable pancreatic ductal adenocarcinoma.

Clinicopathologic and prognostic significance of MKK4 and MKK7 in resectable pancreatic ductal adenocarcinoma.

Hum Pathol. 2018 Dec 08;:

Authors: Lu J, Zhou L, Yang G, Liang ZY, Zhou WX, You L, Yuan D, Li BQ, Guo JC, Zhao YP

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 clinicopathologic 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 down-regulated, while nuclear MKK4 expression was significantly up-regulated in tumor tissues compared with non-tumor tissues. Tumor cytoplasmic MKK4 and MKK7 expressions were significantly negatively associated with histological 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 [95%CI]: 0.510-0.974), with a similar trend observed for MKK7 expression. High MKK4 and MKK7 mRNA expressions were significantly associated with longer overall survival in the TCGA 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%CI: 0.126-0.752). Furthermore, combined analysis of MKK4 and MKK7 greatly increased the prognostic predictive power. In addition, down-regulation 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.

PMID: 30537492 [PubMed - as supplied by publisher]

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