Objective: As an activator of JNK and p38, phosphorylated MKK4 is considered to be associated with tumor progression and prognosis. This study was to examine the expression of pMKK4 and evaluate its prognostic significance in colorectal carcinoma.
Methods: A total of 343 cases of colorectal cancer were followed up to analyze the associations between the expression of pMKK4 and various clinicopathological factors. The expression of Serine-257/Threonine-261 pMKK4 was detected immunohistochemically by tissue microarray.
Results: The staining of pMKK4 was present in cytoplasm of colorectal carcinoma. And the expression of pMKK4 was correlated with invasion depth (P = 0.003), differentiation (P = 0.018), lymph node metastasis (P < 0.001), metastasis (P < 0.001), hepatic metastasis (P = 0.039) and TNM stage (P < 0.001). The patients with strong pMKK4 staining had a better overall survival than those with lowered levels (Log rank = 4.531, P = 0.033). Univariate analysis indicated that the expression of pMKK4 was correlated with either overall survival (HR = 0.785, P = 0.035) or relapse-free survival (HR = 0.788, P = 0.044). In multivariate analysis, there was no prognostic significance of pMKK4 after adjusting for invasion depth, differentiation, lymph node metastasis, metastasis, liver metastasis and TNM stage.
Conclusions: The down-regulation of S257/T261 pMKK4 is associated with more advanced stages and it plays an important role in tumor progression. A high-level expression of pMKK4 indicates favorable clinical outcomes, but it is not an independent predictor.