Expression of phosphorylated extracellular signal-regulated kinase at the invasive front of hepatic colorectal metastasis

Raf-1 kinase inhibitory protein (RKIP), an endogenous inhibitor of the extracellular signal-regulated kinase (ERK) pathway, suppresses metastasis in a number of cancer types, including colorectal carcinoma (CRC); thus, RKIP downregulation significantly contributes to CRC invasiveness and metastatic potential. However, our previous study demonstrated that RKIP-positive tumors in CRC patients are predictive of hepatic colorectal metastases (HCMs). Based on the previous finding that the ERK pathway can be activated independently of RKIP, we hypothesized that RKIP-expressing HCMs may express significant levels of phosphorylated ERK (pERK). Thus, the present study evaluated the expression of RKIP and pERK in 68 HCM tissue samples using immunohistochemistry. RKIP expression was positive in 22 (32.4%) of the 68 samples, seven (31.8%) of which exhibited nuclear pERK immunoreactivity exclusively at the invasive tumor front. Furthermore, pERK expression at the invasive front was significantly associated with recurrent HCM following hepatic resection, and pERK expression observed at the invasive front of RKIP-expressing HCMs indicated that the activation of the ERK pathway may also be involved in the invasive process of these tumors, despite the presence of RKIP. A strong association between pERK expression and the presence of recurrent HCM may indicate that the ERK pathway is important in the metastatic recurrence of RKIP-positive HCM.