Aim
Sorafenib inhibits multiple kinase signaling pathways, including the rat sarcoma virus (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogenâactivated protein kinase kinase (MEK)/extracellular signalâregulated kinase (ERK) pathway, and is a promising therapy for hepatocellular carcinoma (HCC). However, the role of ERK activation in HCC remains unclear. This study was designed to investigate the potential link between ERK activation and aggressive HCC phenotypes.
Methods
We evaluated nuclear ERK expression by immunohistochemistry in 154 resected HCC nodules from 136 patients. We then investigated the associations of ERK expression with the clinicopathological characteristics of HCC, câMET expression, and the molecular subclass biomarkers Kiâ67, keratin 19 (KRT19, CK19, or K19), and salâlike protein 4. Multivariate Cox regression analysis was carried out to determine independent prognostic factors for overall survival and recurrenceâfree survival. The effects of ERK activation by hepatocyte growth factor (HGF) on eight HCC cell lines were further examined.
Results
Highâlevel nuclear expression of ERK was observed in 20 (13%) of 154 nodules and was significantly associated with higher serum alphaâfetoprotein levels (Pâ=â0.034), poorer differentiation (Pâ=â0.003), a higher Kiâ67 index (Pâ<â0.001), highâlevel expression of câMET (Pâ=â0.008), KRT19 (Pâ=â0.002), or salâlike protein 4 (Pâ<â0.001), and shorter overall survival (multivariate hazard ratio 3.448; Pâ=â0.028) and recurrenceâfree survival (multivariate hazard ratio 2.755; Pâ=â0.004). HCC cells treated with hepatocyte growth factor showed enhanced cell proliferation together with ERK activation and upregulated KRT19 expression, both of which were inhibited by sorafenib.
Conclusions
Highâlevel ERK activation is associated with a KRT19âpositive highly proliferative subtype of HCC with a dismal prognosis. These findings support the key role of the hepatocyte growth factor/câMET/ERK axis in HCC progression.