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Activation of extracellular signal-regulated kinase is associated with hepatocellular carcinoma with aggressive

Takuya Minagawa^1,2, Ken Yamazaki¹, Yohei Masugi¹

¹Department of Pathology, Keio University School of Medicine, Tokyo, Japan.

Hepatology Research : the Official Journal of the Japan Society of Hepatology

|November 9, 2019

Abstract

Aim:

Sorafenib inhibits multiple kinase signaling pathways, including the rat sarcoma virus (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated 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, c-MET expression, and the molecular subclass biomarkers Ki-67, keratin 19 (KRT19, CK19, or K19), and sal-like protein 4. Multivariate Cox regression analysis was carried out to determine independent prognostic factors for overall survival and recurrence-free survival. The effects of ERK activation by hepatocyte growth factor (HGF) on eight HCC cell lines were further examined.

Results:

High-level nuclear expression of ERK was observed in 20 (13%) of 154 nodules and was significantly associated with higher serum alpha-fetoprotein levels (P = 0.034), poorer differentiation (P = 0.003), a higher Ki-67 index (P < 0.001), high-level expression of c-MET (P = 0.008), KRT19 (P = 0.002), or sal-like protein 4 (P < 0.001), and shorter overall survival (multivariate hazard ratio 3.448; P = 0.028) and recurrence-free survival (multivariate hazard ratio 2.755; P = 0.004). 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:

High-level ERK activation is associated with a KRT19-positive highly proliferative subtype of HCC with a dismal prognosis. These findings support the key role of the hepatocyte growth factor/c-MET/ERK axis in HCC progression.

Insights

High extracellular signal-regulated kinase (ERK) activation in hepatocellular carcinoma (HCC) correlates with aggressive disease and poor prognosis. Targeting the hepatocyte growth factor/c-MET/ERK pathway may offer new therapeutic strategies for HCC.

Area of Science:

Oncology
Molecular Biology
Cancer Research

Background:

Sorafenib, a kinase inhibitor, shows promise for hepatocellular carcinoma (HCC) by targeting pathways like Ras/Raf/MEK/ERK.
The specific role of ERK activation in aggressive HCC phenotypes remains unclear.

Purpose of the Study:

To investigate the association between ERK activation and aggressive HCC phenotypes.
To explore the link between ERK activation, clinicopathological characteristics, and patient survival.

Main Methods:

Immunohistochemistry was used to assess nuclear ERK expression in 154 HCC nodules.
Associations with clinicopathological features, c-MET, Ki-67, KRT19, and sal-like protein 4 were analyzed.
Multivariate Cox regression determined prognostic factors, and HCC cell lines were used to examine HGF effects on ERK activation.

Main Results:

High nuclear ERK expression (13%) was linked to higher AFP, poorer differentiation, increased Ki-67, and elevated c-MET, KRT19, and sal-like protein 4.
High ERK expression correlated with significantly shorter overall and recurrence-free survival.
Hepatocyte growth factor (HGF) induced HCC cell proliferation, ERK activation, and KRT19 upregulation, effects inhibited by sorafenib.

Conclusions:

Elevated ERK activation signifies a KRT19-positive, highly proliferative HCC subtype with a poor prognosis.
The hepatocyte growth factor/c-MET/ERK axis plays a crucial role in HCC progression.
These findings highlight potential therapeutic targets for advanced HCC.

Read full analysis

Keywords:

extracellular signal-regulated MAP kinases hepatocellular carcinoma keratin 19 molecular targeted therapy tumor biomarkers

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