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

Takuya Minagawa, Ken Yamazaki, Yohei Masugi, Hanako Tsujikawa, Hidenori Ojima, Taizo Hibi, Yuta Abe, Hiroshi Yagi, Minoru Kitago, Masahiro Shinoda, Osamu Itano, Yuko Kitagawa, Michiie Sakamoto

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalHepatology Research
DOIs
Publication statusAccepted/In press - 2019 Jan 1

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Extracellular Signal-Regulated MAP Kinases
Hepatocellular Carcinoma
Phenotype
Hepatocyte Growth Factor
Survival
Mitogen-Activated Protein Kinase Kinases
Recurrence
Parvovirus
Fibrosarcoma
alpha-Fetoproteins
Sarcoma
Phosphotransferases
Biomarkers
Immunohistochemistry
Regression Analysis
Cell Proliferation
Cell Line

Keywords

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

ASJC Scopus subject areas

  • Hepatology
  • Infectious Diseases

Cite this

Activation of extracellular signal-regulated kinase is associated with hepatocellular carcinoma with aggressive phenotypes. / Minagawa, Takuya; Yamazaki, Ken; Masugi, Yohei; Tsujikawa, Hanako; Ojima, Hidenori; Hibi, Taizo; Abe, Yuta; Yagi, Hiroshi; Kitago, Minoru; Shinoda, Masahiro; Itano, Osamu; Kitagawa, Yuko; Sakamoto, Michiie.

In: Hepatology Research, 01.01.2019.

Research output: Contribution to journalArticle

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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.",
keywords = "extracellular signal-regulated MAP kinases, hepatocellular carcinoma, keratin 19, molecular targeted therapy, tumor biomarkers",
author = "Takuya Minagawa and Ken Yamazaki and Yohei Masugi and Hanako Tsujikawa and Hidenori Ojima and Taizo Hibi and Yuta Abe and Hiroshi Yagi and Minoru Kitago and Masahiro Shinoda and Osamu Itano and Yuko Kitagawa and Michiie Sakamoto",
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T1 - Activation of extracellular signal-regulated kinase is associated with hepatocellular carcinoma with aggressive phenotypes

AU - Minagawa, Takuya

AU - Yamazaki, Ken

AU - Masugi, Yohei

AU - Tsujikawa, Hanako

AU - Ojima, Hidenori

AU - Hibi, Taizo

AU - Abe, Yuta

AU - Yagi, Hiroshi

AU - Kitago, Minoru

AU - Shinoda, Masahiro

AU - Itano, Osamu

AU - Kitagawa, Yuko

AU - Sakamoto, Michiie

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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