MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma.

Hyuk Moon,Simon Weonsang Ro

doi:10.3390/cancers13123026

Hyuk Moon, Simon Weonsang Ro

Open Access

https://doi.org/10.3390/cancers13123026

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Journal: Cancers	Publication Date: Jun 17, 2021
Citations: 117	License type: CC BY 4.0

Affiliation: Kyung Hee University

Abstract

Simple SummaryThe mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway is frequently activated in liver cancer, which is one of the most lethal cancers in humans. In addition to genetic mutation leading to persistent activation of effector molecules in the MAPK/ERK signaling cascade, there are alternative means by which the MAPK/ERK signaling pathway is activated in cancer. In this review, we will introduce the diverse modulators regulating the MAPK/ERK signaling pathway and consider the possibility of targeting the effectors and regulators in order to suppress the pro-tumorigenic MAPK/ERK signaling pathway, especially in liver cancer.Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence is increasing steadily. Recently, the MAPK/ERK signaling pathway in HCC has gained renewed attention from basic and clinical researchers. The MAPK/ERK signaling pathway is activated in more than 50% of human HCC cases; however, activating mutations in RAS and RAF genes are rarely found in HCC, which are major genetic events leading to the activation of the MAPK/ERK signaling pathway in other cancers. This suggests that there is an alternative mechanism behind the activation of the signaling pathway in HCC. Here, we will review recent advances in understanding the cellular and molecular mechanisms involved in the activation of the MAPK/ERK signaling pathway and discuss potential therapeutic strategies targeting the signaling pathway in the context of HCC.

Highlights

The World Health Organization reported that the number of deaths due to liver cancer reached 830,000 in 2020 and ranked it the third most lethal cancer
A precise understanding of the molecular pathway toward carcinogenesis will allow the patient response to targeted therapies to be predicted, which can have a substantial impact on clinical decision-making
Among the various oncogenic signals, MAPK/ERK signaling is activated in approximately 50% of earlystage Hepatocellular carcinoma (HCC) patients and in the majority of patients with advanced HCC [14]

Summary

Introduction

The World Health Organization reported that the number of deaths due to liver cancer reached 830,000 in 2020 and ranked it the third most lethal cancer. Recent advances in molecular pathogenesis studies have defined various molecular signaling pathways that are critical to tumor initiation, progression, and metastasis in HCC They include the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), phosphatidylinositol. Receptors that can activate the MAPK/ERK signaling pathway include the epidermal growth factor receptor (EGFR), the fibroblast growth factor receptor (FGFR), the platelet-derived growth factor receptor (PDGFR), the vascular endothelial growth factor receptor (VEGFR), the insulin-like growth factor receptor (IGFR), the hepatocyte growth factor receptor (HGFR; known as c-Met), and the stem cell growth factor receptor (SCFR; known as KIT) [4] Ligand binding to these receptors leads to the activation of cytoplasmic tyrosine kinases (TKs), which phosphorylate tyrosine residues at the cytoplasmic tails. In most human HCCs, activation of the MAPK/ERK signaling pathway is observed in the presence of the wild-type genesMechanisms of RAS, RAF, andthe downstream components [20]

Alternative Mechanisms

Findings

Perspectives and Conclusions