The Ras/Raf/MEK/ERK signaling pathway and its role in the occurrence and development of HCC

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common tumor worldwide and has a very poor prognosis. Its occurrence has been on the increase in recent years. Surgical resection and liver transplantation are the primary methods of treatment for HCC patients, but can only be applied to 15% of patients. The median survival time of unresectable or metastasizing HCC patients is only a few months. Existing systemic treatment methods are not effective for advanced HCC patients and a new method of treatment is needed for these patients. It has been established that the HCC occurs in multiple stages, however, the pathogenesis at a molecular level is not clear and many key factors are yet to be determined. In the past 30 years, it has become evident that the Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) signaling pathway plays a significant role in the occurrence and development of HCC. This review focused on the association between the Ras/Raf/MEK/ERK signaling pathway and HCC.

RETRACTED ARTICLE: Chemical inhibition reveals differential requirements of signaling pathways in krasV12- and Myc-induced liver tumors in transgenic zebrafish

“…In this study, two oncogene transgenic lines, Tg(fabp10:rtTA2s-M2; TRE2:EGFP-kras V12 ) (gz32Tg) and Tg(fabp10:TA; TRE:myc; CK:RFP ) (gz26Tg) in a Tet-On system to control the hepatocyte-specific expression of oncogenic kras V12 or Myc respectively1214, were employed and they are termed as kras +, and Myc + respectively in this report. kras V12 - or Myc- induced HCC have been found as an elevated MAPK/ERK and MYC signaling in approximately 30% and 70% of HCC patients respectively1718. Transcriptomic analyses of our transgenic zebrafish models indicated that kras V12 - and Myc -induced zebrafish HCC shared conserved gene expression signatures with 23.5% and 23.8% of human HCC, respectively19.…”

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

“…ERK is activated by phosphorylation of its tyrosine residues, allowing it to migrate into the nucleus and activate transcription factors that regulate critical cellular biological processes including the cell cycle, apoptosis, and cell differentiation . In the present study, the activation of ERK in HCC tissues was immunohistochemically evaluated based on nuclear expression levels of ERK within tumor cells.…”

“…Once activated by phosphorylation, phosphorylated ERK (pERK) translocates into the nucleus where it induces genes involved in cell proliferation and anti‐apoptosis. pERK thereby promotes tumorigenesis and tumor growth in various types of cancer cells . Experimental evidence also shows that constitutive activation of cellular ERK1/2 is important for the proliferation and invasion of human HCC cells .…”

Tumor Microenvironment, a Paradigm in Hepatocellular Carcinoma Progression and Therapy

“…Extracellular signals are usually growth factors (including EGF, FGF and PDGF), hormones or differentiation inducers [20]. The cascade begins with binding of a ligand to the surface receptor tyrosine kinase (RTK).…”