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1.
Introduction
Hepatocellular carcinoma (HCC), is the fifth most common tumor worldwide and has a poor prognosis. Its occurrence has been on the increase in recent years. The estimated incidence of new cases is approximately 500,000–1,000,000 annually, causing 600,000 mortalities globally per year (1). Surgical resection and liver transplantation are the primary methods of treatment for HCC patients, but can only be applied to 15% of patients (2,3). Previous studies have demonstrated that the Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) signaling pathway is important in the occurrence and development of HCC (3). This review focused on the association between the Ras/Raf/MEK/ERK signaling pathway and HCC.
2.Mechanism of Ras/Raf/MEK/ERK cascade reaction
Mitogen-activated protein kinase (MAPK) is a serine/threonine protein kinase that is widely present in eukaryotic cells. Previous studies found four different MAPKs: i) ERK; ii) c-Jun N-terminal kinase (JNK); iii) ERK5; and iv) p38 MAPK (p38) (4). ERK cascade reaction can be activated by various stimuli, such as receptor tyrosine kinase (RTK) and G protein-coupled receptors. After activation it can regulate the proliferation, differentiation and apoptosis (5).
Ras/Raf/MEK/ERK cascade reaction is an important signaling pathway in MAPKs. Various stimuli can activate the corresponding cell surface receptors that, in turn, activates the signal transduction pathway and produce an appropriate biological response (6). The Ras/Raf/MEK/ERK cascade reaction is the key factor in integrating the signal transduction pathway. By transmitting the signals received by the receptor, Ras/Raf/MEK/ERK cascade reaction activates transcription factors and regulates gene expression. Briefly, the process involves: i) Ras recruits and activates the protein kinase Raf; ii) Raf serine/threonine protein kinase promotes MEK1/2 (MAPK/ERK kinase) dual-specificity protein kinase and the activation of ERK1/2; and iii) activated ERK1/2 phosphorylated several substrates and regulate different transcription factors, leading to different gene expression (7).
3.The role of Ras/Raf/MEK/ERK pathway in tumor cells
Various mechanisms can activate the Ras/Raf/MEK/ERK cascade in tumor cells: i) chromosome ectopic, such as BCR-ABL; ii) cytokine mutations, such as Flt-3, Fms and Kit; and iii) overexpression of wild or mutant receptors, such as epidermal growth factor receptor (EGFR). Ras/Raf/MEK/ERK cascade plays an important role in the apoptosis process by phosphorylating various apoptosis regulating factors, such as Bad, Bim, Mcl-1, caspase-9 and the controversial Bcl-2. Ras/Raf/MEK/ERK cascade plays a variety of roles in cell cycle...