Targeting the Ras/Raf/MEK/ERK pathway in hepatocellular carcinoma

Abstract

Abstract. Although the biological basis of hepatocellular carcinoma (HCC) remains unclear, effective treatments and improvement of the survival rate remain worthwhile research goals. Abnormal protein signaling pathways contributing to uncontrolled cell proliferation, differentiation, survival and apoptosis are biomarkers of the carcinogenic process. Certain mutated components or overexpression of the rat sarcoma virus (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway are increasingly being studied in HCC carcinogenesis. The present review addresses the effect of the Ras/Raf/MEK/ERK signaling pathway on the pathogenesis of HCC, and provides an update on the preclinical and clinical development of various inhibitors targeting this core signaling pathway, which include various Ras inhibitors, Raf inhibitors and MEK inhibitors for HCC.

Capicua suppresses hepatocellular carcinoma progression by controlling the ETV4–MMP1 axis

“…These findings suggest that activation of ERK and its upstream signaling cascades might be involved in the down‐regulation of CIC protein levels. Many studies have demonstrated that the RAS/RAF/MEK/ERK signaling pathway is associated with HCC pathogenesis . Levels of total or phosphorylated ERK are often higher in HCC cells than in normal liver cells .…”

“…Many studies have demonstrated that the RAS/RAF/MEK/ ERK signaling pathway is associated with HCC pathogenesis. (46,47) Levels of total or phosphorylated ERK are often higher in HCC cells than in normal liver cells. (48,49) Moreover, it was reported that ERK is mainly found in the nucleus of HCC cells.…”

NAD(P)H Quinone Dehydrogenase 1 Ablation Inhibits Activation of the Phosphoinositide 3‐Kinase/Akt Serine/Threonine Kinase and Mitogen‐Activated Protein Kinase/Extracellular Signal‐Regulated Kinase Pathways and Blocks Metabolic Adaptation in Hepatocellular Carcinoma

“…These signaling pathways are often dysregulated and hyperactivated in HCC and promote cancer cell metabolic adaptation, proliferation, and tumor growth. (1,6,7,33,(41)(42)(43) Nqo1-KD in liver cancer cells blunted activation of both the PI3K/Akt and MAPK/ERK signaling pathways, indicating that Nqo1 functions upstream and is required for the activation of these pathways. How does Nqo1 regulate these two pathways simultaneously?…”

“…Most significantly, we discovered that Nqo1 is required for the activation of two major pro‐oncogenic signaling pathways in liver cancer cells: PI3K/Akt and MAPK/ERK. These signaling pathways are often dysregulated and hyperactivated in HCC and promote cancer cell metabolic adaptation, proliferation, and tumor growth . Nqo1‐KD in liver cancer cells blunted activation of both the PI3K/Akt and MAPK/ERK signaling pathways, indicating that Nqo1 functions upstream and is required for the activation of these pathways.…”

An ethyl acetate fraction of Artemisia capillaris (ACE‐63) induced apoptosis and anti‐angiogenesis via inhibition of PI3K/AKT signaling in hepatocellular carcinoma

“…To further investigate the possible target mechanism involved in the anticancer activities of ACE‐63, we used a phosphokinase array. Numerous studies have indicated that the PI3K/AKT and RAF/MAPK pathways are dysregulated in a large proportion of human HCC, and this signaling was associated with aggressive tumor phenotype, poor prognosis, and inhibition of the apoptotic response in human HCC (Matter, Decaens, Andersen, & Thorgeirsson, ; Minguez, Tovar, Chiang, et al, ; Will, Qin, Toy, et al, ; Yang, ). Indeed, we observed that the PI3K/AKT and RAF/MAPK pathways were highly activated in HepG2 cells using a phosphokinase array.…”