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Review
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Mitogen-Activated Protein Kinases (MAPKs) and Cholangiocarcinoma: The Missing Link

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Review

Mitogen-Activated Protein Kinases (MAPKs) and Cholangiocarcinoma: The Missing Link

Chaobo Chen et al. Cells.

Abstract

In recent years, the incidence of both liver and biliary tract cancer has increased. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common types of hepatic malignancies. Whereas HCC is the fifth most common malignant tumor in Western countries, the prevalence of CCA has taken an alarming increase from 0.3 to 2.1 cases per 100,000 people. The lack of specific biomarkers makes diagnosis very difficult in the early stages of this fatal cancer. Thus, the prognosis of CCA is dismal and surgery is the only effective treatment, whilst recurrence after resection is common. Even though chemotherapy and radiotherapy may prolong survival in patients with CCA, the 5-year survival rate is still very low-a significant global problem in clinical diagnosis and therapy. The mitogen-activated protein kinase (MAPK) pathway plays an important role in signal transduction by converting extracellular stimuli into a wide range of cellular responses including inflammatory response, stress response, differentiation, survival, and tumorigenesis. Dysregulation of the MAPK cascade involves key signaling components and phosphorylation events that play an important role in tumorigenesis. In this review, we discuss the pathophysiological role of MAPK, current therapeutic options, and the current situation of MAPK-targeted therapies in CCA.

Keywords: cancer-associated fibroblasts (CAFs); cholangiocarcinoma (CCA); cholangiocytes; epithelial to mesenchymal transition (EMT); hepatocytes; mitogen-activated protein kinases (MAPK).

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
MAPK signaling pathway: ERK1/2, JNK1/2, and p38. Activation of ERK begins with the phosphorylation of MEK1/2, followed by activation of tyrosine and threonine residues. Activated RAF binds to and phosphorylates the kinases MEK1/2 as well as activated RAS. The RAS activation occurs at the plasma membrane and is mediated by son of sevenless (SOS), a guanine nucleotide exchange factor (GEF). Signals from cell surface receptors are passed through RAS-GTP to the RAF(A/B/C) and/or PI3K, the latter then activates the PI3K/AKT signaling pathway. RAF also receives signals from the activated ligands’ G protein-coupled receptors (GPCRs). Activated RAF is capable of phosphorylating MEK, and subsequently, the ERK/MAPK signaling pathway. After activation of ERK, ERK1/2 moves to the cytoplasm and nucleus to phosphorylate other proteins. These proteins are responsible for cell regulation, growth, differentiation, and mitosis. JNK is activated in response to cytokines, growth factors, pathogens, stress, etc., and is associated with the transformation of oncogenes and growth factor pathways. Activation of JNK requires dual phosphorylation tyrosine and threonine, the MAP2Ks that catalyze this reaction are known as MKK4 (also known as SEK1) and MKK7. MKK4/7 are phosphorylated and activated by MAP3Ks, TAK1, and ASK1. Tumor necrosis factor (TNF) receptor signaling and ROS might be the major upstream mediators of JNK activation. Abnormal activation of the JNK signaling pathway is linked to the development of cancer, diabetes, inflammatory diseases, and neurodegenerative diseases. The activation of p38 is mediated by upstream kinases, MAP kinase 3 (MKK3), and MAP kinase 6 (MKK6). MKK3/6 are activated by MAP3Ks such as ASK1 and TAK1, which respond to various extracellular stimuli including osmotic shock, inflammatory cytokines, lipopolysaccharides (LPS), UV light, and growth factors.
Figure 2
Figure 2
The hierarchy of cholangiocarcinoma stem cells. Hepatic stem cells grow and differentiate into hepatic progenitor cells and mature hepatocytes (hepatocytes and cholangiocytes). CCA stem cells are produced by genetic abnormalities of hepatic stem cells, hepatic progenitor cells, or CCA cells, which then grow and differentiate to CCA cells. The NOTCH signaling pathway might induce mature hepatocytes to develop into CCA (in mice). Cholangiocytes can also transform into CCA cells through ROS and inflammation-induced genetic and epigenetic variation.
Figure 3
Figure 3
Schematic diagram of the EMT and MET progress in the CCA program. Healthy epithelial cells have a tight junction between the apical-basal polarity and interaction with the basement membrane. These cells express markers of epithelial cell lines such as the adhesive connexin E-cadherin. After stimulation, epithelial cells undergo EMT progression (EMT-induced EMT-TFs results in downregulation), lose cell to cell and cell–ECM connections, lose epithelial markers, express interstitial markers (N-CADHERIN, β-CATENIN), obtain front–back polarity, and enhance migration. During tissue repair or inflammation regression, MET is initiated, and the cells reacquire their epithelial phenotype. Cytokines (TGF-β, TNF-α, and IL-6), tyrosine kinase receptors (EGF, HB-EGF), and their receptors (TGFβR, EGFR, TNFR, and ILR) involved in developmental processes play a key role in the induction of the EMT program by activating intracellular signaling pathways (including MAPKs, IL-6/STAT3, NOTCH/JAG1, and WNT), involved in CCA progression and metastasis.

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