The Carcinogenic Role of the Notch Signaling Pathway in the Development of Hepatocellular Carcinoma

Abstract

The Notch signaling pathway, known to be a highly conserved signaling pathway in embryonic development and adult tissue homeostasis, participates in cell fate decisions that include cellular differentiation, cell survival and cell death. However, other studies have shown that aberrant in Notch signaling is pro-tumorigenic, particularly in hepatocellular carcinoma (HCC). HCC is one of the most common malignant tumors in the world and has a high mortality rate. Growing evidence supports that Notch signaling plays a critical role in the development of HCC by regulating the tumor microenvironment, tumorigenesis, progression, angiogenesis, invasion and metastasis. Accordingly, overexpression of Notch is closely associated with poor prognosis in HCC. In this review, we focus on the pro-tumorigenic role of Notch signaling in HCC, summarize the current knowledge of Notch signaling and its role in HCC development, and outline the therapeutic potential of targeting Notch signaling in HCC.

Keywords: Notch signaling pathway; carcinogenesis; hepatocellular carcinoma; therapeutics.

Figure 1

Canonical Notch signaling pathway. Notch signaling is initiated by cell-to-cell contact allowing for interaction of Notch receptors and ligands. There are 3 major cleavage processes: S1 cleavage occurs in the trans-Golgi when a Furin-like convertase cleaves Notch receptors to produce heterodimeric receptors. Then, Notch receptors are transported to the cell surface of the receiving cell. When the extracellular domain of Notch receptor combines with its ligand, the Notch receptor is cleaved by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), ADAM17 or TNF-α-converting enzyme (TACE) metalloprotease in S2 cleavage site, releasing an extracellular fragment. Afterwards, the remnant receptor is cleaved again by the γ-secretase complex in its transmembrane domain at S3 cleavage site, releasing the active intracellular domain of Notch (ICN). ICN translocates to the nucleus of the receiving cell and binds to the DNA-binding transcription factor CSL (CBF1/RBPJ-kappa/Su (H)/Lag1). Thereafter, ICN competitively replaces the co-repressor (CoR) followed by the recruitment of the co-activator mastermind-like 1(MAML) to form a complex, initiating the transcription of CSL-dependent Notch target genes.