Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy.
Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi University Hospital, 40138 Bologna, Italy.
Cells. 2021 Mar 1;10(3):521. doi: 10.3390/cells10030521.
The Notch family includes evolutionary conserved genes that encode for single-pass transmembrane receptors involved in stem cell maintenance, development and cell fate determination of many cell lineages. Upon activation by different ligands, and depending on the cell type, Notch signaling plays pleomorphic roles in hepatocellular carcinoma (HCC) affecting neoplastic growth, invasion capability and stem like properties. A specific knowledge of the deregulated expression of each Notch receptor and ligand, coupled with resultant phenotypic changes, is still lacking in HCC. Therefore, while interfering with Notch signaling might represent a promising therapeutic approach, the complexity of Notch/ligands interactions and the variable consequences of their modulations raises concerns when performed in undefined molecular background. The gamma-secretase inhibitors (GSIs), representing the most utilized approach for Notch inhibition in clinical trials, are characterized by important adverse effects due to the non-specific nature of GSIs themselves and to the lack of molecular criteria guiding patient selection. In this review, we briefly summarize the mechanisms involved in Notch pathway activation in HCC supporting the development of alternatives to the γ-secretase pan-inhibitor for HCC therapy.
Notch 家族包括进化上保守的基因，这些基因编码单跨膜受体，参与许多细胞谱系的干细胞维持、发育和细胞命运决定。 Notch 信号在肝癌 (HCC) 中的作用多种多样，取决于不同的配体和细胞类型，影响肿瘤生长、侵袭能力和干细胞特性。在 HCC 中， Notch 受体和配体的表达失调及其表型变化的特异性知识仍然缺乏。因此，尽管干扰 Notch 信号可能代表一种有前途的治疗方法，但 Notch/配体相互作用的复杂性及其调节的可变后果，在未定义的分子背景下进行时引起了关注。 γ-分泌酶抑制剂 (GSIs) 是临床试验中 Notch 抑制最常用的方法，由于 GSI 本身的非特异性性质和缺乏指导患者选择的分子标准，它们具有重要的不良反应。在这篇综述中，我们简要总结了 Notch 途径在 HCC 中的激活机制，为 HCC 治疗的替代 γ-分泌酶泛抑制剂提供了支持。
