The role of YAP1 in liver cancer stem cells: proven and potential mechanisms

Abstract

YAP1 (Yes-associated protein 1) is one of the principal factors that mediates oncogenesis by acting as a driver of gene expression. It has been confirmed to play an important role in organ volume control, stem cell function, tissue regeneration, tumorigenesis and tumor metastasis. Recent research findings show that YAP1 is correlated with the stemness of liver cancer stem cells, and liver cancer stem cells are closely associated with YAP1-induced tumor initiation and progression. This article reviews the advancements made in research on the mechanisms by which YAP1 promotes liver cancer stem cells and discusses some potential mechanisms that require further study.

Fig. 1

Schematic representation depicting the structure of YAP1 gene and protein. A YAP gene is located on 11q22.1. There are nine known isoforms of YAP, of which YAP1 isoform 1 (NM_001130145.3) is the most common transcript variant and contains 9 exons. B Schematic structure of human YAP1 proteins. TBD, TEAD-binding domain; WW, W-containing domain; CC, coiled-coil domain; TAD, transactivation domain

Fig. 2

Signaling pathways involved in YAP1-related LCSCs. Several signaling pathways listed above have been found to be involved in the promotion of YAP1-induced LCSCs. Among them, the Notch pathway and IGF pathway are affected by YAP1 in turn by positive feedback loops. The interactions between these pathways also play roles in YAP1-induced LCSCs, and the Wnt pathway suppresses the YAP1-Notch positive feedback loop and upstream components in the Hippo cascade

Fig. 3

Physical and cellular factors in the microenvironment involved in YAP1-induced promotion of LCSCs. Physical factors, including hypoxic conditions and a high cell density, have been found to promote liver cancer stemness by activating YAP1. TAM recruitment by YAP1 overexpression also leads to the promotion of LCSCs. For CAFs, although they are directly related to the progression of LCSCs and YAP1 overexpression, further studies are needed to determine whether there is a causal relationship between the three. In addition, whether there are other mechanisms of mechanical stress-mediated YAP1-induced promotion of LCSCs remains to be explored