Downregulation of YAP inhibits proliferation, invasion and increases cisplatin sensitivity in human hepatocellular carcinoma cells

Abstract

Abstract. Yes-associated protein (YAP) serves an essential role in tumorigenesis. However, the potential role and the molecular mechanism underlying the effect of YAP on hepatocellular carcinoma (HCC) cells have not been elucidated. In the current study, it was revealed that YAP expression was increased significantly in HCC cancer tissues and its overexpression was associated with tumor differentiation. The silencing of YAP by small interferring RNA led to the inhibition of HCC cell growth, which was associated with the promotion of apoptosis. The silencing of YAP also decreased the invasive potential of HCC cells and the activity of the phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling pathway. Furthermore, silencing of YAP increased the chemosensitivity of HCC cells to cisplatin (CDDP) through inactivation of the PI3K/AKT signaling pathway. In vivo studies using PDTX model suggested a promotive role for YAP in the growth of HCC and knockdown of YAP increased the anti-tumor activity of CDDP. Taken together, these results revealed that YAP is overexpressed in HCC, and promotes proliferation, invasion and drug resistance of HCC cells. Inhibition of YAP, alone or in combination with traditional chemotherapy, may effectively combat HCC.

YAP/TAZ Signaling and Resistance to Cancer Therapy

“…Hippo signaling was linked to resistance to DNA damaging agents in numerous studies [77,82,83,88,104,108,110,[117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133][134]. While YAP/TAZ confer resistance to DNA damaging agents through a similar set of transcriptional targets as to other chemo drugs [66,77,82,89,92,118,119,127,128,135,136], distinct upstream mechanisms appear to underlie YAP/TAZ activation. Three studies reported downregulation of MST1 following doxorubicin or cisplatin treatment either due to Hsp70-mediated degradation or translation blockade caused by miR-149-5p, which also targets the scaffolding protein SAV1 [110,123,129].…”

The Ambivalent Function of YAP in Apoptosis and Cancer

“…In addition, several studies proved that the YAP gene is amplified in cervical, ovarian, and fallopian tube cancers [30,31]. Moreover, silencing the expression of YAP gene by shRNA [18,32,33] or siRNA [15,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48] could induce apoptosis (Table 1). Consistent with this finding, overexpressing YAP significantly inhibited apoptosis of liver [38,49,50], pancreas [39], colorectal cancer [15,51], and lung cancer cells [52].…”

LGR5 promotes invasion and migration by regulating YAP activity in hypopharyngeal squamous cell carcinoma cells

“…Therefore, we believe that the in ammatory microenvironment causes high LGR5 expression, which will inhibit the phosphorylation of YAP, resulting in markedly increased YAP-TEAD binding, high expression of EMT-related proteins, and enhanced invasion and metastasis ability of tumor cells. Low expression of the YAP gene by shRNA [31,32] and interference of the formation of the YAP-TEAD complex by VP [33,34] have been reported to induce apoptosis. In this study, VP was also used to phosphorylate YAP, but many cells died after siRNA inhibition of LGR5 expression; however, few of the cells died in the LGR5 overexpression group (Figure 6A-f,B-f).…”