Transcatheter arterial chemoembolization combined with Hippo/YAP inhibition significantly improve the survival of rats with transplanted hepatocellular carcinoma

Yi Quan,Jundi Liang,Zhi Li,Kangshun Zhu,Kangshun Zhu

doi:10.1186/s12944-021-01486-w

Abstract

BackgroundThis study aimed to explore the effect of inhibiting the Hippo/Yes-associated protein (YAP) signaling pathway on the outcomes of transcatheter arterial chemoembolization (TACE) in treating transplanted hepatocellular carcinoma (HCC).MethodsA transplanted HCC rat model was established. Then, rats were randomly divided into four groups: Sham, TACE, verteporfin (inhibitor of Hippo/YAP), and TACE+verteporfin. Lent-OE-YAP was transfected into rats to overexpress YAP in vivo. After treatments, morphological changes, tumor weight, and the overall survival of rats in different groups were analyzed. Real-time PCR, immunohistochemistry staining, and Western blotting were used to determine the expression of factors related to the Hippo/YAP signaling pathway.ResultsTumor weight and tissue lesions in the TACE and verteporfin groups were significantly reduced compared with the Sham group. Verteporfin significantly decreased tumor weight after TACE treatment. In addition, verteporfin significantly improved the overall survival of rats with transplanted HCC after TACE treatment. Compared with the Sham group, both TACE and verteporfin groups exhibited significantly decreased expression of macrophage-stimulating (MST)1, MST2, long-acting thyroid stimulator 1, transcriptional co-activator with PDZ-binding motif (TAZ), Yes-associated protein (YAP), TEA domain transcription factor (TEAD)1, TEAD2, TEAD3, and TEAD4. TACE plus verteporfin significantly enhanced the downregulation of effectors in the Hippo/YAP signaling pathway and decreased tumor size, while the overexpression of YAP exerted opposite effects.ConclusionThe inhibition of the Hippo/YAP signaling pathway via verteporfin significantly improved the outcomes of TACE in treating transplanted HCC.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and approximate 70% of the cases occur in Asian countries [1]
Morphological analysis showed that tissue injuries in the transcatheter arterial chemoembolization (TACE), verteporfin, and TACE+verteporfin groups were alleviated compared with the Sham group and the symptoms in the TACE+verteporfin group was significantly better than those in the TACE group (Fig. 1A)
These results showed that TACE combined verteporfin significantly suppressed the development of transplanted hepatocellular carcinoma (HCC)

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and approximate 70% of the cases occur in Asian countries [1]. During HBV and HCV infection, environmental and genetic factors may promote the development of HCC [6, 7]. The Hippo/Yes-associated protein (YAP) signaling pathway is commonly involved in the regulation of cell proliferation, differentiation, and metabolism [8, 9]. Zhang et al showed that transforming growth factor beta 1 inhibited the proliferation of HCC tumor cells via targeting the Hippo signaling [13]. The Hippo/YAP/TAZ signaling pathway regulates the pathogenesis of hepatic fibrosis to promote the formation of HCC [16]. This study aimed to explore the effect of inhibiting the Hippo/Yes-associated protein (YAP) signaling pathway on the outcomes of transcatheter arterial chemoembolization (TACE) in treating transplanted hepatocellular carcinoma (HCC)

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