Abstract
Eye absent homolog 4 (EYA4) has been demonstrated to be down‐regulated in hepatocellular carcinoma (HCC), but its biological function and the mechanism in HCC angiogenesis and metastasis remain largely unknown. Herein, we showed that EYA4 expression was frequently low in HCC tissue samples compared with matched adjacent non‐tumourous tissues. In the analysis of 302 HCC specimens, we revealed that decreased expression of EYA4 correlated with tumour differentiation status. Univariate and multivariate analyses identified EYA4 as an independent risk factor for recurrence‐free survival (RFS) and overall survival (OS) among the 302 patients. Functional assays showed that forced expression of EYA4 suppressed HCC cell migration, invasion and capillary tube formation of endothelial cells in vitro, as well as in vivo tumour angiogenesis and metastasis in a mouse model. Furthermore, mechanism study exhibited that EYA4 could inhibit HCC angiogenesis and metastasis by inhibiting c‐JUN/VEGFA pathway. Together, we provide proof that EYA4 is a novel tumour suppressor in HCC and a new prognostic biomarker and therapeutic target in HCC.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most fatal cancer and the third most common cause of cancer‐related deaths in the world, and the number of newly diagnosed cases continues to grow.[1]
Our experiments showed that forced expression of Eye absent homolog 4 (EYA4) suppressed HCC angiogenesis and metastasis via inhibiting c‐JUN/VEGFA path‐ way
We revealed that EYA4 was significantly down‐regu‐ lated in clinical HCC samples and the down‐regulation of EYA4 was associated with poor recurrence‐free survival (RFS) and overall survival (OS) among patients with HCC
Summary
Hepatocellular carcinoma (HCC) is the fifth most fatal cancer and the third most common cause of cancer‐related deaths in the world, and the number of newly diagnosed cases continues to grow.[1]. EYA4 is a promising tumour suppressor gene because it controls the up‐regulation of DKK1 and blocks the Wnt signalling pathway in colorectal cancer.[10] Likewise, lower levels of EYA4 expression are observed in HCC tissues and are an independent predictor of both shorter disease‐free survival (DFS) and overall survival (OS).[11] And more recently, EYA4 was shown to inhibit HCC cell growth and in‐ vasion by suppressing NF‐κB‐dependent RAP1 transactivation.[12] the precise role that EYA4 plays in HCC angiogenesis and metastasis remain largely unknown. Our experiments showed that forced expression of EYA4 suppressed HCC angiogenesis and metastasis via inhibiting c‐JUN/VEGFA path‐ way. These results provide a clearer understanding of the involvement of EYA4 in HCC progression and a potential thera‐ peutic target in HCC
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