Abstract
Metastasis is one of the most common reasons of hepatocellular carcinoma (HCC) death; however, the molecular mechanism underlying HCC metastasis remains incompletely defined. Here we report a new function of Zinc Finger Protein 703 (ZNF703), a member of the NET/NlZ family of zinc finger transcription factors, in promoting hepatocellular carcinoma metastasis. We demonstrated that the overexpression of ZNF703 in human HCC tissue is correlated with tumor metastasis and recurrence, it is also related with the prognosis and survival rate of patients. ZNF703 overexpression promotes HCC progression in vitro and in vivo, whereas ZNF703 knockdown has the opposite effect. In addition, ZNF703 induces epithelialmesenchymal transition (EMT) via directly binding to the CLDN4 promoter and transactivating CLDN4 expression. Downregulation of CLDN4 can attenuate ZNF703-mediated HCC metastasis, whereas upregulation of CLDN4 can reverse the decreased metastasis induced by ZNF703 knockdown. Our data revealed that ZNF703 expression is correlated with CLDN4 level, the overexpression of both ZNF703 and CLDN4 are leaded to poorer prognosis of patients with HCC. Moreover, ZNF703 knockdown can enhance the sensitivity of HCC cell to sorafenib, whereas ZNF703 overexpression has the opposite effect. These results suggested that ZNF703 might be a potential target for cancer therapies and a candidate prognostic biomarker for predicting whether patients with HCC are befitting for sorafenib treatment.
Highlights
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality with nearly 700,000 annual deaths globally[1]
The results showed that Zinc Finger Protein 703 (ZNF703) was primarily localized to the nucleus and was highly expressed in HCC tissues compared to adjacent nontumor tissues (Fig. 1A1)
We demonstrated that ZNF703 were highly expressed in human HCC tissues compared to adjacent nontumor tissues
Summary
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality with nearly 700,000 annual deaths globally[1]. Advances in surgical resection, which remains a potentially curative treatment, the prognosis of patients with HCC is still not optimistic[2]. The majority of HCC patients are diagnosed at an advanced stage, and a radical treatment is not the most suitable option. ZNF703, which is a member of the NET/NlZ family of zinc finger transcription factors, is crucial for the embryonic development of zebrafish[4], Xenopus[5] and Drosophila[6]. Several recent studies reported that the aberrant expression of ZNF703 is involved in tumor progression. It has been shown that ZNF703 induces
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