Abstract
Previous studies provided substantial evidence of a striking suppressive effect of hepatocyte nuclear factor 4α (HNF4α) on hepatocellular carcinoma (HCC). Apoptosis signal-regulating kinase 1 (ASK1) is involved in death receptor-mediated apoptosis and may acts as a tumor suppressor in hepatocarcinogenesis. However, the status and function of ASK1 during HCC progression are unclear. In this study, we found that HNF4α increased ASK1 expression by directly binding to its promoter. ASK1 expression was dramatically suppressed and correlated with HNF4α levels in HCC tissues. Reduced ASK1 expression was associated with aggressive tumors and poor prognosis for human HCC. Moreover, ASK1 inhibited the malignant phenotype of HCC cells in vitro. Intratumoral ASK1 injection significantly suppressed the growth of subcutaneous HCC xenografts in nude mice. More interestingly, systemic ASK1 delivery strikingly inhibited the growth of orthotopic HCC nodules in NOD/SCID mice. In addition, inhibition of endogenous ASK1 partially reversed the suppressive effects of HNF4α on HCC. Collectively, this study highlights the suppressive effect of ASK1 on HCC and its biological significance in HCC development. These outcomes broaden the knowledge of ASK1 function in HCC progression, and provide a novel potential prognostic biomarker and therapeutic target for advanced HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide [1]
As the mitogen-activated protein kinases (MAPKs) signal transduction pathway is crucial for determining cell differentiation [19], we focused on its role in hepatocyte nuclear factor 4α (HNF4α)-mediated cell differentiation
This result confirmed that MAPKs can be activated by HNF4α
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide [1]. Hepatocyte nuclear factor 4α (HNF4α), a principal member of the hepatic transcription factor network, plays an indispensable role in regulating hepatic lineage differentiation and in maintaining liver function [3, 4]. It has been reported that transient suppression of HNF4α initiates hepatocellular transformation [9] and HNF4α knockout in adult hepatocytes leads to hepatocyte proliferation and promotes the development of HCC in mice [10], suggesting that HNF4α plays a critical role in liver carcinogenesis. Molecular mechanisms, such as miRNA cascades and inflammatory signaling pathways, through which HNF4α inhibits HCC have been clarified [9, 12, 15, 16]. As a key hepatic transcription factor, whether other signaling pathways are involved in the mechanisms of HNF4α need for further study
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