Oncotarget

Research Papers:

Apoptosis signal-regulating kinase 1 mediates the inhibitory effect of hepatocyte nuclear factor-4α on hepatocellular carcinoma

Cai-Feng Jiang, Liang-Zhi Wen, Chuan Yin, Wen-Ping Xu, Bin Shi, Xin Zhang and Wei-Fen Xie _

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Oncotarget. 2016; 7:27408-27421. https://doi.org/10.18632/oncotarget.8478

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Abstract

Cai-Feng Jiang1,*, Liang-Zhi Wen1,*, Chuan Yin1,*, Wen-Ping Xu1, Bin Shi1, Xin Zhang1, Wei-Fen Xie1

1Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China

*These authors contributed equally to this work

Correspondence to:

Wei-Fen Xie, e-mail: [email protected]

Keywords: apoptosis signal-regulating kinase 1, hepatocyte nuclear factor 4α, hepatocellular carcinoma, mitogen-activated protein kinases, differentiation therapy

Received: October 16, 2015     Accepted: March 16, 2016     Published: March 30, 2016

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.


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