Oncofetal HLF transactivates c-Jun to promote hepatocellular carcinoma development and sorafenib resistance.
Gut
; 68(10): 1858-1871, 2019 10.
Article
em En
| MEDLINE
| ID: mdl-31118247
ABSTRACT
BACKGROUND AND AIMS:
The unique expression pattern makes oncofetal proteins ideal diagnostic biomarkers and therapeutic targets in cancer. However, few oncofetal proteins have been identified and entered clinical practice.METHODS:
Fetal liver, adult liver and hepatocellular carcinoma (HCC) tissues were employed to assess the expression of hepatic leukaemia factor (HLF). The impact of HLF on HCC onset and progression was investigated both in vivo and in vitro. The association between HLF and patient prognosis was determined in patient cohorts. The correlation between HLF expression and sorafenib benefits in HCC was further evaluated in patient cohorts and patient-derived xenografts (PDXs).RESULTS:
HLF is a novel oncofetal protein which is reactivated in HCC by SOX2 and OCT4. Functional studies revealed that HLF transactivates c-Jun to promote tumour initiating cell (TIC) generation and enhances TIC-like properties of hepatoma cells, thus driving HCC initiation and progression. Consistently, our clinical investigations elucidated the association between HLF and patient prognosis and unravelled the close correlation between HLF levels and c-Jun expression in patient HCCs. Importantly, HLF/c-Jun axis determines the responses of hepatoma cells to sorafenib treatment, and interference of HLF abrogated c-Jun activation and enhanced sorafenib response. Analysis of patient cohorts and PDXs further suggests that HLF/c-Jun axis might serve as a biomarker for sorafenib benefits in HCC patients.CONCLUSIONS:
Our findings uncovered HLF as a novel oncofetal protein and revealed the crucial role of the HLF/c-Jun axis in HCC development and sorafenib response, rendering HLF as an optimal target for the prevention and intervention of HCC.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Genes jun
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Carcinoma Hepatocelular
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Resistencia a Medicamentos Antineoplásicos
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Fatores de Transcrição de Zíper de Leucina Básica
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Sorafenibe
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Neoplasias Hepáticas
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
Gut
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
China