TY - JOUR T1 - Oncofetal HLF transactivates c-Jun to promote hepatocellular carcinoma development and sorafenib resistance JF - Gut JO - Gut SP - 1858 LP - 1871 DO - 10.1136/gutjnl-2018-317440 VL - 68 IS - 10 AU - Dai-Min Xiang AU - Wen Sun AU - Tengfei Zhou AU - Cheng Zhang AU - Zhuo Cheng AU - Shi-Chao Li AU - Weiqi Jiang AU - Ruoyu Wang AU - Gongbo Fu AU - Xiuliang Cui AU - Guojun Hou AU - Guang-Zhi Jin AU - Hengyu Li AU - Caiying Hou AU - Hui Liu AU - Hongyang Wang AU - Jin Ding Y1 - 2019/10/01 UR - http://gut.bmj.com/content/68/10/1858.abstract N2 - 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. ER -