Oncofetal HLF transactivates c-Jun to promote hepatocellular carcinoma development and sorafenib resistance

• Published in: Gut Vol. 68; no. 10; pp. 1858 - 1871
• Main Authors: Xiang, Dai-Min, Sun, Wen, Zhou, Tengfei, Zhang, Cheng, Cheng, Zhuo, Li, Shi-Chao, Jiang, Weiqi, Wang, Ruoyu, Fu, Gongbo, Cui, Xiuliang, Hou, Guojun, Jin, Guang-Zhi, Li, Hengyu, Hou, Caiying, Liu, Hui, Wang, Hongyang, Ding, Jin
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.10.2019; BMJ Publishing Group LTD
• Subjects: Adult; Antineoplastic Agents - pharmacology; Apoptosis; Basic-Leucine Zipper Transcription Factors - biosynthesis; Basic-Leucine Zipper Transcription Factors - genetics; Biomarkers; c-Jun protein; Cancer therapies; carcinogenesis; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Clinical medicine; Disease Progression; DNA, Neoplasm - genetics; drug resistance; Drug Resistance, Neoplasm; Female; Fetuses; Gene expression; Genes, jun - genetics; Hepatocellular carcinoma; Hepatology; Hepatoma; Hospitals; Humans; Immunoprecipitation; Inhibitor drugs; Kinases; Leucine Zippers; Leukemia; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Male; Medical diagnosis; Medical prognosis; Oct-4 protein; oncogenes; Patients; Prognosis; Proteins; Signal transduction; Sorafenib - pharmacology; Stem cells; Surgery; Targeted cancer therapy; Therapeutic applications; Transcription factors; Tumors; tumour markers; Xenografts; China; oncogenes; tumour markers; drug resistance; carcinogenesis; hepatocellular carcinoma
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gutjnl-2018-317440

Background and aimsThe 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.MethodsFetal 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).ResultsHLF 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.ConclusionsOur 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.