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Oncofetal HLF transactivates c-Jun to promote hepatocellular carcinoma development and sorafenib resistance
  1. Dai-Min Xiang1,2,
  2. Wen Sun1,
  3. Tengfei Zhou1,
  4. Cheng Zhang1,
  5. Zhuo Cheng1,
  6. Shi-Chao Li1,
  7. Weiqi Jiang1,
  8. Ruoyu Wang3,
  9. Gongbo Fu1,
  10. Xiuliang Cui1,
  11. Guojun Hou3,
  12. Guang-Zhi Jin4,
  13. Hengyu Li5,
  14. Caiying Hou6,
  15. Hui Liu3,
  16. Hongyang Wang1,2,
  17. Jin Ding1,2
  1. 1 International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, the Second Military Medical University, shanghai, China
  2. 2 National Center for Liver Cancer, shanghai, China
  3. 3 The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, the Second Military MedicalUniversity, shanghai, China
  4. 4 Department of Pathology, Eastern Hepatobiliary Surgery Hospital/Institute, the Second MilitaryMedical University, shanghai, China
  5. 5 Department of Breast and Thyroid surgery, First Affiliated Hospital of Second Military Medical University, shanghai, China
  6. 6 General Hospital of PLA Rocket Force, Beijing, China
  1. Correspondence to Hongyang Wang and Jin Ding, International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, 225 Changhai Road, 200438 Shanghai, China; hywangk{at}vip.sina.com, dingjin1103{at}163.com

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.

  • hepatocellular carcinoma
  • oncogenes
  • tumour markers
  • carcinogenesis
  • drug resistance
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Footnotes

  • D-MX, WS and TZ contributed equally.

  • Contributors D-MX and TFZ conducted all experiments and analysed the data. HL, RYW, HYL, GJH and CYH provided clinical samples. G-ZJ provided pathology evaluation and D-MX analysed clinical data. ZC, S-CL, XLC, WQJ and GF provided support with experimental techniques. WS wrote the manuscript and JD contributed to the revision. JD and HYW conceived the project and supervised all experiments.

  • Funding This work was supported by grants from the State Key Project of China (2017YFA0504503), the National Natural Science Foundation of China 81572897, 81770602 and 81702736, Program of Shanghai Municipal Commission of Health (20174Y0144), Shanghai Rising-Star Program (18QA1405300) and Program of Shanghai Academic Research Leader (18XD1405400).

  • Competing interests None declared.

  • Ethics approval The procedure of patient specimen collection was approved by the Ethics Committee of Eastern Hepatobiliary Surgery Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent for publication Obtained.

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