Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Recapitulation of pharmacogenomic data reveals that invalidation of SULF2 enhance sorafenib susceptibility in liver cancer

Oncogene volume 37, pages 4443–4454 (2018)Cite this article

Subjects

Abstract

Gene mutations play critical roles during cancer development and progression, and therefore represent targets for precision medicine. Here we recapitulated the pharmacogenomic data to delineate novel candidates for actionable mutations and therapeutic target drugs. As a proof-of-concept, we demonstrated that the loss-of-function of SULF2 by mutation (N491K) or inhibition enhanced sorafenib sensitivity in liver cancer cells and in vivo mouse models. This effect was mediated by deregulation of EGFR signaling and downstream expression of LCN2. We also report that the liver cancer patients non-responding to sorafenib treatment exhibit higher expression of SULF2 and LCN2. In conclusion, we suggest that SULF2 plays a key role in sorafenib susceptibility and resistance in liver cancer via deregulation of LCN2. Diagnostic or therapeutic targeting of SULF2 (e.g., OKN-007) and/or LCN2 can be a novel precision strategy for sorafenib treatment in cancer patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Basu A, Bodycombe NE, Cheah JH, Price EV, Liu K, Schaefer GI, et al. An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules. Cell. 2013;154:1151–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Iorio F, Knijnenburg TA, Vis DJ, Bignell GR, Menden MP, Schubert M, et al. A landscape of pharmacogenomic interactions in. Cancer Cell. 2016;166:740–54.

    CAS  Google Scholar 

  3. Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483:603–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Haibe-Kains B, El-Hachem N, Birkbak NJ, Jin AC, Beck AH, Aerts HJ, et al. Inconsistency in large pharmacogenomic studies. Nature. 2013;504:389–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Lai JP, Sandhu DS, Yu C, Han T, Moser CD, Jackson KK, et al. Sulfatase 2 up-regulates glypican 3, promotes fibroblast growth factor signaling, and decreases survival in hepatocellular carcinoma. Hepatology. 2008;47:1211–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Chen G, Nakamura I, Dhanasekaran R, Iguchi E, Tolosa EJ, Romecin PA, et al. Transcriptional induction of periostin by a sulfatase 2-TGFbeta1-SMAD signaling axis mediates tumor angiogenesis in hepatocellular carcinoma. Cancer Res. 2017;77:632–45.

    Article  PubMed  CAS  Google Scholar 

  7. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.

    Article  PubMed  CAS  Google Scholar 

  8. Park JG. Long-term outcomes of patients with advanced hepatocellular carcinoma who achieved complete remission after sorafenib therapy. Clin Mol Hepatol. 2015;21:287–94.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Morimoto-Tomita M, Uchimura K, Werb Z, Hemmerich S, Rosen SD. Cloning and characterization of two extracellular heparin-degrading endosulfatases in mice and humans. J Biol Chem. 2002;277:49175–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Lai JP, Oseini AM, Moser CD, Yu C, Elsawa SF, Hu C, et al. The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent Wnt activation. Hepatology. 2010;52:1680–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Viau A, El Karoui K, Laouari D, Burtin M, Nguyen C, Mori K, et al. Lipocalin 2 is essential for chronic kidney disease progression in mice and humans. J Clin Invest. 2010;120:4065–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Zhao P, Stephens JM. STAT1, NF-kappaB and ERKs play a role in the induction of lipocalin-2 expression in adipocytes. Mol Metab. 2013;2:161–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Yoo J, Rodriguez Perez CE, Nie W, Edwards RA, Sinnett-Smith J, Rozengurt E. TNF-alpha induces upregulation of EGFR expression and signaling in human colonic myofibroblasts. Am J Physiol Gastrointest Liver Physiol. 2012;302:G805–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Ding G, Fang J, Tong S, Qu L, Jiang H, Ding Q, et al. Over-expression of lipocalin 2 promotes cell migration and invasion through activating ERK signaling to increase SLUG expression in prostate cancer. Prostate. 2015;75:957–68.

    Article  PubMed  CAS  Google Scholar 

  15. Blivet-Van Eggelpoel MJ, Chettouh H, Fartoux L, Aoudjehane L, Barbu V, Rey C, et al. Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells. J Hepatol. 2012;57:108–15.

    Article  PubMed  CAS  Google Scholar 

  16. Yonesaka K, Zejnullahu K, Lindeman N, Homes AJ, Jackman DM, Zhao F, et al. Autocrine production of amphiregulin predicts sensitivity to both gefitinib and cetuximab in EGFR wild-type cancers. Clin Cancer Res. 2008;14:6963–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Rosen SD, Lemjabbar-Alaoui H. Sulf-2: an extracellular modulator of cell signaling and a cancer target candidate. Expert Opin Ther Targets. 2010;14:935–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Frese MA, Milz F, Dick M, Lamanna WC, Dierks T. Characterization of the human sulfatase Sulf1 and its high affinity heparin/heparan sulfate interaction domain. J Biol Chem. 2009;284:28033–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Tang R, Rosen SD. Functional consequences of the subdomain organization of the sulfs. J Biol Chem. 2009;284:21505–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Berasain C. Hepatocellular carcinoma and sorafenib: too many resistance mechanisms? Gut. 2013;62:1674–5.

    Article  PubMed  CAS  Google Scholar 

  21. Leung L, Radulovich N, Zhu CQ, Organ S, Bandarchi B, Pintilie M, et al. Lipocalin2 promotes invasion, tumorigenicity and gemcitabine resistance in pancreatic ductal adenocarcinoma. PLoS ONE. 2012;7:e46677.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Shiiba M, Saito K, Fushimi K, Ishigami T, Shinozuka K, Nakashima D, et al. Lipocalin-2 is associated with radioresistance in oral cancer and lung cancer cells. Int J Oncol. 2013;42:1197–204.

    Article  PubMed  Google Scholar 

  23. Yang J, Bielenberg DR, Rodig SJ, Doiron R, Clifton MC, Kung AL, et al. Lipocalin 2 promotes breast cancer progression. Proc Natl Acad Sci USA. 2009;106:3913–8.

    Article  PubMed  Google Scholar 

  24. Zhang Y, Fan Y, Mei Z. NGAL and NGALR overexpression in human hepatocellular carcinoma toward a molecular prognostic classification. Cancer Epidemiol. 2012;36:e294–299.

    Article  PubMed  CAS  Google Scholar 

  25. Nishida N, Kitano M, Sakurai T, Kudo M. Molecular mechanism and prediction of sorafenib chemoresistance in human hepatocellular carcinoma. Dig Dis. 2015;33:771–9.

    Article  PubMed  Google Scholar 

  26. Peng S, Wang Y, Peng H, Chen D, Shen S, Peng B, et al. Autocrine vascular endothelial growth factor signaling promotes cell proliferation and modulates sorafenib treatment efficacy in hepatocellular carcinoma. Hepatology. 2014;60:1264–77.

    Article  PubMed  CAS  Google Scholar 

  27. Tovar V, Cornella H, Moeini A, Vidal S, Hoshida Y, Sia D, et al. Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma. Gut. 2015;66:530–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Rudalska R, Dauch D, Longerich T, McJunkin K, Wuestefeld T, Kang TW, et al. In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat Med. 2014;20:1138–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Chen HA, Kuo TC, Tseng CF, Ma JT, Yang ST, Yen CJ, et al. Angiopoietin-like protein 1 antagonizes MET receptor activity to repress sorafenib resistance and cancer stemness in hepatocellular carcinoma. Hepatology. 2016;64:1637–51.

    Article  PubMed  CAS  Google Scholar 

  30. Sun X, Niu X, Chen R, He W, Chen D, Kang R, et al. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology. 2016;64:488–500.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–109.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Korea Healthcare Technology R&D Project, Ministry of Health & Welfare (HI15C1551 and HI14C3392) and from the National Research Foundation of Korea (NRF) funded by the Korea government (MSIP) (NRF-2017M3A9B6061509, NRF-2017R1E1A1A01074733, and NRF-2015R1D1A4A01020022).

Authors contributions:

SY performed experiments. E-JL performed analysis. Both SY and E-JL wrote the manuscript that was edited by all co-authors. J-HC, H-HK, and HCK performed analysis. J-YI performed experiments. TC, DYK. M-HB, J-HK, YNP, and H-JW provided tissues and performed analysis. HGW contributed to overall study design and directed the study.

Author information

Author notes

    Authors and Affiliations

    1. Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea

      Sarah Yoon, Eun-Ju Lee, Ji-Hye Choi, Jong-Yeop Im & Hyun Goo Woo

    2. Department of Biomedical Science, Graduate School, Ajou University, Suwon, Republic of Korea

      Ji-Hye Choi, Jong-Yeop Im & Hyun Goo Woo

    3. Department of Pathology and BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea

      Taek Chung & Young Nyun Park

    4. Department of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea

      Do Young Kim

    5. CbsBioscience, Inc, Daejeon, Republic of Korea

      Myung-Ho Bae & Jung-Hee Kwon

    6. Department of Emergency Medicine, Ajou University School of Medicine, Suwon, Republic of Korea

      Hyuk-Hoon Kim

    7. Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

      Hyung Chul Kim

    8. Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea

      Hee-Jung Wang

    Authors
    1. Sarah Yoon
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Eun-Ju Lee
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Ji-Hye Choi
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Taek Chung
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Do Young Kim
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Jong-Yeop Im
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Myung-Ho Bae
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Jung-Hee Kwon
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Hyuk-Hoon Kim
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Hyung Chul Kim
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Young Nyun Park
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Hee-Jung Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Hyun Goo Woo
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Hyun Goo Woo.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Additional information

    These authors contributed equally: Sarah Yoon, Eun-Ju Lee.

    Electronic supplementary material

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Yoon, S., Lee, EJ., Choi, JH. et al. Recapitulation of pharmacogenomic data reveals that invalidation of SULF2 enhance sorafenib susceptibility in liver cancer. Oncogene 37, 4443–4454 (2018). https://doi.org/10.1038/s41388-018-0291-3

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1038/s41388-018-0291-3

    This article is cited by

    Search

    Advanced search

    Quick links