Hepatocellular carcinoma (HCC) causes about 700,000 deaths each year, and its incidence in the US has tripled over the past 30 years. Available therapies are curative only in early-stage HCC. Better early-detection methods and treatments will require a greater understanding of the molecular mechanisms regulating the initiation and growth of HCC. We have identified a role for sulfatase 2 (SULF2), an extracellular endosulfatase, in HCC pathogenesis and are especially excited about the recent spontaneous development of liver cancers in our transgenic mice overexpressing SULF2 in the liver. Our previous work has shown that SULF2 releases heparin-binding growth factors from heparan sulfate glycosaminoglycan (HSGAG) storage sites in the extracellular compartment, increases growth factor signaling, and promotes HCC tumorigenesis. These results show that SULF2 exerts its effects in HCC in part through modulation of the Wnt signaling pathway. We have now identified the target molecule of this newly identified SULF2-Wnt signaling as the transcriptional factor GLI1, an effector of the Hedgehog pathway. Moreover, we have discovered that this newly identified SULF2-Wnt-GLI1 axis activates two major regulators of the HCC tumor microenvironment, transforming growth factor ? (TGF?) and interleukin 6 (IL-6). We will use biochemical and cell biology methods, structural and functional analyses, and in vitro and in vivo approaches to systemically investigate the mechanistic role of the novel SULF2-Wnt-GLI1 axis in the HCC microenvironment and tumorigenesis. Successful completion of these studies will increase our understanding of the pathogenesis of HCC and allow future testing of rational strategies for treatment of HCC based on these findings. Overall, this proposal is potentially of high impact given the lack of effective treatments for advanced HCC. The findings from this research will also likely be generalizable to other cancer types because of the known involvement of SULF2, the Wnt pathway, and GLI1 in other tumors.

Public Health Relevance

Liver cancer is a leading cause of death from cancer worldwide and has become three times more common in the US over the past 30 years. Medications currently being used to treat liver cancer are not very effective. Therefore, there is a vital need to develop additional drug treatments that will provide multiple approaches for treating all individuals afflicted with this debilitating illness. This research should provide important information that can be used in developing new liver cancer therapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Lin, Alison J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Wang, Yu; Ding, Xiwei; Wang, Shaoqing et al. (2016) Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein. Cancer Lett 380:163-73
Ding, Xiwei; Chaiteerakij, Roongruedee; Moser, Catherine D et al. (2016) Antitumor effect of the novel sphingosine kinase 2 inhibitor ABC294640 is enhanced by inhibition of autophagy and by sorafenib in human cholangiocarcinoma cells. Oncotarget 7:20080-92
Dhanasekaran, Renumathy; Venkatesh, Sudhakar K; Torbenson, Michael S et al. (2016) Clinical implications of basic research in hepatocellular carcinoma. J Hepatol 64:736-45
Yang, Ju Dong; Campion, Michael B; Liu, Minetta C et al. (2016) Circulating tumor cells are associated with poor overall survival in patients with cholangiocarcinoma. Hepatology 63:148-58
Dhanasekaran, Renumathy; Nakamura, Ikuo; Hu, Chunling et al. (2015) Activation of the transforming growth factor-β/SMAD transcriptional pathway underlies a novel tumor-promoting role of sulfatase 1 in hepatocellular carcinoma. Hepatology 61:1269-83
Vriend, Henrike J; Bogaards, Johannes A; van Bergen, Jan E A M et al. (2015) Incidence and persistence of carcinogenic genital human papillomavirus infections in young women with or without Chlamydia trachomatis co-infection. Cancer Med 4:1589-98
Chaiteerakij, Roongruedee; Addissie, Benyam D; Roberts, Lewis R (2015) Update on biomarkers of hepatocellular carcinoma. Clin Gastroenterol Hepatol 13:237-45
Cornella, Helena; Alsinet, Clara; Sayols, Sergi et al. (2015) Unique genomic profile of fibrolamellar hepatocellular carcinoma. Gastroenterology 148:806-18.e10
Shire, Abdirashid; Lomberk, Gwen; Lai, Jin-Ping et al. (2015) Restoration of epigenetically silenced SULF1 expression by 5-aza-2-deoxycytidine sensitizes hepatocellular carcinoma cells to chemotherapy-induced apoptosis. Med Epigenet 3:1-18
Chaiteerakij, Roongruedee; Juran, Brian D; Aboelsoud, Mohammed M et al. (2015) Association between variants in inflammation and cancer-associated genes and risk and survival of cholangiocarcinoma. Cancer Med 4:1599-602

Showing the most recent 10 out of 26 publications