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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA165076-03S1
Application #
8795283
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Lin, Alison J
Project Start
2012-03-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
$86,573
Indirect Cost
$32,125
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Bhat, Mamatha; Chaiteerakij, Roongruedee; Harmsen, William S et al. (2014) Metformin does not improve survival in patients with hepatocellular carcinoma. World J Gastroenterol 20:15750-5
Rizvi, Sumera; Mertens, Joachim C; Bronk, Steven F et al. (2014) Platelet-derived growth factor primes cancer-associated fibroblasts for apoptosis. J Biol Chem 289:22835-49
Zhang, Xiaodan; Harmsen, William S; Mettler, Teresa A et al. (2014) Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes. Hepatology 60:2008-16
Venkatesh, Sudhakar K; Chandan, Vishal; Roberts, Lewis R (2014) Liver masses: a clinical, radiologic, and pathologic perspective. Clin Gastroenterol Hepatol 12:1414-29
Villegas, Victoria E; Rahman, Mohammed Ferdous-Ur; Fernandez-Barrena, Maite G et al. (2014) Identification of novel non-coding RNA-based negative feedback regulating the expression of the oncogenic transcription factor GLI1. Mol Oncol 8:912-26
Singh, Siddharth; Singh, Preet Paul; Roberts, Lewis R et al. (2014) Chemopreventive strategies in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 11:45-54
Fernandez-Zapico, Martin E (2013) GLI1 finds a new role in cancer stem cell biology. EMBO Mol Med 5:483-5
Zheng, Xin; Gai, Xiaohong; Han, Shaoshan et al. (2013) The human sulfatase 2 inhibitor 2,4-disulfonylphenyl-tert-butylnitrone (OKN-007) has an antitumor effect in hepatocellular carcinoma mediated via suppression of TGFB1/SMAD2 and Hedgehog/GLI1 signaling. Genes Chromosomes Cancer 52:225-36
Nakamura, Ikuo; Fernandez-Barrena, Maite G; Ortiz-Ruiz, Maria C et al. (2013) Activation of the transcription factor GLI1 by WNT signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration. J Biol Chem 288:21389-98
Chaiteerakij, Roongruedee; Yang, Ju Dong; Harmsen, William S et al. (2013) Risk factors for intrahepatic cholangiocarcinoma: association between metformin use and reduced cancer risk. Hepatology 57:648-55