The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent Wnt activation

Jin Ping Lai, Abdul M. Oseini, Catherine D. Moser, Chunrong Yu, Sherine F. Elsawa, Chunling Hu, Ikuo Nakamura, Tao Han, Ileana Aderca, Hajime Isomoto, Megan M. Garrity-Park, Abdirashid M. Shire, Jia Li, Schuyler O. Sanderson, Alex Adjei, Martin E Fernandez-Zapico, Lewis Rowland Roberts

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Abstract

Heparan sulfate proteoglycans (HSPGs) act as coreceptors or storage sites for growth factors and cytokines such as fibroblast growth factor and Wnts. Glypican 3 (GPC3) is the most highly expressed HSPG in hepatocellular carcinoma (HCC). Sulfatase 2 (SULF2), an enzyme with 6-O-desulfatase activity on HSPGs, is up-regulated in 60% of primary HCCs and is associated with a worse prognosis. We have previously shown that the oncogenic effect of SULF2 in HCC may be mediated in part through up-regulation of GPC3. Here we demonstrate that GPC3 stimulates the Wnt/β-catenin pathway and mediates the oncogenic function of SULF2 in HCC. Wnt signaling in vitro and in vivo was assessed in SULF2-negative Hep3B HCC cells transfected with SULF2 and in SULF2-expressing Huh7 cells transfected with short hairpin RNA targeting SULF2. The interaction between GPC3, SULF2, and Wnt3a was assessed by coimmunoprecipitation and flow cytometry. β-catenin-dependent transcriptional activity was assessed with the TOPFLASH (T cell factor reporter plasmid) luciferase assay. In HCC cells, SULF2 increased cell surface GPC3 and Wnt3a expression, stabilized β-catenin, and activated T cell factor transcription factor activity and expression of the Wnt/β-catenin target gene cyclin D1. Opposite effects were observed in SULF2-knockdown models. In vivo, nude mouse xenografts established from SULF2-transfected Hep3B cells showed enhanced GPC3, Wnt3a, and β-catenin levels. Conclusion: Together, these findings identify a novel mechanism mediating the oncogenic function of SULF2 in HCC that includes GPC3-mediated activation of Wnt signaling via the Wnt3a/glycogen synthase kinase 3 beta axis.

Original languageEnglish (US)
Pages (from-to)1680-1689
Number of pages10
JournalHepatology
Volume52
Issue number5
DOIs
StatePublished - Nov 2010

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Glypicans
Sulfatases
Hepatocellular Carcinoma
Catenins
Heparan Sulfate Proteoglycans
TCF Transcription Factors
bcl-1 Genes
Wnt Signaling Pathway
Fibroblast Growth Factors
Luciferases
Heterografts
Nude Mice
Small Interfering RNA

ASJC Scopus subject areas

  • Hepatology

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The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent Wnt activation. / Lai, Jin Ping; Oseini, Abdul M.; Moser, Catherine D.; Yu, Chunrong; Elsawa, Sherine F.; Hu, Chunling; Nakamura, Ikuo; Han, Tao; Aderca, Ileana; Isomoto, Hajime; Garrity-Park, Megan M.; Shire, Abdirashid M.; Li, Jia; Sanderson, Schuyler O.; Adjei, Alex; Fernandez-Zapico, Martin E; Roberts, Lewis Rowland.

In: Hepatology, Vol. 52, No. 5, 11.2010, p. 1680-1689.

Research output: Contribution to journalArticle

Lai, JP, Oseini, AM, Moser, CD, Yu, C, Elsawa, SF, Hu, C, Nakamura, I, Han, T, Aderca, I, Isomoto, H, Garrity-Park, MM, Shire, AM, Li, J, Sanderson, SO, Adjei, A, Fernandez-Zapico, ME & Roberts, LR 2010, 'The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent Wnt activation', Hepatology, vol. 52, no. 5, pp. 1680-1689. https://doi.org/10.1002/hep.23848
Lai, Jin Ping ; Oseini, Abdul M. ; Moser, Catherine D. ; Yu, Chunrong ; Elsawa, Sherine F. ; Hu, Chunling ; Nakamura, Ikuo ; Han, Tao ; Aderca, Ileana ; Isomoto, Hajime ; Garrity-Park, Megan M. ; Shire, Abdirashid M. ; Li, Jia ; Sanderson, Schuyler O. ; Adjei, Alex ; Fernandez-Zapico, Martin E ; Roberts, Lewis Rowland. / The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent Wnt activation. In: Hepatology. 2010 ; Vol. 52, No. 5. pp. 1680-1689.
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abstract = "Heparan sulfate proteoglycans (HSPGs) act as coreceptors or storage sites for growth factors and cytokines such as fibroblast growth factor and Wnts. Glypican 3 (GPC3) is the most highly expressed HSPG in hepatocellular carcinoma (HCC). Sulfatase 2 (SULF2), an enzyme with 6-O-desulfatase activity on HSPGs, is up-regulated in 60{\%} of primary HCCs and is associated with a worse prognosis. We have previously shown that the oncogenic effect of SULF2 in HCC may be mediated in part through up-regulation of GPC3. Here we demonstrate that GPC3 stimulates the Wnt/β-catenin pathway and mediates the oncogenic function of SULF2 in HCC. Wnt signaling in vitro and in vivo was assessed in SULF2-negative Hep3B HCC cells transfected with SULF2 and in SULF2-expressing Huh7 cells transfected with short hairpin RNA targeting SULF2. The interaction between GPC3, SULF2, and Wnt3a was assessed by coimmunoprecipitation and flow cytometry. β-catenin-dependent transcriptional activity was assessed with the TOPFLASH (T cell factor reporter plasmid) luciferase assay. In HCC cells, SULF2 increased cell surface GPC3 and Wnt3a expression, stabilized β-catenin, and activated T cell factor transcription factor activity and expression of the Wnt/β-catenin target gene cyclin D1. Opposite effects were observed in SULF2-knockdown models. In vivo, nude mouse xenografts established from SULF2-transfected Hep3B cells showed enhanced GPC3, Wnt3a, and β-catenin levels. Conclusion: Together, these findings identify a novel mechanism mediating the oncogenic function of SULF2 in HCC that includes GPC3-mediated activation of Wnt signaling via the Wnt3a/glycogen synthase kinase 3 beta axis.",
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T1 - The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent Wnt activation

AU - Lai, Jin Ping

AU - Oseini, Abdul M.

AU - Moser, Catherine D.

AU - Yu, Chunrong

AU - Elsawa, Sherine F.

AU - Hu, Chunling

AU - Nakamura, Ikuo

AU - Han, Tao

AU - Aderca, Ileana

AU - Isomoto, Hajime

AU - Garrity-Park, Megan M.

AU - Shire, Abdirashid M.

AU - Li, Jia

AU - Sanderson, Schuyler O.

AU - Adjei, Alex

AU - Fernandez-Zapico, Martin E

AU - Roberts, Lewis Rowland

PY - 2010/11

Y1 - 2010/11

N2 - Heparan sulfate proteoglycans (HSPGs) act as coreceptors or storage sites for growth factors and cytokines such as fibroblast growth factor and Wnts. Glypican 3 (GPC3) is the most highly expressed HSPG in hepatocellular carcinoma (HCC). Sulfatase 2 (SULF2), an enzyme with 6-O-desulfatase activity on HSPGs, is up-regulated in 60% of primary HCCs and is associated with a worse prognosis. We have previously shown that the oncogenic effect of SULF2 in HCC may be mediated in part through up-regulation of GPC3. Here we demonstrate that GPC3 stimulates the Wnt/β-catenin pathway and mediates the oncogenic function of SULF2 in HCC. Wnt signaling in vitro and in vivo was assessed in SULF2-negative Hep3B HCC cells transfected with SULF2 and in SULF2-expressing Huh7 cells transfected with short hairpin RNA targeting SULF2. The interaction between GPC3, SULF2, and Wnt3a was assessed by coimmunoprecipitation and flow cytometry. β-catenin-dependent transcriptional activity was assessed with the TOPFLASH (T cell factor reporter plasmid) luciferase assay. In HCC cells, SULF2 increased cell surface GPC3 and Wnt3a expression, stabilized β-catenin, and activated T cell factor transcription factor activity and expression of the Wnt/β-catenin target gene cyclin D1. Opposite effects were observed in SULF2-knockdown models. In vivo, nude mouse xenografts established from SULF2-transfected Hep3B cells showed enhanced GPC3, Wnt3a, and β-catenin levels. Conclusion: Together, these findings identify a novel mechanism mediating the oncogenic function of SULF2 in HCC that includes GPC3-mediated activation of Wnt signaling via the Wnt3a/glycogen synthase kinase 3 beta axis.

AB - Heparan sulfate proteoglycans (HSPGs) act as coreceptors or storage sites for growth factors and cytokines such as fibroblast growth factor and Wnts. Glypican 3 (GPC3) is the most highly expressed HSPG in hepatocellular carcinoma (HCC). Sulfatase 2 (SULF2), an enzyme with 6-O-desulfatase activity on HSPGs, is up-regulated in 60% of primary HCCs and is associated with a worse prognosis. We have previously shown that the oncogenic effect of SULF2 in HCC may be mediated in part through up-regulation of GPC3. Here we demonstrate that GPC3 stimulates the Wnt/β-catenin pathway and mediates the oncogenic function of SULF2 in HCC. Wnt signaling in vitro and in vivo was assessed in SULF2-negative Hep3B HCC cells transfected with SULF2 and in SULF2-expressing Huh7 cells transfected with short hairpin RNA targeting SULF2. The interaction between GPC3, SULF2, and Wnt3a was assessed by coimmunoprecipitation and flow cytometry. β-catenin-dependent transcriptional activity was assessed with the TOPFLASH (T cell factor reporter plasmid) luciferase assay. In HCC cells, SULF2 increased cell surface GPC3 and Wnt3a expression, stabilized β-catenin, and activated T cell factor transcription factor activity and expression of the Wnt/β-catenin target gene cyclin D1. Opposite effects were observed in SULF2-knockdown models. In vivo, nude mouse xenografts established from SULF2-transfected Hep3B cells showed enhanced GPC3, Wnt3a, and β-catenin levels. Conclusion: Together, these findings identify a novel mechanism mediating the oncogenic function of SULF2 in HCC that includes GPC3-mediated activation of Wnt signaling via the Wnt3a/glycogen synthase kinase 3 beta axis.

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