Sonic Hedgehog inhibition as a strategy to augment radiosensitivity of hepatocellular carcinoma.

Abstract:

BACKGROUND AND AIM:Sonic Hedgehog (SHH) is a regulator in tumorigenesis of hepatocellular carcinoma (HCC). This study aimed to determine whether radiation-induced SHH signaling occurs in HCC and whether SHH inhibitor acts as a radiosensitizer. METHODS:The in vitro effects of combining SHH ligand (recombinant human SHH) or inhibitor (cyclopamine) with irradiation were evaluated in the human HCC cell lines, Huh-7 and PLC/PRF/5, and murine cell line BNL. Cell survival and apoptosis were measured using a colony formation assay, annexin-V staining, and poly (ADP-ribose) polymerase activation. Western blotting and immunofluorescence staining were used to detect protein expression. The in vivo response to radiotherapy and/or cyclopamine was tested in BALB/c mice bearing an orthotopic allogeneic tumor. RESULTS:Treatment of HCC cells with irradiation and SHH ligand had a protective effect on clonogenic cell survival. Treatment with irradiation and cyclopamine was a more potent inhibitor of cell proliferation than either modality alone. The antiproliferative activity of cyclopamine was attributable to apoptosis induction. Radiation dose-dependently upregulated the expression of Gli-1 (a transcription factor induced by SHH), and this effect was observed mainly in the nucleus. When combined with cyclopamine, irradiation inhibited Gli-1 and increased DNA double-strand breakage. Radiotherapy increased SHH and Gli-1 expression in allogeneic tumor. When compared with radiotherapy alone, cyclopamine with radiotherapy reduced the mean tumor size of orthotopic tumors by 67% (P < 0.05). CONCLUSION:Combining an SHH inhibitor with radiotherapy may enhance HCC cell and orthotopic tumor radiosensitivity.

authors

Tsai CL,Hsu FM,Tzen KY,Liu WL,Cheng AL,Cheng JC

doi

10.1111/jgh.12931

subject

Has Abstract

pub_date

2015-08-01 00:00:00

pages

1317-24

issue

8

eissn

0815-9319

issn

1440-1746

journal_volume

30

pub_type

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