Non-canonical Hedgehog signaling activation in ovarian borderline tumors and ovarian carcinomas

Int J Oncol. 2017 Dec;51(6):1869-1877. doi: 10.3892/ijo.2017.4156. Epub 2017 Oct 12.

Abstract

Hedgehog signaling pathway has been implicated in the pathology of ovarian cancer, and Survivin (BIRC5) has been suggested as a novel target of this pathway. Herein we investigated the role of Hedgehog signaling pathway and Survivin in ovarian carcinoma and borderline tumor samples. We aimed to determine possible ways of pathway modulation on primary ovarian cancer cells and an established cell line. RNA was extracted from fresh tumors and control tissues and gene expression was examined using qRT-PCR. Pathway activity in cell lines was examined after treatment with cyclopamine, SHH protein, GANT-61 or lithium chloride using qRT-PCR, western blot and confocal microscopy. The difference between control tissue, borderline tumors and carcinomas can be seen in GLI1 and SUFU gene expression, which is significantly higher in borderline tumors compared to carcinomas. SUFU also shows lower expression levels in higher FIGO stages relative to lower stages. BIRC5 is expressed in all tumors and in healthy ovarian tissues compared to our control tissue, healthy fallopian tube samples. Primary cells developed from ovarian carcinoma tissue respond to cyclopamine treatment with a short-term decrease in cell proliferation, downregulation of Hedgehog pathway genes, including BIRC5, and changes in protein dynamics. Stimulation with SHH protein results in increased cell migration, while GLI1 transfection or PTCH1 silencing demonstrate pathway upregulation. The pathway activity can be modulated by LiCl at the GSK3β-SUFU-GLI level, suggesting at least partial non-canonical activation. Downregulation of the pathway with GANT-61 has proved to be more effective than cyclopamine. GLI inhibitors may be a superior treatment option in ovarian cancer compared to SMO inhibitors.

MeSH terms

  • Carcinoma / genetics
  • Carcinoma / metabolism*
  • Carcinoma / pathology
  • Carcinoma, Ovarian Epithelial
  • Case-Control Studies
  • Female
  • Gene Expression
  • Hedgehog Proteins / metabolism*
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism
  • Neoplasm Staging
  • Neoplasms, Glandular and Epithelial / genetics
  • Neoplasms, Glandular and Epithelial / metabolism*
  • Neoplasms, Glandular and Epithelial / pathology
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Repressor Proteins / biosynthesis
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Survivin
  • Zinc Finger Protein GLI1 / biosynthesis
  • Zinc Finger Protein GLI1 / genetics
  • Zinc Finger Protein GLI1 / metabolism

Substances

  • BIRC5 protein, human
  • GLI1 protein, human
  • Hedgehog Proteins
  • Inhibitor of Apoptosis Proteins
  • Repressor Proteins
  • SUFU protein, human
  • Survivin
  • Zinc Finger Protein GLI1