Aberrant methylation of the Human Hedgehog interacting protein (HHIP) gene in pancreatic neoplasms

S. T. Martin, N. Sato, S. Dhara, R. Chang, S. R. Hustinx, T. Abe, A. Maitra, Michael S Goggins

Research output: Contribution to journalArticle

Abstract

Hedgehog pathway overactivity has been implicated in the development of a variety of human cancers. The Human Hedgehog interacting protein (HHIP), a negative regulator of hedgehog signaling, has been shown to be underexpressed in pancreatic cancers. In this study we determined if the HHIP gene is a target for genetic and epigenetic alterations. While no mutations of HHIP were identified, we found complete methylation of the HHIP promoter CpG island in three pancreatic cancer cell lines, and partial hypermethylation in 13/17 (80%) pancreatic cancer cell lines, 35/75 (46%) primary pancreatic cancers and 14/18 (78%) pancreatic cancer xenografts, but no methylation in 13 normal pancreata. In pancreatic cancer cell lines, complete methylation was associated with absent or reduced HHIP expression by real-time RT-PCR. HHIP expression could be restored in methylated cell lines using epigenetic modifier drugs. Restoring the expression of HHIP in pancreatic cancer cells by 5-aza-2′-deoxycytidine led to a decrease in Gli reporter activity, consistent with downregulation of Hedgehog signaling. These results indicate in some pancreatic adenocarcinomas that HHIP is epigenetically inactivated by promoter methylation, and its silencing could contribute to the increased Hedgehog signaling observed in pancreatic neoplasms.

Original languageEnglish (US)
Pages (from-to)728-733
Number of pages6
JournalCancer Biology and Therapy
Volume4
Issue number7
StatePublished - Jul 2005

Fingerprint

Pancreatic Neoplasms
Methylation
Genes
Cell Line
decitabine
Epigenomics
CpG Islands
human HHIP protein
Heterografts
Real-Time Polymerase Chain Reaction
Pancreas
Adenocarcinoma
Down-Regulation
Mutation
Pharmaceutical Preparations
Neoplasms

Keywords

  • Hedgehog interacting protein
  • Hedgehog pathway
  • HHIP
  • Methylation
  • Pancreatic cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Martin, S. T., Sato, N., Dhara, S., Chang, R., Hustinx, S. R., Abe, T., ... Goggins, M. S. (2005). Aberrant methylation of the Human Hedgehog interacting protein (HHIP) gene in pancreatic neoplasms. Cancer Biology and Therapy, 4(7), 728-733.

Aberrant methylation of the Human Hedgehog interacting protein (HHIP) gene in pancreatic neoplasms. / Martin, S. T.; Sato, N.; Dhara, S.; Chang, R.; Hustinx, S. R.; Abe, T.; Maitra, A.; Goggins, Michael S.

In: Cancer Biology and Therapy, Vol. 4, No. 7, 07.2005, p. 728-733.

Research output: Contribution to journalArticle

Martin, ST, Sato, N, Dhara, S, Chang, R, Hustinx, SR, Abe, T, Maitra, A & Goggins, MS 2005, 'Aberrant methylation of the Human Hedgehog interacting protein (HHIP) gene in pancreatic neoplasms', Cancer Biology and Therapy, vol. 4, no. 7, pp. 728-733.
Martin ST, Sato N, Dhara S, Chang R, Hustinx SR, Abe T et al. Aberrant methylation of the Human Hedgehog interacting protein (HHIP) gene in pancreatic neoplasms. Cancer Biology and Therapy. 2005 Jul;4(7):728-733.
Martin, S. T. ; Sato, N. ; Dhara, S. ; Chang, R. ; Hustinx, S. R. ; Abe, T. ; Maitra, A. ; Goggins, Michael S. / Aberrant methylation of the Human Hedgehog interacting protein (HHIP) gene in pancreatic neoplasms. In: Cancer Biology and Therapy. 2005 ; Vol. 4, No. 7. pp. 728-733.
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