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Research Paper
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 and M. Goggins
volume 4 | issue 7
july 2005Pages: 728-733
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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 3 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.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.