Expression of p18^INK4C is Down-regulated in Human Pituitary Adenomas

Cyclin-dependent kinase inhibitors represented by the INK4 family comprising p16^INK4A, p15^INK4B, p18^INK4C, and p19^INK4D are regulators of the cell cycle shown to be aberrant in many types of cancer. Mice lacking p18^Ink4c exhibit a series of phenotypes including the development of widespread organomegaly and pituitary adenomas. The objective of our study is to examine the role of p18^INK4C in the pathogenesis of human pituitary tumors. The protein and mRNA levels of p18^INK4C were examined by immunohistochemistry and real-time reverse transcription-polymerase chain reaction, respectively. The methylation status of the p18^INK4C gene promoter and somatic mutations of the p18^INK4C gene were also investigated. p18^INK4C protein expression was lost or significantly reduced in 64% of pituitary adenomas compared with levels in normal pituitary glands. p18^INK4C mRNA levels were low in all ACTH adenomas and non-functioning (NF)-FSH and in 42%, 70% and 66% of GH, PRL, and subtype 3 adenomas, respectively. p18^INK4C mRNA levels were significantly associated with p18^INK4C protein levels. Neither methylated promoters in pituitary adenomas, except in one NF-FSH adenoma, nor somatic mutations of the p18^INK4C gene in any pituitary adenomas were detected. The down-regulation of p18^INK4C expression may contribute to the tumorigenesis of pituitary adenomas.