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.