Cyclin-dependent kinase 4 (CDK4) expression in pancreatic endocrine tumors.
OBJECTIVE
Pancreatic endocrine tumors (PETs) occur sporadically, in association with the multiple endocrine neoplasia type 1 (MEN1) and the von Hippel-Lindau syndromes. CDK4 is central to the cell cycle control in pancreatic beta cells, and we have assessed whether CDK4 expression is deregulated in 18 human sporadic or familial PETs.


METHODS
Real-time quantitative PCR, immunohistochemistry, DNA sequencing, and Western blot analysis were used.


RESULTS
CDK4 mRNA was expressed in all PETs within the range of the arbitrary control. CDK4 protein was absent in normal pancreatic islets but distinctly expressed in all PETs as determined by immunohistochemistry. CDK4 expression was confirmed by Western blot analysis. No significant differences of CDK4 expression were observed between the groups of benign and malignant PETs or between tumors with or without MEN1 gene mutations. CDK4 expression was not due to gene amplification, and no mutations were identified in coding exons and RNA splice sites. c-Myc is known to be overexpressed in PETs and directly augments CDK4 expression in other cell types. Analysis of consecutive tissue sections for CDK4 and c-Myc showed overlapping homo- or heterogeneous immunostaining in all 18 PETs.


CONCLUSIONS
We conclude that CDK4 and c-Myc is generally expressed in benign and malignant PETs, and regardless of MEN1 mutational status. Targeting of CDK4 may present an alternative to traditional chemotherapy of PETs in the future.
Department of Surgical Sciences, Endocrine Unit, Uppsala University Hospital, Uppsala, Sweden.
Daniel
D
Lindberg
Ola
O
Hessman
Göran
G
Akerström
Gunnar
G
Westin
D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000473:pathology; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006623:von Hippel-Lindau Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology
C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4