P27/CDKN1B Translational Regulators in Pituitary Tumorigenesis.
In pituitary tumors, P27(CDKN1B) is underexpressed. We aimed to clarify whether translational regulation underlies this phenomenon. This study evaluated the expression ofP27/CDKN1B, its targets (CCNE1,CDK2) and translational regulators (DKC1,RPS13,miR221,miR222) and screened forDKC1variants in sporadic pituitary adenomas. Samples were obtained during transsphenoidal surgery from 48 patients with pituitary adenomas: 10 ACTH-, 17 GH-secreting, and 21 nonfunctioning (NFPA). The control group comprised 7 normal pituitaries (NP) obtained during autopsies. Gene expression was assessed by RT-PCR and protein expression by immunohistochemistry. The 15 exons ofDKC1were sequenced. P27 protein underexpression was observed in all adenomas subtypes (p=0.001).CCNE1mRNA (p=0.01) overexpression, but not protein, was observed in NFPA. No differential gene expression among groups was observed inCDKN1BregulatorsRPS13(p=0.23) andDKC1(p=0.34). The expression ofmiR221andmiR222was similar among tumors and NP. FrequentDKC1variants (SNPs) were found in exon 14 and in the 3'-UTR in similar frequency to NCBI-dsSNP databases. We also observed rareDKC1variants in 11% of the studied tumor samples, indicating a high prevalence in pituitary adenomas, however, in silico studies failed to indicate deleterious effects. The high frequency ofDKC1variants may influence, in some extent, pituitary tumors development, without clear role in its tumorigenesis. Our data reinforce the P27 underexpression in pituitary adenomas and provide further evidence of the post-translational machinery involvement, although this phenomenon cannot be explained either by mis-expression of P27 translational regulators -DKC1,RPS13,miR221,miR222- or directly byDKC1mutations.
Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
C S
CS
Martins
Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
R C
RC
Camargo
Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
F P
FP
Saggioro
Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
L
L
Neder
Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Brazil.
H R
HR
Machado
Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
A C
AC
Moreira
Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
M
M
de Castro
D001483:Base Sequence; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014176:Protein Biosynthesis; D012015:Reference Standards
C436291:CDKN1B protein, human; D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27