title: Phosphorylation of cAMP response element binding protein (CREB) as a marker of hypoxia in pituitary adenoma.
abstract: Hypoxia appears to be causatively related to pituitary adenoma. Currently, no biomarkers are available for the postoperative assessment of hypoxia in patient samples. Since the cAMP response element binding protein (CREB) is phosphorylated under hypoxic conditions, we examined whether CREB phosphorylation levels may be exploited as a novel biomarker for hypoxia in pituitary adenoma tissues. HP-75 human pituitary adenoma cells were incubated in 21% or 1% oxygen (normoxia and hypoxia, respectively), and Western blotting was employed to compare the levels of CREB and phosphorylated CREB (p-CREB). Our results show that p-CREB levels are significantly elevated under 1% oxygen, whereas the total CREB concentration remains unchanged. We further tested whether this phosphorylation is applicable as a marker of hypoxia in pituitary adenoma tissues removed by transsphenoidal surgery from 45 patients (32 females and 13 males, 22-78 years old). Fluorescence double immunohistochemistry data revealed that p-CREB in adenoma tissues is significantly elevated, and displays a positive correlation with Knosp grading (Spearman rank correlation; P = 0.0483, r = 0.3412), but no significant association with tumor subtype (Kruskal-Wallis analysis, CREB, P = 0.1072; p-CREB, P = 0.1888; phosphorylation ratio, P = 0.4916). Our findings collectively suggest that CREB phosphorylation may be employed as an in situ marker for hypoxia. Moreover, hypoxia and/or phosphorylation of CREB are associated with the cell invasiveness of pituitary adenomas.
authors.affiliation: Department of Neurosurgery, Nippon Medical School, 113-8603, Tokyo, Japan. dai_sampo@yahoo.co.jp
authors.forename: Daijiro
authors.initials: D
authors.lastname: Morimoto
authors.forename: Daizo
authors.initials: D
authors.lastname: Yoshida
authors.forename: Masahiro
authors.initials: M
authors.lastname: Noha
authors.forename: Masanori
authors.initials: M
authors.lastname: Suzuki
authors.forename: R Yoshiyuki
authors.initials: RY
authors.lastname: Osamura
authors.forename: Akira
authors.initials: A
authors.lastname: Teramoto
mesh_terms: D000236:Adenoma / Q000378:metabolism*; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D010766:Phosphorylation; D010911:Pituitary Neoplasms / Q000378:metabolism*; D018709:Statistics, Nonparametric
chemical_list: D015415:Biomarkers; D017362:Cyclic AMP Response Element-Binding Protein