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.