Urocortin and corticotropin-releasing factor receptor 2 in human renal cell carcinoma: disruption of an endogenous inhibitor of angiogenesis and proliferation

Abstract

Purpose Urocortin (Ucn) exerts its actions through activation of two corticotropin-releasing factor receptors (CRFRs), CRFR1 and CRFR2. Involvement of Ucn/ CRFR2 system in pathophysiological conditions such as the regulation of angiogenesis and inhibition of proliferation has been already reported. Suppression of neovascularization through reduction of vascular endothelial growth factor and inhibition of tumor cell cycling is modulated mainly through activation of CRFR2. To Wnd out a possible involvement of Ucn/CRFR2 in kidney tumor, we examined the expression of Ucn and CRFR2 in normal and tumoral kidney specimens. Methods We applied reverse transcriptase PCR (n = 14), immunoXuorescence (IF) on tissue microarrays (n = 25) and confocal microscopy to examine the mRNA expression and peptide/protein localization of Ucn and CRFR2 in normal kidney versus clear cell renal cell carcinoma, respectively.Results Ucn and CRFR2 mRNAs are expressed in normal and tumor specimens. In normal tissue, IF showed a cytoplasmic staining of Ucn mainly in proximal tubules, whereas a diVuse nuclear staining with diverse intensity was observed in tumoral tissues. CRFR2 was detected in proximal tubules and vasculature of normal specimens. Intriguingly, an almost complete loss of CRFR2 was observed in epithelial cells and microvessels within tumor tissues. Conclusions Here, and for the Wrst time, we show the expression of Ucn and CRFR2 in human kidney and renal cell carcinoma. We propose that the nuclear translocation of Ucn along with the loss of CRFR2 in epithelial cells and microvasculature of tumoral specimens may be involved in the pathobiology of renal cell carcinoma.

Hormone signaling pathways as treatment targets in renal cell cancer (Review)

“…The effects of Urocortin (Ucn) are also exerted through the activation of CRFRs and the involvement of the Ucn-CRFR system in pathophysiological conditions, including the regulation of angiogenesis and the inhibition of its proliferation was described in RCC. Suppression of neovascularization through VEGF reduction and tumor cell cycling inhibition is modulated mainly through the activation of CRHR2 (39). The direct activity of corticotropin-releasing hormones on ccRCC cells was only described recently.…”

Corticotropin Releasing Hormone and Urocortin 3 Stimulate Vascular Endothelial Growth Factor Expression through the cAMP/CREB Pathway

“…For instance, CRHR2-deficient mice become hypervascularized postnatally, the expression level of CRHR2 is diminished in tumor tissues along with increased microvessels, and the viral expression of Ucn 2 inhibits tumor vascularization (25)(26)(27)(28). Our recent study also suggests that activation of CRHR1 increases, while activation of CRHR2 decreases colitis-associated angiogenesis (29).…”

Interactions of Enhanced Urocortin 2 and Mineralocorticoid Receptor Antagonism in Experimental Heart Failure

“…Direct tubular actions of Ucn2 are also plausible given that not only is the CRF 2 receptor present in the proximal tubules of the kidney, 29 but also administration of the peptide is accompanied by increases in urine cAMP (Ucn2's intracellular second messenger). 12,15 Of interest, Ucn2 treatment in diabetic rodents improves renal structure and function in association with reduced kidney levels of transforming growth factor-β1, vascular endothelial growth factor and malonaldehyde (a marker of oxidative stress), and increased superoxide dismutase activity (an antioxidant with powerful anti-inflammatory actions).…”