RSUME is implicated in HIF-1-induced VEGF-A production in pituitary tumour cells

SHAN, B.; GEREZ, J.A.; HAEDO, M.R.; FUERTES, M.; THEODOROPOULOU, M.; BUCHFELDER, M.; LOSA, M.; STALLA, G.K.; ARZT, E.; RENNER, U.

ENDOCRINE - RELATED CANCER

BIOSCIENTIFICA LTD

Lugar: Bristol; Año: 2012 vol. 19 p. 13 - 27

1351-0088

The recently cloned small RWD-domain containing protein RSUME was shown to increase proteinlevels of hypoxia-inducible factor-1alpha (HIF-1alpha). The latter is the oxygen-regulated subunit of HIF-1,the most important transcription factor of the cellular adaptive processes to hypoxic conditions.It is also a major regulator of vascular endothelial growth factor-A (VEGF-A), which is criticallyinvolved in the complex process of tumour neovascularisation. In this study, the expression androle of RSUME in pituitary tumours was studied. We found that RSUME mRNA was up-regulatedin pituitary adenomas and significantly correlated with HIF-1alpha mRNA levels. Hypoxia (1% O2) ortreatment with hypoxia-mimicking CoCl2 enhanced RSUME and HIF-1alpha expression, inducedtranslocation of HIF-1a to the nuclei and stimulated VEGF-A production both in pituitary tumourcell lines and primary human pituitary adenoma cell cultures. When RSUME expression wasspecifically down-regulated by siRNA, the CoCl2-induced increase VEGF-A secretion wasstrongly reduced which was shown to be a consequence of the RSUME knockdown-associatedreduction of HIF-1alpha synthesis. Thus, RSUME plays an important role in initiating pituitary tumourneovascularisation through regulating HIF-1a levels and subsequent VEGF-A production and maytherefore be critically involved in pituitary adenoma progression.