We observed consistent down-regulation of the bona fide YAP targe

We observed consistent down-regulation of the bona fide YAP target gene CYR61 on YAP knockdown in all cell lines examined. CYR61 is a positive regulator of cell growth [28] and has been implicated as a proangiogenic factor in highly vascularized RCC, acting alongside vascular endothelial growth factor (VEGF) and exerting additive nonoverlapping functions [29]. CYR61 up-regulation correlated with loss of von Hippel-Lindau protein expression, although its expression was only partly dependent on Hypoxia-inducible factor 2-alpha

function, suggesting additional mechanisms that contribute to CYR61 up-regulation in RCC [29]. Furthermore, recent reports linked CYR61 with integrin-mediated cell migration and invasion RO4929097 price in prostate cancer cell lines, AC220 datasheet hinting at a potential role in metastasis [30]. THBS1 is one of the most potent physiological

antiangiogenic factors and its expression has been reported as an independent prognostic factor in ccRCC with retained expression being associated with increased survival [31]. It is therefore somewhat surprising to observe down-regulation of THBS1 mRNA on YAP knockdown in all cell lines analyzed. YAP might interfere with the network of proangiogenic and antiangiogenic factors, such as CYR61 and THBS1, in ccRCC, tipping the balance toward a homeostasis that favors the proliferation and survival of the tumor cells. EDN1 and EDN2 were the most prominently downregulated genes in MZ1774 cells on YAP knockdown. Endothelins are important regulators of

kidney function, and endogenous endothelin is involved in the regulation of renal cell growth and proliferation, as well as fluid and electrolyte excretion. Production Liothyronine Sodium of endothelins in the kidney is increased in numerous renal diseases [32], and ccRCC tumors have been reported to express EDN1 and its receptor ETA with ccRCC cell lines secreting EDN1 [33] and [34]. The selective endothelin-A receptor antagonist atrasentan has been used in combination with interferon-alpha in a phase I study in metastatic RCC, albeit with moderate clinical antitumor effects [35]. The impact of YAP knockdown on EDN2 expression was most pronounced and present in all three cell lines tested, whereas EDN1 down-regulation could be cross-validated in A498 but not in ACHN YAP knockdown cells. As ACHN YAP knockdown cells displayed the same phenotype in respect to reduced cancer cell proliferation and migration and did form smaller xenograft tumors in vivo, EDN2 seems to be one of the main effectors responsible for these effects. In line with this hypothesis, we found that YAP and EDN2 expression correlates in clinical tumor specimen of patients with ccRCC as assessed by immunohistochemistry.

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