Role of altered expression of Nedd4L in the pathogenesis of systemic malignancies

Abstract

I read with great interest the recent article by Takeuchi et al. (2011) in a recent issue of your journal. The article provides highly interesting reading. Interestingly, the past few years have seen the identification of new evidence that points to a significant role of altered Nedd4L expression in the pathogenesis of several systemic malignancies besides the gallbladder cancers reported in this study. For instance, decreased Nedd4L expression is associated with an increased risk of prostate carcinomas. In fact, higher Gleason scores are seen in prostate carcinomas with attenuated Nedd4L expression Hu et al. 2009. Similarly, decreased Nedd4L expression in gastric carcinomas correlates with a poor prognosis given the augmentation in metastatic capacity of the tumours Gao et al. 2011. Nedd4L is upregulated by N-myc downstream-regulated gene-1 (NDRG1) in pancreatic tissue: as a result, the Ras oncogenic pathway is inhibited by NDRG1, while the SMAD4 and PTEN tumour suppressor genes are up-regulated, and this therefore alters tumour invasion and metastasis in pancreatic tumours Kovacevic et al. 2012. Clearly, decreased expression of NDRG-1 and thereby downregulation of Nedd4L increase the malignant potential of pancreatic tumours. Interestingly, patients with Sezary syndrome demonstrate significantly accentuated expression of Nedd4L (Booken et al. 2008). Downregulation of Nedd4L correlates with aggressive progression of malignant gliomas (He et al. 2012. Likewise, Wnt/beta-catenin activation leads to upregulation of Nedd4L in hepatic tissue. Altered Wnt/beta-catenin activation and thereby dis-regulated Nedd4L expression can play a role in the pathogenesis of hepatocellular carcinomas (Lee et al. 2007. Based upon the observations noted here it is clear taht Clearly, Nedd4L expression and regulation plays a key role in the pathogenesis of several tumours in addition to the gallbladder cancers. Hopefully, the coming few years will see the development of novel new agents that can alter Nedd4L expression and thereby attenuate the malignant potential of tumours.