The classical view of the RAS is presented as a hormonal circulating system that is centred on the active peptide Angiotensin II (AngII). Angiotensinogen (AGT) is synthesised and released by the liver into the blood flow in response to decreased blood pressure or plasma sodium. The juxtaglo merular cells of the kidneys release aspartyl protease renin, which cleaves AGT at its N-terminus, AbstractThe hallmarks of cancer are described as the distinctive and complementary capacities that cells must acquire during the multistep development of becoming a cancer cell that allow them to survive, proliferate and disseminate. The reninangiotensin system (RAS) was first discovered and extensively studied in the physiological regulation of systemic arterial pressure. RAS signalling increases cell proliferation in malignancy by directly affecting tumour and stromal cells and by indirectly modulating the growth of vascular cells during angiogenesis. We aim to describe and give a general view of how the RAS is involved in several hallmarks of cancer and how this could open a window to several interesting treatments.

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Recent reports have indicated the participation of tight junction (TJ) proteins in the regulation of gene expression and cell proliferation. Here, we have studied the role of zona occludens (ZO)-2, a TJ peripheral protein, in the regulation of cyclin D1 transcription. We found that ZO-2 down-regulates cyclin D1 transcription in a dose-dependent manner. To understand how ZO-2 represses cyclin D1 promoter activity, we used deletion analyses and found that ZO-2 negatively regulates cyclin D1 transcription via an E box and that it diminishes cell proliferation. Because ZO-2 does not associate directly with DNA, electrophoretic mobility shift assay and chromatin immunoprecipitation (ChIP) assay were used to identify the transcription factors mediating the ZO-2-repressive effect. c-Myc was found to bind the E box present in the cyclin D1 promoter, and the overexpression of c-Myc augmented the inhibition generated by ZO-2 transfection. The presence of ZO-2 and c-Myc in the same complex was further demonstrated by immunoprecipitation. ChIP and reporter gene assays using histone deacetylases (HDACs) inhibitors demonstrated that HDACs are necessary for ZO-2 repression and that HDAC1 is recruited to the E box. We conclude that ZO-2 down-regulates cyclin D1 transcription by interacting with the c-Myc/E box element and by recruiting HDAC1.

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