Angiotensin 1-7 inhibits angiotensin II-stimulated oral cancer cell motility

In addition to its well documented vasoactive properties, angiotensin II (Ang II) is able to stimulate angiogenesis and act as a mitogen, promoting cellular proliferation; these effects are predominantly mediated through a G protein coupled receptor AT1R. Blockade of AT1R inhibits angiogenesis and cancer cell proliferation in a number of tumour types. Recently, evidence has emerged that Ang II is also able to promote tumour invasion, although the mechanisms by which it does so remain largely obscure, and nothing is known of its role in oral cancer. Objectives: In this BSOMP and Yorkshire Cancer Research-funded project we investigated the possibility that Ang II may promote oral cancer cell motility and that inhibiting Ang II activity may be a novel strategy to inhibit oral cancer progression. Methods: The abundance of AT1R transcripts was assessed in primary normal oral keratinocytes, normal oral fibroblasts, and cell lines derived from dysplasias, oral squamous cell carcinomas (OSCC) and a metastatic lesion, by qPCR. The ability of Ang II and Ang 1-7 to influence OSCC cell migration and invasion was analysed using transwells and Matrigel invasion assays, respectively. Results: We show that Ang II can promote the invasion and migration of OSCC cells in an autocrine and paracrine manner. This is mediated via AT1R, which we show is dramatically over-expressed in OSCC cells compared to normal keratinocytes, and highly expressed in oral fibroblasts. The effects of Ang II on autocrine and paracrine signalling are inhibited by an AT1R antagonist and by Ang 1-7, a peptide produced from Ang II by the action of angiotensin converting enzyme 2, via its receptor, MasR. Conclusions: These data are the first to demonstrate a role for the renin-angiotensin system in oral carcinogenesis and raise the possibility of utilising AT1R receptor antagonsists and/or Ang 1-7 as novel therapeutic agents for OSCC.