Treatment with Angiotensin-(1-7) Prevents Development of Oral Papilloma Induced in K-ras Transgenic Mice

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

MOLECULAR DIVERSITY PRESERVATION INTERNATIONAL-MDPI

Lugar: Basel; Año: 2022

1422-0067

Oral Squamous Cell Carcinoma (OSCC) is the most common malignant cancer affectingthe oral cavity. It is characterized by high morbidity and very few therapeutic options. Angiotensin(Ang)-(1-7) is a biologically active heptapeptide, generated predominantly from AngII (Ang-(1-8)) bythe enzymatic activity of angiotensin-converting enzyme 2 (ACE 2). Previous studies have shown thatAng-(1-7) counterbalances AngII pro-tumorigenic actions in different pathophysiological settings,exhibiting antiproliferative and anti-angiogenic properties in cancer cells. However, the prevailingeffects of Ang-(1-7) in the oral epithelium have not been established in vivo. Here, we used aninducible oral-specific mouse model, where the expression of a tamoxifen-inducible Cre recombinase(CreERtam), which is under the control of the cytokeratin 14 promoter (K14-CreERtam), induces theexpression of the K-ras oncogenic variant KrasG12D (LSLK-rasG12D). These mice develop highlyproliferative squamous papilloma in the oral cavity and hyperplasia exclusively in oral mucosawithin one month after tamoxifen treatment. Ang-(1-7) treated mice showed a reduced papillomadevelopment accompanied by a significant reduction in cell proliferation and a decrease in pS6positivity, the most downstream target of the PI3K/Akt/mTOR signaling route in oral papilloma.These results suggest that Ang-(1-7) may be a novel therapeutic target for OSCC.