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

International Journal of Molecular Sciences

Thomas Walther¹  Melisa Suberbordes²  Ana R. Raimondi²  Marina Ayre²  Carolina Schere-Levy²  Albana Gattelli²  Edith C. Kordon²  Darío M. Ferri² 

[1] Department of Pharmacology and Therapeutics, School of Medicine and School of Pharmacy, University College Cork, T12 YN60 Cork, Ireland;Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (UBA), Buenos Aires C1428EGA, Argentina;

关键词: Ang-(1-7);    K-ras;    mTor;    oral cancer;    papilloma;    tumor;   

DOI  :  10.3390/ijms23073642

来源: DOAJ

【 摘 要 】

Oral Squamous Cell Carcinoma (OSCC) is the most common malignant cancer affecting the 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)) by the enzymatic activity of angiotensin-converting enzyme 2 (ACE 2). Previous studies have shown that Ang-(1-7) counterbalances AngII pro-tumorigenic actions in different pathophysiological settings, exhibiting antiproliferative and anti-angiogenic properties in cancer cells. However, the prevailing effects of Ang-(1-7) in the oral epithelium have not been established in vivo. Here, we used an inducible oral-specific mouse model, where the expression of a tamoxifen-inducible Cre recombinase (CreER^tam), which is under the control of the cytokeratin 14 promoter (K14-CreER^tam), induces the expression of the K-ras oncogenic variant KrasG12D (LSLK-ras^G12D). These mice develop highly proliferative squamous papilloma in the oral cavity and hyperplasia exclusively in oral mucosa within one month after tamoxifen treatment. Ang-(1-7) treated mice showed a reduced papilloma development accompanied by a significant reduction in cell proliferation and a decrease in pS6 positivity, 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.

【 授权许可】

Unknown