Significance of intranuclear angiotensin-II type 2 receptor in oral squamous cell carcinoma
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Sayako Matsushima-Otsuka1, Rina Fujiwara-Tani1, Takamitsu Sasaki1, Hitoshi Ohmori1, Chie Nakashima1, Shingo Kishi1, Yukiko Nishiguchi1, Kiyomu Fujii1, Yi Luo2 and Hiroki Kuniyasu1
1Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
2Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China
Hiroki Kuniyasu, email: [email protected]
Keywords: AGTR2; renin-angiotensin system; ARB
Received: August 01, 2018 Accepted: November 01, 2018 Published: November 27, 2018
The renin-angiotensin system (RAS) is implicated in the maintenance of blood pressure and in many other biological processes including tumorigenesis and metastasis formation. Angiotensin-II (A-II) type 2 receptor (AGTR2) seems to be involved in different types of cancer; its role, however, is still unclear. Here, we investigated the role of RAS, and specifically that of AGTR2, in oral squamous cell carcinoma (OSCC) progression. AGTR2 has opposite effect on vasodilation and blood pressure compared to AGTR1. In 23 OSCCs, we found that the AGTR1/AGTR2 mRNA ratio was inversely associated with disease progression, while nuclear AGTR2 positivity was associated with disease progression. In the human OSCC cell lines HSC3 and HSC4, AGTR1 was associated with proliferation and invasion, while AGTR2 was associated with anti-apoptosis and anti-oxidative stress. Levels of nuclear AGTR2 confirmed by subcellular fractionation increased in hypoxic and hyperglycemic conditions, in which apoptosis and oxidative stress were suppressed and the redox status altered to reduction. Accumulation of nuclear AGTR2 by inhibition of extranuclear transportation decreased apoptosis and increased proliferation and invasion in HSC3 cells. Intratumoral angiotensin-II (but not serum angiotensin-II) levels were associated with stage and nuclear AGTR2 positivity. In OSCC cell lines, intracellular angiotensin-II was produced by themselves. Notably, losartan, an angiotensin receptor blocker, inhibited intracellular angiotensin-II production and AGTR2 nuclear localization to enhance the antitumoral effect of 5-FU in an OSCC tumor model. While the precise role of nuclear AGTR2 requires further examination, these data suggest that the intracellular angiotensin system might be a significant target for OSCC.
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