Abstract
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.
Highlights
Angiotensin II (A-II) is converted into angiotensin by renin and causes vessel constriction and a rise in blood pressure by binding to the angiotensin type 1 receptor (AGTR1)
Nuclear angiotensin-II type 2 receptor (AGTR2) positivity was associated with tumor expansion, nodal metastasis and clinical stage (Table 1)
We found that the expression of angiotensin-II type 1 receptor (AGTR1) and AGTR2 increased as disease progressed; AGTR2 showed a more pronounced increment than AGTR1 and, the AGTR1 to AGTR2 ratio decreased in advanced-stage cases
Summary
Angiotensin II (A-II) is converted into angiotensin by renin and causes vessel constriction and a rise in blood pressure by binding to the angiotensin type 1 receptor (AGTR1). A-II induces cancer cell growth and invasion via AGTR1 [1]. In colorectal cancer (CRC) associated with diabetes, the activation of the reninangiotensin system (RAS) is caused by hyperglycemic stimuli, which promote liver metastasis [2]. The activation of RAS is associated with malignant phenotypes through AGTR1 [1, 3]. A-II binds to angiotensin type 2 receptor (AGTR2) to cause effects opposite to those of AGTR1: vasodilatation and a fall in blood pressure [4]. Recent investigations have reported a role of AGTR2 in cardiovascular system, brain and renal function and the modulation of various processes in organ development, cell differentiation, and tissue repair [5]
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