Abstract
We recently confirmed that angiotensin II (Ang II) type 1 receptor (AT1R) was overexpressed in hepatocellular carcinoma tissue using a murine hepatoma model. Angiotensin(Ang)-(1-7) has been found beneficial in ameliorating lung cancer and prostate cancer. Which receptor of Ang-(1-7) is activated to mediate its effects is much speculated. This study was designed to investigate the effects of Ang-(1-7) on hepatocellular carcinoma, as well as the probable mechanisms. H22 hepatoma-bearing mice were randomly divided into five groups for treatment: mock group, low-dose Ang-(1-7), high-dose Ang-(1-7), high-dose Ang-(1-7) + A779 and high-dose Ang-(1-7) + PD123319. Ang-(1-7) treatment inhibited tumor growth time- and dose-dependently by arresting tumor proliferation and promoting tumor apoptosis as well as inhibiting tumor angiogenesis. The effects of Ang-(1-7) on tumor proliferation and apoptosis were reversed by coadministration with A779 or PD123319, whereas the effects on tumor angiogenesis were completely reversed by A779 but not by PD123319. Moreover, Ang-(1-7) downregulated AT1R mRNA, upregulated mRNA levels of Ang II type 2 receptor (AT2R) and Mas receptor (MasR) and p38-MAPK phosphorylation and suppressed H22 cell-endothelial cell communication. Thus, Ang-(1-7) administration suppresses hepatocellular carcinoma via complex interactions of AT1R, AT2R and MasR and may provide a novel and promising approach for the treatment of hepatocellular carcinoma.
Highlights
A functional renin-angiotensin system (RAS) has been identified in a variety of tumors, including breast cancer, cervical cancer, prostate cancer, pancreatic carcinoma and colon cancer (1)
A wealth of evidence indicates that RAS plays an important role in the pathogenesis of cancer, and angiotensin-converting enzyme (ACE), angiotensin I (Ang I), angiotensin II (Ang II), angiotensin-converting enzyme 2 (ACE2) and angiotensin (Ang)
The salutary effects of Ang-(1–7) on tumor growth were largely offset by A779 or PD123319
Summary
A functional renin-angiotensin system (RAS) has been identified in a variety of tumors, including breast cancer, cervical cancer, prostate cancer, pancreatic carcinoma and colon cancer (1). A wealth of evidence indicates that RAS plays an important role in the pathogenesis of cancer, and angiotensin-converting enzyme (ACE), angiotensin I (Ang I), angiotensin II (Ang II), angiotensin-converting enzyme 2 (ACE2) and angiotensin (Ang)-. Ang II mediates biological effects by activating two distinct G protein-coupled receptors, the Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R). RAS is a potential chemotherapeutic target for cancer because Ang II, though activation of AT1R, regulates cell proliferation and migration, angiogenesis, inflammation and extracellular matrix formation. Ang-(1–7), a heptapeptide converted from Ang I by ACE and endopeptidases (including prolyl oligopeptidase, neprilysin and thimet oligopeptidase) and from Ang II by ACE2, binds to a distinct plasma membrane G protein–coupled
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