Effects of Angiotensin II Type 2 Receptor Overexpression on the Growth of Hepatocellular Carcinoma Cells In Vitro and In Vivo

Abstract

Increasing evidence suggests that the renin-angiotensin system (RAS) plays an important role in tumorigenesis. The interaction between Angiotensin II (AngII) and angiotensin type 1 receptor (AT1R) may have a pivotal role in hepatocellular carcinoma (HCC) and therefore, AT1R blocker and angiotensin I-converting enzyme (ACE) inhibitors may have therapeutic potential in the treatment of hepatic cancer. Although the involvement of AT1R has been well explored, the role of the angiotensin II Type 2 receptor (AT2R) in HCC progression remains poorly understood. Thus, the aim of this study was to explore the effects of AT2R overexpression on HCC cells in vitro and in mouse models of human HCC. An AT2R recombinant adenoviral vector (Ad-G-AT2R-EGFP) was transduced into HCC cell lines and orthotopic tumor grafts. The results indicate that the high dose of Ad-G-AT2R-EGFP–induced overexpression of AT2R in transduced HCC cell lines produced apoptosis. AT2R overexpression in SMMC7721 cells inhibited cell proliferation with a significant reduction of S-phase cells and an enrichment of G1-phase cells through changing expression of CDK4 and cyclinD1. The data also indicate that overexpression of AT2R led to apoptosis via cell death signaling pathway that is dependent on activation of p38 MAPK, pJNK, caspase-8 and caspase-3 and inactivation of pp42/44 MAPK (Erk1/2). Finally, we demonstrated that moderately increasing AT2R expression could increase the growth of HCC tumors and the proliferation of HCC cells in vivo. Our findings suggest that AT2R overexpression regulates proliferation of hepatocellular carcinoma cells in vitro and in vivo, and the precise mechanisms of this phenomenon are yet to be fully determined.

Angiotensin II Enhances Proliferation and Inflammation through AT1/PKC/NF-κB Signaling Pathway in Hepatocellular Carcinoma Cells

“…Firstly, our present results revealed increased expression of AT1 and decreased expression of AT2 in HCC cells and tissues by RT-PCR, Western Blot and IHC analysis, which is consistent with previous studies [36,46]. Next, blocking AT1 and AT1 siRNA significantly inhibited Ang II-induced cell proliferation and inflammatory responses in HCC cell lines, thus we could draw the conclusion that Ang II might be an important factor in proliferation and inflammation of HCC via the activation of AT1.…”

“…Ang II, the key effector in the RAS, acts through two well-defined receptors: AT1 and AT2 [35,36]. Recent study reported that AT1 expression was associated with enhance angiogenesis and cellular proliferation rate, but no relationship was found with AT2 in breast cancer [8].…”

Angiotensin-(1–1) Suppresses Hepatocellular Carcinoma Growth and Angiogenesis via Complex Interactions of Angiotensin II Type 1 Receptor, Angiotensin II Type 2 Receptor and Mas Receptor

“…In prostate cancer cells, AT 2 R overexpression induced apoptosis independently of Ang II but depended on p38-MAPK, caspase 3 and caspase 8 and was mediated via an extrinsic cell death-signaling pathway that partially depended on P53 activation (29). Consistent with this, AT 2 R overexpression in hepatocellular carcinoma cells also induced apoptosis, which was associated with a significant increase in caspase 3 activity and p38 phosphorylation (25). As noted above, Ang-(1-7) might promote tumor cell apoptosis by disrupting the stoichiometry of the AT 1 R and AT 2 R and subsequently altering their signaling.…”

“…In addition, PI3K/Akt signaling and epithelial growth factor receptor transactivation are involved in the regulation of AT 1 R-induced tumor cell proliferation (23,24). AT 2 R counteracts the effects of AT 1 R and exerts antiproliferative action by reducing S-phase cells and increasing G1-phase cells via suppression of CDK4 and cyclinD1 expression (25). AT 2 R also stimulates the activity of phosphotyrosine phosphatases (PTPs), which have been implicated in cell growth and differentiation (26).…”

Local ablative treatments for hepatocellular carcinoma: An updated review

“…The apparent superiority of sartans over ACE I may be due to the selective inhibition of angiotensin II receptor 1, responsible of the pro-fibrogenic and pro-angiogenic activity of angiotensin, while pro-apoptotic and anti-tumorigenic activity of receptor 2 is preserved and even enhanced in patients administered sartans unlike ACE I which prevent the binding of angiotensin II to both receptors[37]. However, these preliminary results still need further confirmation.…”