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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common human cancers worldwide and the third most common cause of cancer-related deaths
Recombinant Adenoviral Constructs For these experiments, we constructed and prepared two recombinant adenoviral vectors as detailed previously [22]: an adenoviral vector containing the enhanced green fluorescent protein gene controlled by a cytomegalovirus promoter (Ad-CMVEGFP) and an adenoviral vector containing genomic angiotensin II Type 2 receptor (AT2R) (GAT2R) DNA with introns 1 and 2 and the encoding region and enhanced green fluorescent protein gene controlled by cytomegalovirus promoters (Ad-G-AT2R-EGFP)
Our data demonstrate that the high Ad-GAT2R-EGFP dose –induced AT2R overexpression in all the HCC cell lines tested produced apoptosis (Fig. 4) involving cell death signaling pathway that is dependent on activation of p38 MAPK, pJNK, and caspase-3 and inactivation of pp42/44 MAPK
Summary
Hepatocellular carcinoma (HCC) is one of the most common human cancers worldwide and the third most common cause of cancer-related deaths. More than 80% of HCC cases originate in developing countries [1]. Diagnosis of advanced stage of HCC is a devastating experience for both patients and family. HCC is often diagnosed at an advanced stage when it is no longer susceptible to curative therapies. The highly drug-metabolic and multidrug resistant transporter proteins in tumor cells further diminish the efficacy of current therapeutic regimens for HCC [2]. Alternative approaches are needed to overcome these barriers to enhance therapeutic efficacy
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