研究显示AT2R具有抑制生长诱导凋亡的作用，机制尚未明确。前期发现：AT2R过表达能够抑制肝癌细胞增殖、促进凋亡，此过程涉及MAPK途径p38和JNK的激活及Erk的抑制；酵母双杂交筛选AT2R相互作用蛋白得到ATIP（抑癌基因MTUS1的产物），由此推测AT2R可能通过ATIP调控MAPK通路从而诱导肝癌细胞发生凋亡，假设尚需证实。本项目拟1.通过Pull-down、免疫共沉淀以及干扰技术验证AT2R/ATIP的相互作用；2.探究AT2R/ATIP对MAPK通路（包括p38、Erk以及JNK）的调控方式，并采用PCR Array技术通量寻找凋亡相关调节分子；3.在肝癌移植瘤模型上研究嗜肝靶向性腺相关病毒介导的AT2R过表达对肿瘤生长及相关预后指标的影响。本研究有望深入揭示AT2R 促肝癌细胞凋亡的分子机制，同时对AT2R作为凋亡诱导因子的肿瘤治疗进行初步尝试，为肝癌基因治疗研究奠定基础。

Hepatocellular carcinoma (HCC) is one of the major malignant tumors in China, which is characterized of high lethality only listing behind the lung cancer and threatens to human health. A lot of research had proved that endogenous apoptosis inducers and cell growth regulators were important targets of treating with cancers. Angiotensin II (AngII), a main biopolypeptide of the RAS, has important pathophysiologic roles participating in cardiac hypertrophy, vascular cell proliferation, inflammation, and tissue remodeling acting through G-protein-coupled receptors (GPCRs), Type 1 (AT1R) and Type 2 (AT2R). . Some studies have shown antigrowth, antiproliferative and apoptosis-inducing effects of Ang II via AT2R in some non-tumor cells. Recently, our study demonstrated that AT2R overexpression caused inhibition of growth and stimulation of apoptosis in hepatocellular carcinoma cells. A recombinant adenoviral vector expressing AT2R (Ad-G-AT2R-EGFP) was transduced into two HCC cell lines, SMMC7721 and Bel7402. Following transduction, apoptosis was analyzed by terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining. The data indicate that increased expression of AT2R alone resulted in apoptosis in the HCC cell lines. Furthermore, AT2R overexpression in SMMC7721 cells inhibited cell proliferation with a significant reduction of S-phase cells and an enrichment of G1-phase cells. This demonstrates that increased AT2R expression in HCC cells may have potential therapeutic applications for this disease, and suggest that AT2R is a promising novel target gene for HCC gene therapy (PLoS One, 2013, 8(12):e83754). However, the mechanism of AT2R inducing tumor apoptosis remains unclear. . In our early studies, it had been found 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). Moreover, a candidate for interacting with AT2R, ATIP, which a product of tumor suppressor gene MTUS1, had been found. Therefore, it was supposed that MAPK-induced apoptosis was regulated by AT2R/ATIP. In this project, we plan to test our hypothesis by pursuing the following three specific aims: 1.Interaction between AT2R and ATIP would be further verified by Pull-down,Co-IP and RNA interference. 2. Regulating pattern of MAPK pathway, including p38, Erk and JNK, by AT2R/ATIP and other regulatory moleculars participating in apoptosis would be further uncovered. 3. Mice HCC model will be used to study the anticancer and prognostic effects of AT2R overexpression mediated by mutant adeno-associated virus targeting liver..