Abstract
Amplified in breast cancer 1 (AIB1) is a transcriptional coactivator for nuclear receptors and other transcription factors. AIB1 has an important role in malignancy of several cancers such as breast and prostate cancers. However, its involvement in human hepatocellular carcinoma (HCC) progression remains unclear. Here, we found that AIB1 protein was overexpressed in 23 of 34 human HCC specimens (68%). Down-regulation of AIB1 reduced HCC cell proliferation, migration, invasion, colony formation ability and tumorigenic potential in nude mice. These phenotypic changes caused by AIB1 knockdown correlated with increased expression of the cell cycle inhibitor p21(Cip1/Waf1) and decreased Akt activation and the expression of proliferating cell nuclear antigen (PCNA) and matrix metallopeptidase MMP-9. In agreement with these findings, clinical AIB1-positive HCC expressed higher levels of PCNA than AIB1-negative HCC. A positive correlation was established between the levels of AIB1 protein and PCNA protein in HCC, suggesting that AIB1 may contribute to HCC cell proliferation. In addition, MMP-9 expression in AIB1-postive HCC was significantly higher than that in AIB1-negative HCC, suggesting that AIB1-postive HCC may be more invasive. Collectively, our results show that overexpression of AIB1 promotes human HCC progression by enhancing cell proliferation and invasiveness. Therefore, AIB1 is a master regulator of human HCC growth and might be a useful molecular target for HCC prognosis and treatment.
Highlights
Hepatocellular carcinoma (HCC) grows rapidly and frequently associates with vascular invasion, metastasis, recurrence and poor prognosis
Amplified in breast cancer 1 (AIB1) can interact with nuclear receptors such as estrogen receptor and androgen receptor (AR), as well as other transcription factors such as activator protein-1 (AP-1), nuclear factor-kB (NF-kB) and E2F1 to enhance their effects on target gene transcription (Anzick et al, 1997; Chen et al, 1997; Li et al, 1997; Torchia et al, 1997; Tan et al, 2000; Werbajh et al, 2000; Louie et al, 2004)
We report that the expression of AIB1 protein is significantly increased in 68% of primary HCC samples
Summary
Hepatocellular carcinoma (HCC) grows rapidly and frequently associates with vascular invasion, metastasis, recurrence and poor prognosis. Overexpression of AIB1 in transgenic mouse mammary glands causes a high incidence of spontaneous breast cancer (TorresArzayus et al, 2004), whereas AIB1 deficiency impairs the insulin-like growth factor-I/Akt signaling pathway, inhibits cell proliferation and migration and significantly suppresses the mouse mammary tumor induced by oncogene H-ras or chemical carcinogen (Wang et al, 2000; Xu et al, 2000; Kuang et al, 2004, 2005). These results indicate that AIB1 has a critical role in breast cancer initiation and progression. These results indicate that AIB1 is a bona fide oncogene
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