Abstract
Bromodomain-containing protein 7 (BRD7) is a subunit of the PBAF complex, which functions as a transcriptional cofactor for the tumor suppressor protein p53. Down-regulation of BRD7 has been demonstrated in multiple types of cancer. This study aimed to investigate BRD7 expression and its tumor suppressive effect in hepatocellular carcinoma (HCC). The expression of BRD7 was examined in clinical specimens of primary HCC and in HCC cell lines through real-time quantitative PCR, western blot and immunohistochemistry. The prognostic value of BRD7 expression and its correlation with the clinicopathological features of HCC patients were statistically analyzed. The effect of BRD7 on the tumorigenicity of HCC was also examined using proliferation and colony-formation assays, cell-cycle assays, migration and cell-invasion assays, and xenograft nude mouse models. BRD7 was down-regulated in tumor tissues and HCC cell lines. BRD7 protein expression was strongly associated with clinical stage and tumor size. Kaplan-Meier survival curves revealed higher survival rates in patients with higher BRD7 expression levels compared to those with lower BRD7 levels. A multivariate analysis indicated that BRD7 expression was an independent prognostic marker. The re-introduction of BRD7 expression significantly inhibited proliferation, colony formation, migration and invasion and led to cell cycle arrest in HCC cells in vitro. Furthermore, experiments in mice suggested that BRD7 overexpression suppresses HCC tumorigenicity in vivo. In conclusions, our data indicated that BRD7 may serve as a tumor suppressor in HCC and may be a novel molecular target for the treatment of HCC.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the second most common cause of cancer-related deaths worldwide, especially in developing countries [1,2,3]
To explore differences in Bromodomain-containing protein 7 (BRD7) expression at the protein level, western blot analyses were performed on the 25 paired tissue samples and on the hepatocellular carcinoma (HCC) cell lines
Precise therapy and a lasting cure for advanced HCC requires deepening our understanding of HCC and identifying specific biomarkers that are involved in these genetic alterations and signaling pathways
Summary
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the second most common cause of cancer-related deaths worldwide, especially in developing countries [1,2,3]. Transarterial chemoembolization (TACE), selective intra-arterial radiotherapy (SIRT) and systemic chemotherapy are used as palliatives in HCC patients, surgery and local ablative therapies remain the only curative treatment options for more advanced disease [4]. Sorafenib, which is the only FDA-approved systemic treatment for HCC, is the current standard of care for patients with advanced HCC [5]. Hepatocarcinogenesis is a multifactorial and multistep process in which many oncogenes and tumor suppressor genes are altered, including inactivation of the tumor suppressor gene p53, activation of the MYC oncogene and mutations in other genes [7, 8]. Identifying and investigating the genetic alterations involved in HCC development and progression are crucial to understanding of the mechanisms of hepatocarcinogenesis and to improving the prognosis of HCC patients [9]
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