BRIT1 Inhibits Invasion and Metastasis by Regulating SERPINA5 in Hepatocellular Carcinoma

Abstract Purpose: BRIT1 (also known as MCPH1) is a DNA repair and tumor suppressor gene, whose alterations might be potentially associated with tumor progression and metastasis in HCC. SERPINA5, also known as Protein C inhibitor, has been reported to be decreased in a variety of human cancers and its decrease is associated with cellular invasion and tumor metastasis. However, little is known about the underlying mechanism of SERPINA5 downregulation and whether BRIT1 deficiency contributed to regulation control of SEPINA5 and invasion and metastasis in HCC.Methods: The expression of BRIT1 and SERPINs in HCC cells or human tumor tissue microarrays were determined by using quantitative real-time PCR, Western blot analysis, or immunohistochemistry. Migratory and invasive capacity of HCC cells were assessed by using in vitro wound-healing and Transwell-based assays or in vivo mouse xenograft tumor model. Dual luciferase reporter assay was performed to measure promoter activity of the SERPINA5 gene. HCC datasets analyzed in this study was performed by using Oncomine and cBioPortal Cancer Genomics with default parameters.Results: In this study we showed that BRIT1 protein was low expressed in HCC cells and tumor tissues. BRIT1 deficiency increased the capacity of migration, invasion and metastasis of HCC in vitro and in vivo; its expression level was positively correlated with that of SERPINA5 in HCC cells and tissue microarray. With the transcription factor E2F1, BRIT1 can upregulated the promoter activity of the SERPINA5 gene in HCC. Conclusion: These findings suggest that BRIT1 deficiency might induce tumor invasion and metastasis of HCC through regulatory control of SERPINA5 with the help of E2F1, and provide convincing evidence that BRIT1/SERPINA5 might be a novel biomarker for HCC metastasis.