Abstract
BackgroundMany tripartite motif (TRIM) family proteins have been reported to be of great importance in the initiation and progression in hepatocellular carcinoma (HCC). However, the biological role and regulatory mechanism of tripartite motif containing 52 (TRIM52) in HCC development and progression are poorly defined.MethodsImmunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) or Western blot analysis was used to detect TRIM52, p21, matrix metalloproteinase 2 (MMP2), protein phosphatase, Mg2+/Mn2+ dependent 1A (PPM1A), p-Smad2/3 and Smad2/3 levels in HCC tissues and cell lines. HCC cell proliferation and cell cycle were measured by Cell Counting Kit-8 (CCK-8) and flow cytometry analysis, respectively. HCC cell migration and invasion were measured by Transwell assay. Tumor growth of HCC cells in vivo was measured using the nude mouse xenograft model. The correlation between TRIM52 and PPM1A was measured by co-immunoprecipitation (Co-IP) and ubiquitination analysis in vitro.ResultsTRIM52 was significantly up-regulated in the HCC tissues in comparison with the adjacent non-tumor hepatic tissues. TRIM52 was also up-regulated in HCC cell lines (MHCC-97H and MHCC-97L cells) compared with normal human liver cell line LO2. TRIM52 down-regulation by RNA interfering in MHCC-97H cells enhanced inhibition of cell proliferation, migration and invasion. TRIM52 down-regulation also induced MHCC-97H cells arrest in G0-G1 phase cell cycle and inhibited MHCC-97H cell growth in the nude mice. However, TRIM52 up-regulation in MHCC-97L cells promoted cell proliferation, migration and invasion. Furthermore, TRIM52 down-regulation significantly increased p21 and PPM1A expression, but inhibited MMP2 expression and induced Smad2/3 dephosphorylation in MHCC-97H cells, which were reversed by TRIM52 up-regulation in MHCC-97L cells. TRIM52 was found interacted with PPM1A and TRIM52 down-regulation inhibited the ubiquitination of PPM1A. Importantly, PPM1A up-regulation in MHCC-97L cells significantly suppressed TRIM52-mediated enhancement on cell proliferation, invasion and migration.ConclusionsOur findings suggest that TRIM52 up-regulation promotes proliferation, migration and invasion of HCC cells through the ubiquitination of PPM1A.
Highlights
Many tripartite motif (TRIM) family proteins have been reported to be of great importance in the initiation and progression in hepatocellular carcinoma (HCC)
QRT-PCR and Western blot analysis showed that tripartite motif containing 52 (TRIM52) was up-regulated in HCC cell lines, including MHCC-97H and MHCC-97L cells, compared with normal human liver cell line LO2 (Fig. 1d–f )
TRIM52 interacts with PPM1A and TRIM52 downregulation inhibits the ubiquitination of PPM1A To elucidate the underlying mechanisms by which TRIM52 exerts its function in HCC carcinogenesis, we identified protein candidates that were functionally associated with TRIM52
Summary
Many tripartite motif (TRIM) family proteins have been reported to be of great importance in the initiation and progression in hepatocellular carcinoma (HCC). The biological role and regulatory mechanism of tripartite motif containing 52 (TRIM52) in HCC development and progression are poorly defined. Hepatocellular carcinoma (HCC) is one of the most common malignant primary liver tumors and is the third leading cause of global cancer death, in East Asia and South Africa [1]. Cirrhosis caused by hepatitis B virus (HBV) or hepatitis C virus (HCV) is reported to be associated with HCC [4]. Understanding the mechanisms underlying key genes is essential for further clarifying the pathogenesis of HCC and can provide opportunities for the development of novel therapeutic strategies
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