TRIM52 up-regulation in hepatocellular carcinoma cells promotes proliferation, migration and invasion through the ubiquitination of PPM1A

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.

N6-Methyladenosine modification of the TRIM7 positively regulates tumorigenesis and chemoresistance in osteosarcoma through ubiquitination of BRMS1

“…BRMS1 has also been found in the nucleus and the cytoplasm, which is consistent with earlier reports that classified BRMS1 as a nucleo-cytoplasmic protein [ 30 , 31 ]. The Ring finger domain of the TRIM family proteins may mediate the ubiquitination and stabilization of different substrates through the E3 ubiquitin ligase activity [ 32 , 33 ]. TRIM7 drives lung tumorigenesis by mediating Lys63-linked ubiquitination of the AP-1 co-activator RACO-1, which leads to RACO-1 protein stabilization [11] .…”

TRIM2 downregulation in clear cell renal cell carcinoma affects cell proliferation, migration, and invasion and predicts poor patients’ survival

“…In recent years, the novel tumor promoters or tumor suppressors’ role of tripartite motif containing (TRIM) proteins in various cancers has attracted much attention to different tumor researchers. 12 , 13 TRIM protein has been widely reported to have an extensive range role in biological processes of autophagy, inflammation, immunity, and cancer. 14 NHL is the subgroup of TRIM protein, which contains four mammalian paralogs (TRIM2, TRIM3, TRIM32, and TRIM71), and TRIM3 acts as tumor suppressor, can block tumor growth by preventing cyclin D1-cdk4 accumulation through sequestering p21 in glioblastomas, and also can regulate stem cell factors and epithelial–mesenchymal transition (EMT) regulators in gastric cancer.…”

miR-378a-3p inhibits ischemia/reperfusion-induced apoptosis in H9C2 cardiomyocytes by targeting TRIM55 via the DUSP1-JNK1/2 signaling pathway

“…The TRIM protein family is a family of E3 ubiquitin ligases, including TRIM31 [27], TRIM52 [28], TRIM50 [29], and TRIM18 [30], and were found to be related to a broad range of biological and pathological processes via ubiquitination. TRIM55 was also identified as the first ubiquitin ligase to inhibit PPAR expression via posttranslational ubiquitination and to protect against diabetic cardiomyopathy [31].…”