Abstract
BackgroundEpithelial-mesenchymal transition (EMT) elicits dramatic changes, including cytoskeleton remodelling as well as changes in gene expression and cellular phenotypes. During this process, actin filament assembly plays an important role in maintaining the morphology and movement of tumour cells. Capping protein, a protein complex referred to as CapZ, is an actin-binding complex that can regulate actin cytoskeleton remodelling. CAPZA1 is the α1 subunit of this complex, and we hypothesized that CAPZA1 regulates EMT through the regulation of actin filaments assembly, thus reducing the metastatic ability of hepatocellular carcinoma (HCC) cells.MethodsImmunohistochemistry was used to detect CAPZA1 expression in 129 HCC tissues. Western blotting and qPCR were used to detect CAPZA1, EMT markers and EMT transcription factors in HCC cells. Transwell migration and invasion assays were performed to observe the migration and invasion of HCC cells. Cell Counting Kit-8 (CCK-8) was used to detect the proliferation of HCC cells. Immunoprecipitation was used to detect the interaction between CAPZA1 and actin filaments. Finally, a small animal magnetic resonance imager (MRI) was used to observe metastases in HCC cell xenografts in the liver.ResultsCAPZA1 expression levels were negatively correlated with the biological characteristics of primary HCC and patient prognosis. CAPZA1 expression was negatively correlated with the migration and invasion of HCC cells. CAPZA1 down regulation promoted the migration and invasion of HCC cells. Conversely, CAPZA1 overexpression significantly inhibited the migration and invasion of HCC cells. Moreover, CAPZA1 expression levels were correlated with the expression of the EMT markers E-cadherin, N-cadherin and Vimentin. Furthermore, the expression of Snail1 and ZEB1 were negatively correlated with CAPZA1 expression levels. Similarly, CAPZA1 significantly inhibited intrahepatic metastases of HCC cells in an orthotopic transplantation tumour model.ConclusionsCAPZA1 inhibits EMT in HCC cells by regulating actin cytoskeleton remodelling, thereby reducing the metastatic ability of the cells. Together, our data suggest that CAPZA1 could be a useful biomarker for clinical determination of the prognosis of HCC patients.
Highlights
Epithelial-mesenchymal transition (EMT) elicits dramatic changes, including cytoskeleton remodelling as well as changes in gene expression and cellular phenotypes
By hepatocellular carcinoma (HCC) differentiation the patients were divided into well differentiated: 10.4% (n = 10), moderately differentiated: 73.3% (n = 94), and poorly differentiated: 16.3% (n = 25). 9.3% (n = 12) of patients had lymph node metastasis, 44.1% (n = 53) of patients had vascular invasion, 28.7% (n = 37) of patients had extrahepatic metastasis before or after surgery, 70.5% (n = 91) of patients had recurrence within 5 years of surgery, 62.8% (n = 81) of patients died from cancer-related deaths within 5 years of surgery, and 3.1% (n = 4) of patients died from non-cancer-related deaths (Table 2)
Capping protein α1 subunit (CAPZA1) expression is negatively correlated with the biological characteristics of primary HCC and patient prognosis CAPZA1 immunohistochemistry was conducted on the 129 HCC tissue samples and scored according to staining intensity
Summary
Epithelial-mesenchymal transition (EMT) elicits dramatic changes, including cytoskeleton remodelling as well as changes in gene expression and cellular phenotypes. During this process, actin filament assembly plays an important role in maintaining the morphology and movement of tumour cells. EMT refers to the biological process wherein epithelial cells gain a mesenchymal phenotype through specific changes in gene expression [5]. As with many other cancer cells, HCC cells can obtain mesenchymal characteristics through EMT This allows cells to detach from the primary lesion, invade blood vessels and colonize distant sites, forming metastatic lesions [7]. Inhibiting metastasis by regulating EMT in HCC has become a key objective over recent years
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