Abstract
BackgroundHepatocellular carcinoma (HCC) is the most major type of primary hepatic cancer. Serine hydroxymethyltransferase 1 (SHMT1) is recently found to play critical roles in human cancers including lung cancer, ovarian cancer and intestinal cancer. However, the expression, function and the underlying mechanisms of SHMT1 in HCC remain uncovered.MethodsqRT-PCR, immunohistochemistry and immunoblotting were performed to detect the expression of SHMT1 in HCC tissues and cell lines. HCC cell migration and invasion were determined by Boyden chamber and Transwell assay in vitro, and tumor metastasis was assessed via lung metastasis model in mice. The expression of key factors involved in epithelial-to-mesenchymal transition (EMT) process was evaluated by western blotting.ResultsIn this study, data mining of public databases and analysis of clinical specimens demonstrated that SHMT1 expression was decreased in HCC. Reduced SHMT1 level was correlated with unfavorable clinicopathological features and poor prognosis of HCC patients. Gain- and loss-of-function experiments showed that SHMT1 overexpression inhibited the migration and invasion of HCCLM3 cells while SHMT1 knockdown enhanced the metastatic ability of Hep3B cells. Furthermore, qRT-PCR and western blotting showed that SHMT1 inhibited EMT and matrix metallopeptidase 2 (MMP2) expression. In vivo experiments showed that SHMT1 suppressed the lung metastasis of HCC cells in mice. Mechanistically, SHMT1 knockdown enhanced reactive oxygen species (ROS) production, and thus promoted the motility, EMT and MMP2 expression in Hep3B cells. Furthermore, NADPH oxidase 1 (NOX1) was identified to be the downstream target of SHMT1 in HCC. NOX1 expression was negatively correlated with SHMT1 expression in HCC. Rescue experiments revealed that NOX1 mediated the functional influence of SHMT1 on HCC cells.ConclusionsThese data indicate that SHMT1 inhibits the metastasis of HCC by repressing NOX1 mediated ROS production.
Highlights
Hepatocellular carcinoma (HCC) is the most major type of primary hepatic cancer
Serine hydroxymethyltransferase 1 (SHMT1) expression is decreased in HCC tissues and cells To evaluate the expression of SHMT1 in HCC, we first explored the publicly available database compiled at the FireBrowse website
To validate the data obtained from FireBrowse website, we employed the “R2: Genomics Analysis and Visualization Platform” to explore SHMT1 expression in Gene Expression Omnibus (GEO) datasets of HCC
Summary
Serine hydroxymethyltransferase 1 (SHMT1) is recently found to play critical roles in human cancers including lung cancer, ovarian cancer and intestinal cancer. The expression, function and the underlying mechanisms of SHMT1 in HCC remain uncovered. Curative treatment for HCC including surgical resection and liver transplantation are only available for Serine hydroxymethyltransferases (SHMTs) is the key protein regulating one carbon (methyl) metabolism and comprises the cytoplasmic isozyme (SHMT1) and mitochondrial isozyme (SHMT2) [6]. SHMT1 catalyzes the conversion of serine and tetrahydrofolate to glycine and 5, 10 methylene tetrahydrofolates. The expression and function of SHMT1 in HCC remain uncovered
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