Abstract
BackgroundThymosin β10 (Tβ10) expression is associated with malignant phenotypes in many cancers. However, the role and mechanisms of Tβ10 in liver fluke-associated cholangiocarcinoma (CCA) are not fully understood. In this study, we investigated the expression of Tβ10 in CCA tumor tissues and cell lines as well as molecular mechanisms of Tβ10 in tumor metastasis of CCA cell lines.MethodsTβ10 expression was determined by real time RT-PCR or immunocytochemistry. Tβ10 silence or overexpression in CCA cells was achieved using gene delivery techniques. Cell migration was assessed using modified Boyden chamber and wound healing assay. The effect of silencing Tβ10 on CCA tumor metastasis was determined in nude mice. Phosphorylation of ERK1/2 and the expression of EGR1, Snail and matrix metalloproteinases (MMPs) were studied.ResultsTen pairs of CCA tissues (primary and metastatic tumors) and 5 CCA cell lines were studied. With real time RT-PCR and immunostaining analysis, Tβ10 was highly expressed in primary tumors of CCA; while it was relatively low in the metastatic tumors. Five CCA cell lines showed differential expression levels of Tβ10. Silence of Tβ10 significantly increased cell migration, invasion and wound healing of CCA cells in vitro; reversely, overexpression of Tβ10 reduced cell migration compared with control cells (P<0.05). In addition, silence of Tβ10 in CCA cells increased liver metastasis in a nude mouse model of CCA implantation into the spleen. Furthermore, silence of Tβ10 activated ERK1/2 and increased the expression of Snail and MMPs in CCA cell lines. Ras-GTPase inhibitor, FPT inhibitor III, effectively blocked Tβ10 silence-associated ERK1/2 activation, Snail expression and cell migration.ConclusionsLow expression of Tβ10 is associated with metastatic phenotype of CCA in vitro and in vivo, which may be mediated by the activation of Ras, ERK1/2 and upregulation of Snail and MMPs. This study suggests a new molecular pathway of CCA pathogenesis and a novel strategy to treat or prevent CCA metastasis.
Highlights
Thymosin β10 (Tβ10) expression is associated with malignant phenotypes in many cancers
Tβ10 expression is decreased in the metastatic tumor of liver fluke-induced cholangiocarcinoma Our serial analysis of gene expressions (SAGE) data indicates that Tβ10 may play a role in CCA metastasis [9]
We determined the expression of Tβ10 in 10 pairs of CCA surgical specimens and 5 CCA cell lines previously isolated from the CCA tissues [21,22]
Summary
Thymosin β10 (Tβ10) expression is associated with malignant phenotypes in many cancers. The role and mechanisms of Tβ10 in liver fluke-associated cholangiocarcinoma (CCA) are not fully understood. We investigated the expression of Tβ10 in CCA tumor tissues and cell lines as well as molecular mechanisms of Tβ10 in tumor metastasis of CCA cell lines. Cholangiocarcinoma (CCA), the malignancy of bile duct epithelial cells, is a major cancer and a main health problem in the northeast of Thailand [1,2]. CCA is a slow growing but highly metastatic cancer, which is the major cause of death in CCA patients. There are no effective chemotherapeutic drugs and sensitive tumor markers to diagnose or monitor the tumor progression; most of CCA patients present themselves with high metastasis to lymph nodes and blood vessels.
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