Suppression of thymosin β10 increases cell migration and metastasis of cholangiocarcinoma

BMC Cancer

Changyi Chen²  Sopit Wongkham¹  Qizhi Yao²  Sumalee Obchoei¹  Kulthida Vaeteewoottacharn¹  Chaisiri Wongkham¹  Ratthaphol Kraiklang¹  Kanlayanee Sawanyawisuth¹  Sirinapa Sribenja² 

[1]Department of Biochemistry, Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

[2]Molecular Surgeon Research Center, Division of Surgical Research, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA

关键词: MMPs;    ERK1/2;    Snail;    Cancer metastasis;    Cell migration;    Cholangiocarcinoma;    Thymosin β10;   

Others  :  1079561
DOI  :  10.1186/1471-2407-13-430

 received in 2013-05-15, accepted in 2013-09-17,  发布年份 2013

【 摘 要 】

Background

Thymosin 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.

Methods

Tβ10 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.

Results

Ten 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.

Conclusions

Low 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.

【 授权许可】

   
2013 Sribenja et al.; licensee BioMed Central Ltd.

【 图 表 】

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