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Journal of experimental & clinical cancer research : CR

Overexpression of brachyury contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma.


PMID 25499255

Abstract

Brachyury overexpression has been reported in various human malignant neoplasms, but its expression and function in hepatocellular carcinoma progression and metastasis remains unknown. The present study aimed to evaluate the critical role of Brachyury in HCC metastasis. The expression of Brachyury in human HCC (SMMC7721, HepG2, FHCC98, and Hep3B) and control cell lines was analyzed using quantitative reverse-transcriptase polymerase chain reaction and immunoflourence methods. Cancerous tissues collected from patients with HCC (n = 112) were analyzed using immunohistochemical method; a microarray analysis of HCC tissues was performed to explore the clinicopathological variables of HCC. The migratory and invasive capacities of Brachyury-SMMC7721 and Brachyury-HepG2 transfected cells were evaluated using in vitro scratch wound healing and Matrigel invasion assays, respectively. Further, six-week-old male BALB/c nude mice (n = 10) model was used in vivo assay. Elevated expression of Brachyury was detected in HCCs (62.5%) compared with that in adjacent nontumorous tissues. Clinicopathological analysis revealed a close correlation of Brachyury expression with distant metastasis and poor prognosis of HCC. Overexpression of Brachyury promoted epithelial-mesenchymal transition (EMT) and metastasis of HCC cells in vitro and in vivo. Brachyury overexpression enhanced Akt activation by inhibiting phosphatase and tensin homolog (PTEN), which led to subsequent stabilization of Snail, a critical EMT mediator. The study findings suggest that elevated Brachyury facilitates HCC metastasis by promoting EMT via PTEN/Akt/Snail-dependent pathway. Brachyury plays a pivotal role in HCC metastasis and may serve as a novel prognostic biomarker and therapeutic target.