Abstract
AimsBrachyury 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.MethodsThe 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.ResultsElevated 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.ConclusionThe 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.
Highlights
Hepatocellular carcinoma (HCC) is ranked as the fifth most frequent cancer and third most frequent cause of cancer deaths in the world [1]
Expression of brachyury is upregulated in human HCCs To explore the role of Brachyury in HCC development, the expression of Brachyury in various human HCC cell lines were evaluated
Brachyury messenger ribonucleic acid (mRNA) was significantly increased in HCCs relative to paired noncancerous tissues of 40 patients (Figure 1B), which was further confirmed by Western blot assay (Figure 1C,D)
Summary
Hepatocellular carcinoma (HCC) is ranked as the fifth most frequent cancer and third most frequent cause of cancer deaths in the world [1]. In spite of improvements in surveillance and clinical therapeutic strategy, long-term disease-free survival (DFS) of patients with HCC remains unsatisfactory due to tumor recurrence and metastasis of the primary tumor [2,3]. ? 2014 Du et al.; licensee BioMed Central. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. The underlying mechanisms of cancerrelated EMT are not fully elucidated
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