The T-box transcription factor Brachyury regulates epithelial–mesenchymal transition in association with cancer stem-like cells in adenoid cystic carcinoma cells

Shimoda, Miyuki; Sugiura, Tetsuro; Imajyo, Ikumi; Ishii, Kazuya; Chigita, Satomi; Seki, Kiyohiko; Kobayashi, Yousuke; Shirasuna, Kanemitsu

doi:10.1186/1471-2407-12-377

Cited by 51 publications

(64 citation statements)

References 57 publications

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“…These results are consistent with those of previous studies, which revealed that silencing brachyury expression inhibits tumor formation and metastasis in human adenoid cystic carcinoma cells (19,20). In addition, a previous study revealed that brachyury expression is associated with EMT and lymph node metastasis in OSCC patients (22).…”

Section: Discussionsupporting

confidence: 93%

“…However, the role of these genes in CSCs remains unclear. Recently, the T-box transcription factor brachyury, which is essential for mesoderm formation during early development (16,17), has been found to regulate the epithelial-mesenchymal transition (EMT) and CSC potential in human salivary carcinoma cells (18)(19)(20)(21). In addition, brachyury expression was found to correlate with lymph node metastasis in OSCC (22).…”

Section: Introductionmentioning

confidence: 99%

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Expression levels of SOX2, KLF4 and brachyury transcription factors are associated with metastasis and poor prognosis in oral squamous cell carcinoma

et al. 2015

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Abstract. The prognosis of oral squamous cell carcinoma (OSCC) patients is affected by tumor recurrence and metastasis, and cancer stem cells are hypothesized to be involved in these processes. Thus, the aim of the present study was to determine whether the expression levels of five stem cell-related transcription factors, sex determining region Y-box 2 (SOX2), octamer-binding transcription factor 4 (Oct4), avian myelocytomatosis viral oncogene homolog (c-Myc), Krüppel-like factor 4 (KLF4) and brachyury, are associated with metastasis and survival in OSCC. Immunohistochemistry was performed to analyze the expression of these proteins in biopsy specimens obtained from 108 OSCC patients. The results revealed that the expression of SOX2, Oct4, KLF4 and brachyury were significantly associated with lymph node metastasis (P=0.002, P=0.031, P=0.003 and P=0.007, respectively). In addition, the expression of KLF4 and brachyury were significantly associated with distant metastasis (P=0.014 and P=0.012, respectively). Furthermore, multivariate analysis revealed that SOX2 and KLF4 are predictive factors for lymph node metastasis [odds ratios (ORs), 4.526 and 4.851, respectively], and KLF4 is also a predictive factor for distant metastasis (OR, 9.607). In addition, OSCC patients with low co-expression of SOX2, KLF4 and brachyury exhibited a significantly lower disease-specific survival rate (78.6 vs. 100%; P=0.025; χ 2 =5.033) and disease-free survival rate (60.7 vs. 90.9%; P=0.015; χ 2 =5.897) when compared with OSCC patients with high co-expression of these factors. The results indicate that SOX2, KLF4 and brachyury serve important roles in tumor progression, and these transcription factors may thus represent clinically useful prognostic markers for OSCC.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Expression levels of SOX2, KLF4 and brachyury transcription factors are associated with metastasis and poor prognosis in oral squamous cell carcinoma

et al. 2015

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“…As the name implies, chordomas are thought to be of notochordal origin and one of the major roles of T is in the development of the notochord (Nibu et al, 2013). T has also been implicated in controlling EMT in some cancers such as adenoid cystic carcinoma and colorectal cancer (Sarkar et al, 2012;Shimoda et al, 2012).…”

Section: Cip1mentioning

confidence: 99%

The T-box gene family: emerging roles in development, stem cells and cancer

2014

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The T-box family of transcription factors exhibits widespread involvement throughout development in all metazoans. T-box proteins are characterized by a DNA-binding motif known as the T-domain that binds DNA in a sequence-specific manner. In humans, mutations in many of the genes within the T-box family result in developmental syndromes, and there is increasing evidence to support a role for these factors in certain cancers. In addition, although early studies focused on the role of T-box factors in early embryogenesis, recent studies in mice have uncovered additional roles in unsuspected places, for example in adult stem cell populations. Here, I provide an overview of the key features of T-box transcription factors and highlight their roles and mechanisms of action during various stages of development and in stem/progenitor cell populations.

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“…Recently, Brachyury was associated with tumor aggressiveness in several tumor types (6)(7)(8)(9)(10)(11) and was found to be a significant predictor of poor prognosis in early colon cancer (8) and lung cancer (6). In vitro studies suggested that these associations are driven by EMT, accomplished by increased migratory and invasion capacity (12)(13)(14) and increased cancer stem cell features (10,11).…”

Section: Introductionmentioning

confidence: 99%

“…In lung cancer cell lines, it was demonstrated that Brachyury blocks cell-cycle progression and, therefore, mediates tumor resistance (15). However, in adenoid cystic carcinoma cells, Brachyury promoted tumor growth and metastasis formation in vivo (11). Therefore, despite the described oncogenic role of Brachyury, some authors suggest that it can also act as a tumor suppressor gene (16).…”

Section: Introductionmentioning

confidence: 99%

T-box Transcription Factor Brachyury Is Associated with Prostate Cancer Progression and Aggressiveness

Pinto

Pértega‐Gomes

Pereira

et al. 2014

Clinical Cancer Research

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Purpose: Successful therapy of patients with prostate cancer is highly dependent on reliable diagnostic and prognostic biomarkers. Brachyury is considered a negative prognostic factor in colon and lung cancer; however, there are no reports on Brachyury's expression in prostate cancer.Experimental Design: In this study, we aimed to assess the impact of Brachyury expression in prostate tumorigenesis using a large series of human prostate samples comprising benign tissue, prostate intraepithelial neoplasia (PIN) lesions, localized tumor, and metastatic tissues. The results obtained were compared with what can be inferred from the Oncomine database. In addition, multiple in vitro models of prostate cancer were used to dissect the biologic role of Brachyury in prostate cancer progression.Results: We found that Brachyury is significantly overexpressed in prostate cancer and metastatic tumors when compared with normal tissues, both at protein and at mRNA levels. Brachyury expression in the cytoplasm correlates with highly aggressive tumors, whereas the presence of Brachyury in the nucleus is correlated with tumor invasion. We found that Brachyury-positive cells present higher viability, proliferation, migration, and invasion rates than Brachyury-negative cells. Microarray analysis further showed that genes co-expressed with Brachyury are clustered in oncogenic-related pathways, namely cell motility, cellcycle regulation, and cell metabolism.Conclusions: Collectively, the present study suggests that Brachyury plays an important role in prostate cancer aggressiveness and points, for the first time, to Brachyury as a significant predictor of poor prostate cancer prognosis. Our work paves the way for future studies assessing Brachyury as a possible prostate cancer therapeutic target. Clin Cancer Res; 20(18); 4949-61. Ó2014 AACR.

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The T-box transcription factor Brachyury regulates epithelial–mesenchymal transition in association with cancer stem-like cells in adenoid cystic carcinoma cells

Cited by 51 publications

References 57 publications

Expression levels of SOX2, KLF4 and brachyury transcription factors are associated with metastasis and poor prognosis in oral squamous cell carcinoma

Expression levels of SOX2, KLF4 and brachyury transcription factors are associated with metastasis and poor prognosis in oral squamous cell carcinoma

The T-box gene family: emerging roles in development, stem cells and cancer

T-box Transcription Factor Brachyury Is Associated with Prostate Cancer Progression and Aggressiveness

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