GATA3 Expression Is a Poor Prognostic Factor in Soft Tissue Sarcomas

Haraguchi, Toshiaki; Miyoshi, Hiroaki; Hiraoka, Koji; Yokoyama, S.; Ishibashi, Yukinao; Hashiguchi, Toshihiro; Matsuda, Kazunobu; Hamada, Tetsuya; Okawa, Takahiro; Shiba, Naoto; Ohshima, Koichi

doi:10.1371/journal.pone.0156524

Cited by 21 publications

(17 citation statements)

References 37 publications

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“… 10 However, GATA3 is a poor prognostic marker in neuroblastomas, endometrial carcinomas and soft tissue sarcomas. 11 , 12 , 14 The underlying mechanisms of the distinct function of GATA3 still remain unclear. It has been reported that, in breast cancer cells, GATA3 forms a complex with G9A/NuRD (MTA3) to suppress ZEB2 , TGFB1 and other epithelial-to-mesenchymal transition-related genes.…”

Section: Discussionmentioning

confidence: 99%

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GATA3 interacts with and stabilizes HIF-1α to enhance cancer cell invasiveness

et al. 2017

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GATA binding protein 3 (GATA3) is indispensable in development of human organs. However, the role of GATA3 in cancers remains elusive. Hypoxia inducible factor (HIF)-1 plays an important role in pathogenesis of human cancers. Regulation of HIF-1α degradation is orchestrated through collaboration of its interacting proteins. In this study, we discover that GATA3 is upregulated in head and neck squamous cell carcinoma (HNSCC) and is an independent predictor for poor disease-free survival. GATA3 promotes invasive behaviours of HNSCC and melanoma cells in vitro and in immunodeficient mice. Mechanistically, GATA3 physically associates with HIF-1α under hypoxia to inhibit ubiquitination and proteasomal degradation of HIF-1α, which is independent of HIF-1α prolyl hydroxylation. Chromatin immunoprecipitation assays show that the GATA3/HIF-1α complex binds to and regulates HIF-1 target genes, which is also supported by the microarray analysis. Notably, the GATA3-mediated invasiveness can be significantly reversed by HIF-1α knockdown, suggesting a critical role of HIF-1α in the underlying mechanism of GATA3-mediated effects. Our findings suggest that GATA3 stabilizes HIF-1α to enhance cancer invasiveness under hypoxia and support the GATA3/HIF-1α axis as a potential therapeutic target for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

“… 4 , 5 , 6 , 7 , 8 , 9 The association of GATA3 with human malignancies has been reported in breast cancers, neuroblastomas, endometrial carcinomas, urothelial carcinomas and soft tissue sarcomas. 10 , 11 , 12 , 13 , 14 However, its function remains elusive.…”

Section: Introductionmentioning

confidence: 99%

GATA3 interacts with and stabilizes HIF-1α to enhance cancer cell invasiveness

et al. 2017

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“…Based on previous studies [ 19 – 23 ], patients were classified by sex, age (≤60 or >60 years), tumor size (≤5 cm or >5 cm), depth of tumor (superficial or deep), tumor location (extremities or trunk), the French Fédération Nationale des Centres de Lutte Contre le Cancer system (FNCLCC) grade (grade 1 or 2 or 3), tumor differentiation (score 1 or 2 or 3), mitotic count (0–9/10 or ≥10/10 high-power fields [HPF]), tumor necrosis (<50% or ≥50%), the American Joint Committee on Cancer (AJCC) stage (I or II or III), p53 expression (low or high), Ki-67 expression (low or high), and treatment (surgery alone or combined with postoperative therapy).…”

Section: Methodsmentioning

confidence: 99%

Clinicopathological and prognostic value of transforming acidic coiled-coil-containing protein 3 (TACC3) expression in soft tissue sarcomas

et al. 2017

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Transforming acidic coiled-coil-containing protein 3 (TACC3), a microtubule regulator, is associated with various cancers. However, the relationship between TACC3 and soft tissue sarcomas (STS) remains unclear. We investigated the expression of TACC3 in 136 STS patient samples using immunohistochemical (IHC) staining, and the statistical associations between TACC3 expression and clinicopathological characteristics were evaluated. Additionally, the expression levels of the tumor suppressor p53 and of the cell proliferation marker Ki-67 were also assessed by IHC. High TACC3 expression was detected in 94/136 of STS cases (69.1%), and significantly correlated with higher grade according to the French Fédération Nationale des Centres de Lutte Contre le Cancer system (P<0.0001), poorer tumor differentiation (P<0.0001), increased mitotic counts (P<0.0001), advanced stage per American Joint Committee on Cancer guidelines (P<0.0001), higher p53 expression (P = 0.0487), higher Ki-67 expression (P<0.0001), and undergoing postoperative therapy (P = 0.0001). Disease-free survival (DFS) and overall survival (OS) of patients with high TACC3 expression were significantly shorter (P<0.0001 and P<0.0001, respectively). On multivariate analyses, high TACC3 expression was an independent negative prognostic factor for both DFS and OS (hazard ratio [HR]: 3.074; P = 0.0235 and HR: 8.521; P = 0.0415, respectively). Our results suggest that TACC3 is an independent prognostic factor and may be a novel therapeutic target for the treatment of STS.

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“…GATA3, a member of the GATA family (11,12), serves a crucial role in T-cell proliferation and differentiation (13). In addition, numerous studies have demonstrated that GATA3 serves different roles in different cancers, for example, GATA3 serves as a tumour activator in soft tissue sarcomas, endometrial carcinomas and neuroblastomas (14)(15)(16). In addition, GATA3 suppresses cell proliferation, migration and invasion in osteosarcoma (17).…”

Section: Introductionmentioning

confidence: 99%

GATA3 is downregulated in HCC and accelerates HCC aggressiveness by transcriptionally inhibiting slug expression

et al. 2021

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Previous studies have reported that GATA3 is downregulated in multiple types of tumours, including gastric cancer and osteosarcoma. The aim of this study was to explore whether GATA3 serves as a tumour suppressor to inhibit hepatocellular carcinoma (HCC) development. Tumour tissue specimens and adjacent normal tissue specimens were obtained from 162 patients diagnosed with HCC in the Affiliated Hospital of Shaoxing University from July 2000 to May 2018. The result of the present study demonstrated that GATA3 was downregulated in HCC tumour tissues compared with that of adjacent normal tissues. The expression of GATA3 was also negatively associated with tumour size, TNM stage and lymph node metastasis. Additionally, analysis of the follow-up data revealed that low GATA3 expression was closely correlated with poor survival. Gain and loss of function analyses revealed that overexpression of GATA3 decreased the ability of proliferation, migration and invasion in HCC cell lines, whereas inhibition of GATA3 promoted the ability of proliferation, migration and invasion. In addition, GATA3 suppressed EMT through the regulation of slug expression. Additionally, slug overexpression attenuated the inhibitory effects of GATA3 overexpression on cancer cell proliferation, migration and invasion. Thus, GATA3 is downregulated in HCC, and suppresses cell proliferation, migration and invasion. Moreover, GATA3 transcriptionally inhibits slug expression, thereby suppressing EMT in HCC.

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GATA3 Expression Is a Poor Prognostic Factor in Soft Tissue Sarcomas

Cited by 21 publications

References 37 publications

GATA3 interacts with and stabilizes HIF-1α to enhance cancer cell invasiveness

GATA3 interacts with and stabilizes HIF-1α to enhance cancer cell invasiveness

Clinicopathological and prognostic value of transforming acidic coiled-coil-containing protein 3 (TACC3) expression in soft tissue sarcomas

GATA3 is downregulated in HCC and accelerates HCC aggressiveness by transcriptionally inhibiting slug expression

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