Role of GATA-6 and Bone Morphogenetic Protein-2 in Dexamethasone-Induced Cleft Palate Formation in Institute of Cancer Research Mice.

The mechanism of cleft palate induction by dexamethasone is not fully known. Bone morphogenetic protein-2 (BMP-2) has been associated with dexamethasone-induced osteoporosis. In this study, the authors induced cleft palate models in Institute of Cancer Research mice by dexamethasone to investigate the role of BMP-2 and its transcriptional element GATA-6. The authors injected different doses of dexamethasone into pregnant mice (E13), and assessed the histology of the palatal shelf and the expression levels of BMP-2, GATA-6, and specific apoptosis-related proteins. The results showed that cleft palate formation was dependent on dexamethasone dosage, with high incidence (50.55%) at high concentration (50 mg/kg) compared with the low doses (6 mg/kg, 38.10%). Transmission electron microscopy revealed significant cellular changes of the cleft palate shelf, including loose cell connection, cellular swelling, as well as reduced extracellular matrix and mitochondria. Following exposure to dexamethasone, the apoptotic rate in the palate increased with elevated dosage. Western blotting analysis indicated that the expression levels of GATA-6 and BMP-2 were reduced, while the levels of apoptotic proteins bax and caspase-3 were increased. The results of authors' study suggested that dexamethasone-induced cleft palate formation involved apoptosis occurred in a dose-dependent manner. BMP-2 and GATA-6 mediated dexamethasone-induced cleft palate formation.

MicroRNA-10a-5p-mediated downregulation of GATA6 inhibits tumor progression in ovarian cancer.

Ovarian cancer is the common cause of cancer-related death in women and is considered the most deadly gynecological cancer. It has been established that GATA-binding protein 6 (GATA6) is abnormally expressed in several types of malignant tumors and acts as an oncogenic protein or a tumor suppressor. However, the underlying mechanism of GATA6 in ovarian cancer progression has not been elucidated. Data in the present study revealed that GATA6 expression was negatively correlated to microRNA-10a-5p (miR-10a-5p) in ovarian cancer tissue and cells and that GATA6 is directly targeted by miR-10a-5p. Notably, upregulated miR-10a-5p dramatically inhibited ovarian cancer cell proliferation, tumorigenic ability, migration, and invasion by targeting GATA6. In vitro and in vivo experiments confirmed that miR-10a-5p-mediated downregulation of GATA6 suppressed Akt pathway activation. Overall, our findings suggest that miR-10a-5p could be a novel therapeutic target for ovarian cancer, and targeting the miR-10a-5p/GATA6/Akt axis could improve outcomes in this patient population.

Functional Regulatory Mechanisms Underlying Bone Marrow Mesenchymal Stem Cell Senescence During Cell Passages.

Mesenchymal stem cell (MSC) transplantation is an effective periodontal regenerative therapy. MSCs are multipotent, have self-renewal ability, and can differentiate into periodontal cells. However, senescence is inevitable for MSCs. In vitro, cell senescence can be induced by long-term culture with/without cell passage. However, the regulatory mechanism of MSC senescence remains unclear. Undifferentiated MSC-specific transcription factors can regulate MSC function. Herein, we identified the regulatory transcription factors involved in MSC senescence and elucidated their mechanisms of action. We cultured human MSCs (hMSCs) with repetitive cell passages to induce cell senescence and evaluated the mRNA and protein expression of cell senescence-related genes. Additionally, we silenced the cell senescence-induced transcription factors, GATA binding protein 6 (GATA6) and SRY-box 11 (SOX11), and investigated senescence-related signaling pathways. With repeated passages, the number of senescent cells increased, while the cell proliferation capacity decreased; GATA6 mRNA expression was upregulated and that of SOX11 was downregulated. Repetitive cell passages decreased Wnt and bone morphogenetic protein (BMP) signaling pathway-related gene expression. Silencing of GATA6 and SOX11 regulated Wnt and BMP signaling pathway-related genes and affected cell senescence-related genes; moreover, SOX11 silencing regulated GATA6 expression. Hence, we identified them as pair of regulatory transcription factors for cell senescence in hMSCs via the Wnt and BMP signaling pathways.

GATA6 suppression enhances lung specification from human pluripotent stem cells.

The transcription factor GATA6 has been shown to be important for lung development and branching morphogenesis in mouse models, but its role in human lung development is largely unknown. Here, we studied the role of GATA6 during lung differentiation using human pluripotent stem cells. We found that the human stem cell lines most efficient at generating NKX2.1+ lung progenitors express lower endogenous levels of GATA6 during endoderm patterning and that knockdown of GATA6 during endoderm patterning increased the generation of these cells. Complete ablation of GATA6 resulted in the generation of lung progenitors displaying increased cell proliferation with up to a 15-fold expansion compared with control cells, whereas the null cell line displayed a defect in further development into mature lung cell types. Furthermore, transgenic expression of GATA6 at the endoderm anteriorization stage skewed development toward a liver fate at the expense of lung progenitors. Our results suggest a critical dosage effect of GATA6 during human endoderm patterning and a later requirement during terminal lung differentiation. These studies offer an approach of modulating GATA6 expression to enhance the production of lung progenitors from human stem cell sources.

GATA6 predicts prognosis and hepatic metastasis of colorectal cancer.

Liver metastasis is a major cause of mortality for colorectal cancer (CRC). However, the underlying mechanisms remain largely unknown. GATA binding protein 6 (GATA6), a zinc-finger transcription factor, is expressed in the colorectal epithelium. We investigated the clinical significance of GATA6 and its role in invasion and metastasis in CRC. Expression of GATA6 in 89 cancerous, 35 adjacent normal and 39 liver metastatic samples from 89 CRC patients undergoing surgical resection was detected by immunohistochemical (IHC) methods. The effect of GATA6 on invasion and metastasis was assessed in CRC cells by shRNA lentivirus or expressed-plasmid transfection. We found that GATA6 expression was significantly higher in liver metastatic tissues compared with adjacent normal tissues. Aberrant GATA6 expression in CRC was associated with liver metastasis. Kaplan-Meier analysis showed GATA6 expression correlated with poor overall survival (OS) in CRC. The cell invasion and migration of established CRC cell lines were decreased by GATA6 knockdown and enhanced by GATA6 overexpression in vitro. Thus, aberrant expression of GATA6 correlates with poor prognosis and liver metastasis in CRC.

GATA transcription factors integrate Wnt signalling during heart development.

Cardiogenesis is inhibited by canonical Wnt/beta-catenin signalling and stimulated by non-canonical Wnt11/JNK signalling, but how these two signalling pathways crosstalk is currently unknown. Here, we show that Wnt/beta-catenin signalling restricts cardiogenesis via inhibition of GATA gene expression, as experimentally reinstating GATA function overrides beta-catenin-mediated inhibition and restores cardiogenesis. Furthermore, we show that GATA transcription factors in turn directly regulate Wnt11 gene expression, and that Wnt11 is required to a significant degree for mediating the cardiogenesis-promoting function of GATA transcription factors. These results demonstrate that GATA factors occupy a central position between canonical and non-canonical Wnt signalling in regulating heart muscle formation.