Mechanism of FOXA2 in colorectal cancer and its application in diagnosis and treatment / 国际肿瘤学杂志

Forkhead box protein A2 (FOXA2) , characterized by its unique DNA binding domain, plays a key role in transcriptional regulation. FOXA2 transcription factor is highly expressed in colorectal cancer, and binds with corresponding targeted genes to regulate tumor growth and inflammatory response, thus playing the role of oncogenes. In-depth understanding of the role and function of human FOXA2 transcription factor in colorectal cancer will contribute to further development of FOXA2 as a potential therapeutic target and diagnostic and prognostic marker of colorectal cancer.

Expression analysis of Foxa2 gene in NIPBL+/- deficient mice with cardiac atrial septal defect / 医学研究生学报

ObjectiveThe occurrence of atrial septal defect in Cornelia DE Lange syndrome are rarely reported in previous studies. The objective of this study is to investigate the relationship between the formation of atrial septal defect and Foxa2 gene expression in NIPBL+/- mouse model through the analysis of the expression of Foxa2 gene in heart tissue. MethodsThe NIPBL+/- mice were used as the experimental group, and wild-type NIPBL+/+ mice were used as the normal group. There were six mice in each group. The weights of the mice at 1, 2, 3, and 4 weeks were measured and recorded. Mouse heart tissues were collected at 4 weeks, and the expression of Foxa2 gene and protein were determined by real-time fluorescence quantitative PCR (Qrt-PCR) and Western blot. Pathological sections and HE staining were carried out to observe the effect of NIPBL gene defect on the development and changes of the mouse heart, as well as the anatomical structure of the atrial septum of the heart. ResultsThe weight of mice in the experimental group was significantly lower than that of the normal group (P<0.05) at all four time points. Foxa2 gene expression and protein expression in heart tissues of the experimental group were statistically lower than those of the normal group (P<0.05). Abnormal defect was observed in the atrial septum of the heart pathological sections of the NIPBL deficient mice. ConclusionThe decreased expression of Foxa2 gene in the heart tissue of NIPBL+/- deficient mice may be a factor inducing growth retardation and weight loss in mice. The abnormal defect in the atrial septum of nipbl-deficient mice might be associated with the down-regulation of Foxa2 gene expression in cardiomyocytes.

The Use of Foxa2-Overexpressing Adipose Tissue-Derived Stem Cells in a Scaffold System Attenuates Acute Liver Injury

BACKGROUND/AIMS: For the clinical application of stem cell therapy, functional enhancement is needed to increase the survival rate and the engraftment rate. The purpose of this study was to investigate functional enhancement of the paracrine effect using stem cells and hepatocyte-like cells and to minimize stem cell homing by using a scaffold system in a liver disease model. METHODS: A microporator was used to overexpress Foxa2 in adipose tissue-derived stem cells (ADSCs), which were cultured in a poly(lactic-co-glycolic acid) (PLGA) scaffold. Later, the ADSCs were cultured in hepatic differentiation medium for 2 weeks by a 3-step method. For in vivo experiments, Foxa2-overexpressing ADSCs were loaded in the scaffold, cultured in hepatic differentiation medium and later were implanted in the dorsa of nude mice subjected to acute liver injury (thioacetamide intraperitoneal injection). RESULTS: Foxa2-overexpressing ADSCs showed greater increases in hepatocyte-specific gene markers (alpha fetoprotein [AFP], cytokeratin 18 [CK18], and albumin), cytoplasmic glycogen storage, and cytochrome P450 expression than cells that underwent the conventional differentiation method. In vivo experiments using the nude mouse model showed that 2 weeks after scaffold implantation, the mRNA expression of AFP, CK18, dipeptidyl peptidase 4 (CD26), and connexin 32 (CX32) was higher in the Foxa2-overexpressing ADSCs group than in the ADSCs group. The Foxa2-overexpressing ADSCs scaffold treatment group showed attenuated liver injury without stem cell homing in the thioacetamide-induced acute liver injury model. CONCLUSIONS: Foxa2-overexpressing ADSCs applied in a scaffold system enhanced hepatocyte-like differentiation and attenuated acute liver damage in an acute liver injury model without homing effects.

Inhibitory effect of FOXA2 on proliferation and tumorigenesis of hepatocellular carcinoma cells / 实用医学杂志

Objective To investigate the effects of FOXA2 on the proliferation of hepatocellular carcinoma cells and the tumorigenesis of nude mice, and to explore the effect of FOXA2 on the development of hepatocellular carcinoma. Methods Immunohistochemistiy and real-time quantitative PCR were used to detect the expression of FOXA2 in 35 pairs of hepatocellular carcinoma tissues and their matched paracancerous tissues. 293 T cells were used as controls to detect the expression level of FOX A 2 in hepatocellular carcinoma cell lines (HepG2, SMMC-7721 and SK-Hep1) by real-time quantitative PCR. The lentivirus was transfected into HepG2 cells, and there were 3 groups including no virus group (Mock group) , negative control virus group (NC group) and FOXA2-transfected over-expression virus group (FOXA2 group). Plate clone assays were used to detect the effect of FOXA2 on the proliferation of HepG2 cells in vitro and nude mice tumor and formation assays to detect the tumor weight and tumor weight inhibition rate after FOX A2-transfected overexpression of lentivirus-infected cells. Results The results of immunohistochemistry and real-time quantitative PCR showed that the expression of FOXA2 in cancer tissues was significantly lower than that in adjacent tissues (P < 0.01) , And the expression of FOXA2 in hepatoma cell lines (HepG2, SMMC-7721, SK-Hepl) was significantly lower than that of 293 T cells (P < 0.0001). After the lentivirus was transfected into HepG2 cells, the number of clones in the FOXA2 group was significantly less than that in the Mock group and the NC group (P < 0.05). The tumor formation of nude mice showed that the tumor weight of FOXA2 group was smaller than that of the corresponding blank control group and negative control group (P < 0.01).Conclusion FOXA2 is lowly expressed in hepatocellular carcinoma tissues and cells, which has the effect of inhibiting the proliferation of HepG2 cells in vitro and the growth of tumors in nude mice in vivo.

Expression and Regulation of Transcription Factor FoxA2 in Chronic Rhinosinusitis With and Without Nasal Polyps

PURPOSE: Chronic rhinosinusitis (CRS) is characterized by the excessive production of mucus. However, the molecular mechanism underlying mucin overproduction in CRS with or without nasal polyps (CRSwNP and CRSsNP, respectively) is poorly understood. This study was conducted to assess the importance of the transcription factor FoxA2 in mucin production and to investigate the targeting of FoxA2 as a potential therapeutic strategy for mucus hypersecretion in CRS patients. METHODS: We enrolled 15 CRSwNP patients, 15 CRSsNP patients, and 10 normal controls in this study. The expression levels of FoxA2, MUC5AC, and MUC5B in inflamed and healthy nasal tissues were examined via immunohistochemistry and quantitative reverse transcription-polymerase chain reaction, and the levels of several proinflammatory cytokines in nasal secretions were measured via FlowCytomix analysis. In addition, the expression of MUC5AC and FoxA2 was determined in polyp-derived epithelial cells and NCI-H292 cells after in vitro stimulation. RESULTS: FoxA2 was significantly down-regulated, and MUC5AC and MUC5B were significantly up-regulated in both the CRSwNP and CRSsNP patients compared to the controls (P<0.05), and the protein level of FoxA2 was negatively associated with the IL-6 level in the CRS patients (P<0.05). IL-6 significantly increased MUC5AC expression but inhibited FoxA2 expression in vitro (P<0.05). Transfection with a FoxA2 expression plasmid significantly decreased MUC5AC promoter activity (P<0.05) and inhibited IL-6-induced MUC5AC production (P<0.05). In addition, clarithromycin significantly alleviated IL-6-induced FoxA2 suppression and decreased MUC5AC expression in vitro (P<0.05). CONCLUSIONS: Our findings suggest that FoxA2 may be considered a therapeutic target for the modulation of mucus hypersecretion in CRS patients.

Microarray Analysis of Papillary Thyroid Cancers in Korean

BACKGROUND/AIMS: Papillary thyroid cancer (PTC) is the most common malignancy of the thyroid gland. It involves several molecular mechanisms. The BRAF V600E mutation has been identified as the most common genetic abnormality in PTC. Moreover, it is known to be more prevalent in Korean PTC patients than in patients from other countries. We investigated distinct genetic profiles in Korean PTC through cDNA microarray analysis. METHODS: Transcriptional profiles of five PTC samples and five paired normal thyroid tissue samples were generated using cDNA microarrays. The tumors were genotyped for BRAF mutations. The results of the cDNA microarray gene expression analysis were confirmed by real-time PCR and immunohistochemistry analysis of 35 PTC patients. RESULTS: Four of the five patients whose PTC tissues were subjected to microarray analysis were found to carry the BRAF V600E mutation. Microarrays analysis of the five PTC tissue samples showed the expression of 96 genes to be increased and that of 16 genes decreased. Real-time reverse transcription-polymerase chain reaction (RT-PCR) confirmed increased expression of SLC34A2, TM7SF4, COMP, KLK7, and KCNJ2 and decreased expression of FOXA2, SLC4A4, LYVE-1, and TFCP2L1 in PTC compared with normal tissue. Of these genes, TFCP2L1, LYVE-1, and KLK7 were previously unidentified in PTC microarray analysis. Notably, Foxa2 activity in PTC was reduced, as shown by its cytoplasmic localization, in immunohistochemical analyses. CONCLUSIONS: These findings demonstrate both similarities and differences between our results and previous reports. In Korean cases of PTC, Foxa2 activity was reduced with its cytoplasmic accumulation. Further studies are needed to confirm the relationship between FOXA2 and BRAF mutations in Korean cases of PTC.