ABSTRACT
HOXA5, as a transcription factor, plays an important role in a variety of malignant tumors. Nevertheless, its biological role in cervical squamous cell carcinoma (CSCC) is largely unknown. In our study, we aimed to explore the function of HOXA5 in CSCC and its molecular mechanism. Immunohistochemistry showed that HOXA5 expression was downregulated in human CSCC tissues and HOXA5 staining was negatively correlated with tumor size and histological grade of CSCC. Ectopic expression of HOXA5 inhibited proliferative and metastatic abilities of CSCC cells in vitro and in vivo. Furthermore, overexpression of HOXA5 inhibited the cell cycle by arresting the S/G2 phase by flow cytometry and that was related to the downregulation of Cyclin A. Further study showed that HOXA5 suppressed EMT by inhibiting the ß-catenin/Snail signaling resulting in reduced metastasis of CSCC cells. Altogether, our results suggested that HOXA5 inhibited the proliferation and metastasis via repression of the ß-catenin/Snail pathway, proposing the potential role of HOXA5 in the prevention and treatment of CSCC.
Subject(s)
Carcinoma, Squamous Cell , Homeodomain Proteins , Uterine Cervical Neoplasms , Female , Humans , beta Catenin/metabolism , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Cell Proliferation , Homeodomain Proteins/genetics , Signal Transduction , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/pathologyABSTRACT
Formononetin is a natural isoflavone compound found mainly in Chinese herbal medicines such as astragalus and red clover. It is considered to be a typical phytooestrogen. In our previous experiments, it was found that formononetin has a two-way regulatory effect on endothelial cells (ECs): low concentrations promote the proliferation of ECs and high concentrations have an inhibitory effect. To find a specific mechanism of action and provide a better clinical effect, we performed a structural transformation of formononetin and selected better medicinal properties for formononetin modifier J1 and J2 from a variety of modified constructs. The MTT assay measured the effects of drugs on human umbilical vein endothelial cell (HUVEC) activity. Scratch and transwell experiments validated the effects of the drugs on HUVEC migration and invasion. An in vivo assessment effect of the drugs on ovariectomized rats. Long-chain non-coding RNA for EWSAT1, which is abnormally highly expressed in HUVEC, was screened by gene chip, and the effect of the drug on its expression was detected by PCR after the drug was applied. The downstream factors and their pathways were analysed, and the changes in the protein levels after drug treatment were evaluated by Western blot. In conclusion, the mechanism of action of formononetin, J1 and J2 on ECs may be through EWSAT1-TRAF6 and its downstream pathways.
Subject(s)
Gene Expression Regulation/drug effects , Human Umbilical Vein Endothelial Cells/drug effects , Isoflavones/pharmacology , Phytoestrogens/pharmacology , RNA-Binding Protein EWS/metabolism , TNF Receptor-Associated Factor 6/metabolism , Animals , Apoptosis , Cell Movement , Cell Proliferation , Female , Human Umbilical Vein Endothelial Cells/metabolism , Humans , RNA-Binding Protein EWS/genetics , Rats , Rats, Sprague-Dawley , TNF Receptor-Associated Factor 6/geneticsABSTRACT
INTRODUCTION: Conbercept is a new anti-vascular endothelial growth factor drug approved for the treatment of age-related macular degeneration by the China Food and Drug Administration (CFDA) in 2013. In this study, we for the first time evaluated the concentrations of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) after patients with proliferative diabetic retinopathy were treated with intravitreal conbercept (IVC) injection. METHODS: Sixteen patients with proliferative diabetic retinopathy were randomly divided into two equal groups (A and B). Nine patients with rhegmatogenous retinal detachment were used as the control group. The patients in group A received 0.5 mg IVC and their aqueous humor was collected. After 7 days, all patients underwent vitrectomy, and their aqueous and vitreous humor were collected. RESULTS: In the aqueous humor, the concentrations of VEGF and PlGF were higher pre- than post-IVC injection in group A. Similarly, the concentrations of VEGF and PlGF in group A (pre-IVC) and group B were higher than those in the control group. In vitreous humor, the concentrations of VEGF and PlGF were higher in group B than those in the control group, and the concentrations of VEGF were lower in group A (post-IVC) than those in group B. CONCLUSIONS: Our study proved that the concentration of VEGF and PlGF reduced after IVC injection in aqueous humor. However, the concentration of PlGF did not reduce after IVC injection in vitreous humor.
