ABSTRACT
Triple-negative breast cancer (TNBC) represents a unique subgroup of breast cancers (BCa) with potential to be highly proliferative and invasive. Patient with TNBC are prone to developing resistance to chemotherapy. Therefore, TNBC usually has a poor clinical outcome. The key factors driving these malignant features remain poorly understood. In this study, we report for the first time that expression levels of FOXE3, a recently identified lens-specific transcription factor, were preferentially upregulated in TNBC tissues compared to non-TNBC tissues, and this upregulation correlated well to a poor overall/recurrence-free survival in patients. Depletion of FOXE3 in TNBC cell lines promoted cell death, cell cycle arrest, and potentiated sensitivity to docetaxel (DTX), a first-line chemotherapeutic drug for TNBC treatment. These alterations in cell growth/survival properties were accompanied by induction of CDKN1B, a gene encoding the tumor suppressor p27. We further provided the molecular evidence that FOXE3 could directly bind to the CDKN1B promoter and negatively regulate its transcription in TNBC cells. Importantly, knockdown of combined p27 and FOXE3 reversed the DTX-induced cell growth inhibition observed upon FOXE3 knockdown, indicating that the FOXE3's effects on TNBC progression were mediated mainly through transcriptional regulation of the p27 signaling. Together, our findings suggest that FOXE3 may function as a potent oncogene during the progression of TNBC, likely affecting cell proliferation, invasion and chemosensitivity, and functioning at least in part through transcriptional repression of p27 signaling.
Subject(s)
Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Oncogenes/genetics , Triple Negative Breast Neoplasms/genetics , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Docetaxel/pharmacology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Forkhead Transcription Factors/deficiency , Humans , Structure-Activity Relationship , Transcriptional Activation , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Tumor Cells, CulturedABSTRACT
Vascular endothelial dysfunction, a central hallmark of diabetes, predisposes diabetic patients to numerous cardiovascular complications. The POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1), is an important transcriptional regulatory factor and regulates divergent pathways depending on the cellular context, but its role in endothelial cells remains poorly understood. Herein, we report for the first time that endothelial PATZ1 expression was abnormally upregulated in diabetic endothelial cells (ECs) regardless of diabetes classification. This stimulatory effect was further confirmed in the high glucose-treated human umbilical vein endothelial cells (HUVECs). From a functional standpoint, transgenic overexpression of PATZ1 in endothelial colony forming cells (ECFCs) blunted angiogenesis in vivo and rendered endothelial cells unresponsive to established angiogenic factors. Mechanistically, PATZ1 acted as a potent transcriptional corepressor of fatty acid-binding protein 4 (FABP4), an essential convergence point for angiogenic and metabolic signaling pathways in ECs. Taken together, endothelial PATZ1 thus potently inhibits endothelial function and angiogenesis via inhibition of FABP4 expression, and abnormal induction of endothelial PATZ1 may contribute to multiple aspects of vascular dysfunction in diabetes.
Subject(s)
Fatty Acid-Binding Proteins/metabolism , Hyperglycemia/metabolism , Neoplasm Proteins/metabolism , Repressor Proteins/metabolism , Signal Transduction , Animals , Endothelium, Vascular/cytology , Endothelium, Vascular/metabolism , Fatty Acid-Binding Proteins/genetics , Glucose/administration & dosage , Human Umbilical Vein Endothelial Cells , Humans , Male , Mice , Mice, Inbred C57BLABSTRACT
This study was conducted to evaluate the applicability of 99mTc-2beta-[ N, N'-bis (2-mercaptoethyl) ethylenediamino]methyl,3beta(4-chlorophenyl)tropane(TRODAT-1) dopamine transporter(DAT) SPECT imaging in children with autism, and thus to provide an academic basis for the etiology, mechanism and clinical therapy of autism. Ten autistic children and ten healthy controls were examined with 99mTc-TRODAT-1 DAT SPECT imaging. Striatal specific uptake of 99mTc-TRODAT-1 was calculated with region of interest analysis according to the ratics between striatum and cerebellum [(STR-BKG)/BKG]. There was no statistically significant difference in semiquantitative dopamine transporter between the bilateral striata of autistic children (P=0.562), and between those of normal controls (p=0.573); Dopamine transporter in the brain of patients with autism increased significantly as compared with that in the brain of normal controls (P=0.017). Dopaminergic nervous system is dysfunctioning in the brain of children with autism, and DAT 99mTc-TRODAT-1 SPECT imaging on the brain will help the imaging diagnosis of childhcod autism.
