ABSTRACT
Long non-coding RNAs (lncRNAs) can exert effects on drug resistance of cancer cells. This study investigated the role of lncRNA HNF1A-antisense 1 (HNF1A-AS1) in growth and Tamoxifen (TAM) sensitivity of breast cancer (BC) cells. HNF1A-AS1 expression was promoted in BC cells and tissues. BC cells with HNF1A-AS1 silencing were constructed to detect cell proliferation. TAM resistant cell line with HNF1A-AS1 silencing and parent cell line with overexpressed HNF1A-AS1 were constructed to measure drug resistance. Silencing HNF1A-AS1 reduced proliferation and TAM resistance of BC cells. The downstream microRNAs (miRs) of HNF1A-AS1 and its targets were figured out and their functions in TAM resistance of BC cells were identified. HNF1A-AS1 sponged miR-363 to promote SERTAD3 expression. Downregulation of miR-363 or upregulation of SERTAD3 stimulated TAM resistance of BC cells. The findings in vitro were reproduced in in vivo experiments. It could be concluded that silencing HNF1A-AS1 inhibited growth and drug resistance to TAM of BC cells through the miR-363/SERTAD3 axis and the inactivation of the TGF-ß/Smad pathway.
Subject(s)
Breast Neoplasms/drug therapy , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Tamoxifen/pharmacology , Trans-Activators/genetics , Animals , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/pharmacology , Breast Neoplasms/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Down-Regulation , Drug Resistance, Neoplasm/genetics , Female , Gene Expression Regulation, Neoplastic , Gene Silencing , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Tamoxifen/administration & dosage , Up-Regulation , Xenograft Model Antitumor AssaysABSTRACT
Ketamine is a non-competitive antagonist of N-methyl-D-aspartate receptors (NMDARs). Growing evidence suggests that a single dose of ketamine produces a series of rapid and remarkable antidepressant properties. However, the mechanisms remain unclear. In our study, the antidepressant properties of a single dose of ketamine (10â¯mg/kg, i.p.) in mice exposed to chronic unpredictable stress (CUS) were assessed using the open-field test (OFT) and the forced swimming test (FST). Early growth response 1 (Egr-1) and postsynaptic density protein 95 (PSD-95) mRNA and protein expression levels were examined using qRT-PCR and western blot, respectively. Dendritic spine density in the CA1 region of the hippocampus was detected by Golgi staining. AMPAR currents in hippocampal slices were measured by electrophysiology. Our study showed that CUS induced a significant depression-like behavior accompanied by an upregulation of Egr-1 and downregulations of PSD-95, spine density, and AMPAR currents in the hippocampus, and a single dose of ketamine rapidly restored these changes. Interestingly, a single dose of Ro-25-6981 (an GluN2B antagonist, 10â¯mg/kg, i.p.) or Egr-1 siRNA, but not NVP AAM077 (an GluN2A antagonist, 10â¯mg/kg, i.p.), could produce the same antidepressant effects as ketamine. These data demonstrate that ketamine may produce its rapid antidepressant effects by downregulating the expression of Egr-1 via blocking GluN2B in the hippocampus.
Subject(s)
Antidepressive Agents/pharmacology , Depressive Disorder/drug therapy , Early Growth Response Protein 1/metabolism , Ketamine/pharmacology , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Dendritic Spines/drug effects , Dendritic Spines/metabolism , Dendritic Spines/pathology , Depressive Disorder/metabolism , Depressive Disorder/pathology , Disease Models, Animal , Disks Large Homolog 4 Protein/metabolism , Down-Regulation/drug effects , Early Growth Response Protein 1/antagonists & inhibitors , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology , Male , Mice, Inbred C57BL , RNA, Messenger/metabolism , Receptors, AMPA/metabolism , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Stress, Psychological/drug therapy , Stress, Psychological/metabolism , Stress, Psychological/pathology , Tissue Culture Techniques , UncertaintyABSTRACT
BACKGROUND Breast cancer (BC) is the most common malignant tumor in females. This study investigated the role and utility of CTC monitoring in evaluating the prognosis of triple-negative breast cancer patients. MATERIAL AND METHODS We enrolled 286 female triple-negative breast cancer patients who were diagnosed at and received radical resection surgery in our hospital. Peripheral venous blood samples were collected preoperatively and at 3 and 7 days postoperative, and the Cell Search system was used to detect CTC in peripheral blood. We analyzed the relationship between preoperative CTC level and clinical pathological characteristics of patients. Kaplan-Meier method was used to establish progression-free survival curves and overall survival curves, we used the log-rank test to compare the survival rate, and we explored the effects of preoperative and postoperative CTC levels on patient survival. RESULTS Compared with preoperative levels, the average CTC content in peripheral blood of breast cancer patients was significantly increased at 3 days after surgery, and then decreased to the preoperative baseline level by 7 days after surgery. The 3-year overall survival rate and progression-free survival rate in patients with CTC >5/7.5 mL peripheral blood were significantly lower than in patients with CTC <5/7.5 mL peripheral blood detected preoperatively and at 3 and 7 days postoperatively. CONCLUSIONS Dynamic monitoring of preoperative and postoperative CTC levels can accurately predict recurrence and progression of disease, and is important in postoperative monitoring and prognosis evaluation.
