ABSTRACT
Hyaluronic acid (HA), a ligand of CD44, accumulates in some types of tumors and is responsible for tumor progression. The nuclear factor erythroid 2-like 2 (NRF2) regulates cytoprotective genes and drug transporters, which promotes therapy resistance in tumors. Previously, we showed that high levels of CD44 are associated with NRF2 activation in cancer stem like-cells. Herein, we demonstrate that HA production was increased in doxorubicin-resistant breast cancer MCF7 cells (MCF7-DR) via the upregulation of HA synthase-2 (HAS2). HA incubation increased NRF2, aldo-keto reductase 1C1 (AKR1C1), and multidrug resistance gene 1 (MDR1) levels. Silencing of HAS2 or CD44 suppressed NRF2 signaling in MCF7-DR, which was accompanied by increased doxorubicin sensitivity. The treatment with a HAS2 inhibitor, 4-methylumbelliferone (4-MU), decreased NRF2, AKR1C1, and MDR1 levels in MCF7-DR. Subsequently, 4-MU treatment inhibited sphere formation and doxorubicin resistance in MCF7-DR. The Cancer Genome Atlas (TCGA) data analysis across 32 types of tumors indicates the amplification of HAS2 gene is a common genetic alteration and is negatively correlated with the overall survival rate. In addition, high HAS2 mRNA levels are associated with increased NRF2 signaling and poor clinical outcome in breast cancer patients. Collectively, these indicate that HAS2 elevation contributes to chemoresistance and sphere formation capacity of drug-resistant MCF7 cells by activating CD44/ NRF2 signaling, suggesting a potential benefit of HAS2 inhibition.
ABSTRACT
Cancer stem cells (CSCs) are a subset of tumor cells, which are characterized by resistance against chemotherapy and environmental stress, and are known to cause tumor relapse after therapy. A number of molecular mechanisms underlie the chemoresistance of CSCs, including high expression levels of drug efflux transporters. We investigated the role of the antioxidant transcription factor NF-E2-related factor 2 (NRF2) in chemoresistance development, using a CSC-enriched colonosphere system. HCT116 colonospheres were more resistant to doxorubicin-induced cell death and expressed higher levels of drug efflux transporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) compared to HCT116 monolayers. Notably, levels of NRF2 and expression of its target genes were substantially elevated in colonospheres, and these increases were linked to doxorubicin resistance. When NRF2 expression was silenced in colonospheres, Pgp and BCRP expression was downregulated, and doxorubicin resistance was diminished. Collectively, these results indicate that NRF2 activation contributes to chemoresistance acquisition in CSC-enriched colonospheres through the upregulation of drug efflux transporters.
Subject(s)
Breast Neoplasms , Cell Death , Doxorubicin , Drug Therapy , Neoplastic Stem Cells , NF-E2-Related Factor 2 , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Recurrence , Transcription Factors , Up-RegulationABSTRACT
Traumatic spondylolisthesis of the axis is the fracture of both pedicles and is called commonly as hangman' s fracture. The fractures with the anterior displacement more than 3mm and the angulation, more than 11 degrees were classified as unstable and the surgical methods were recommended for the treatment of the fractures. As for the surgical methods, anterior C2-3 fusion with plate fixation or transpedicular screw fixation were used. However, the differences between the clinical results of both methods were not reported in the literatures. In order to clarisy the clinical results of both methods, the authors evaluated the clinical results of 11 patients treated by anterior plate fixation and 7 patients treated by transpedicular fixation who were operated on between Mar. 1987 and,Jan: 1992. Minimum follow-up period was 12 months. 1. As the surgical complications, two cases of transient dysphagia in anterior fixation group and three cases of malinserted screw in transpedicular fixation group were observed. 2. Limitation of rotatory neck motion, less than 20 degrees in one direction was observed in four cases of transpedicular fixation group. 3. Anterior angulation, more than 10 degrees was noted in three cases of transpedicular group. 4. Mild intermittent neck pain was observed in two cases of anterior fixation group and two cases of transpedicular fixation group. Constant neck pain was present in three cases of transpedicular fixation group. 5. Over-all clinical results were excellent or good in all of anterior fixation group, and in four of seven transpedicular group. Although the clinical materials were limited in number, method of anterior plate fixation was recommended by the authors in the management of traumatic spondylolisthesis of axis, because of the easier technique and the better clinical results than the transpedicular screw fixation.
Subject(s)
Humans , Deglutition Disorders , Follow-Up Studies , Methods , Neck , Neck Pain , Spine , SpondylolisthesisABSTRACT
The purpose of this study was to analyse the magnetic resonance (MR) appearance of the patellar tendon autograft for anterior cruciate ligament injury. Among 35 patients of ACL reconstructions with central 1/3 of the patellar tendon autograft and interference screw fixation, 13 patients underwent MRI examination. All examination were performed on 1.5 T magnet(Signa;GE medical system). T1WI, PDI, T2WI Sagittal and coronal images were obtained together with T2WI MPGR and oblique sagittal images. A four-level grading system based on the MR appearance of the ACL graft was developed. A grade I was indiscernible in graft course, Grade II; incomplete in its course, grade III; complete but thin and grade IV; complete and thick. 2 out of 13 patients showed grade I, 3; grade II, 4; grade III and 4 grade IV. Five patients of grade I and II had a finding of roof impingement. However, only one out of 8 grade III and IV revealed such finding. In summary reconstructed ACL had various appearance in MRI, which was considered to be closely related with roof impingement.