ABSTRACT
microRNAs (miRNA), as tumor suppressors or oncogenes, are involved in modulating cancer cell behavior, including cell proliferation and apoptosis. The miR-140-5p acts as a tumor suppressor in several tumors, but the role of miR-140-5p in chronic myeloid leukemia (CML) remains unclear. Here, we investigated the suppression of miR-140-5p in CML patients and CML cell lines using quantitative PCR (qPCR) and fluorescence in situ hybridization (FISH). Overexpression miR-140-5p in CML cells significantly inhibited cell proliferation as revealed by the CCK-8 assay and promoted cell apoptosis as revealed by flow cytometry. Moreover, the sine oculis homeobox 1 (SIX1) gene had been confirmed as a direct target of miR-140-5p using bioinformatics analysis and luciferase reporter assays. Overexpression of miR-140-5p decreased the SIX1 protein level in CML cells. SIX1 mRNA and protein levels were significantly up-regulated in CML patients and CML cell lines. Knockdown of SIX1 expression significantly inhibited CML cell proliferation and promoted cell apoptosis. Furthermore, SIX1 as a transcriptional factor positively regulated pyruvate kinase isozyme type M2 (PKM2) expression and played an important role in the Warburg effect. In addition, these findings indicated that miR-140-5p functions as a tumor suppressor and plays a critical role in CML cell apoptosis and metabolism by targeting SIX1. Moreover, the miR-140-5p/SIX1 axis may be a potential therapeutic target in CML.
Subject(s)
Homeodomain Proteins/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , MicroRNAs/genetics , Adult , Aged , Apoptosis/genetics , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Line, Tumor , Female , Gene Expression Regulation, Leukemic , Humans , K562 Cells , Leukocytes, Mononuclear/pathology , Leukocytes, Mononuclear/physiology , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , MicroRNAs/metabolism , Middle Aged , Thyroid Hormones/genetics , Thyroid Hormones/metabolism , Thyroid Hormone-Binding ProteinsABSTRACT
BACKGROUND: Long non-coding (lnc) RNAs plays an important role in chronic myeloid leukemia (CML). In this study, we aimed to uncover the mechanism of the lncRNA maternally expressed 3 (MEG3) and its target microRNA-147 (miR-147) in CML. METHODS: Sixty CML patients and 10 healthy donors were included in the study. The methylation of MEG3 and miR-147 promoter was determined by methylation-specific PCR. The relationship of MEG3 and miR-147 was explored by luciferase assay. The interactions of proteins were studied by RNA pull-down assay, RNA immunoprecipitation and co-immunoprecipitation. FINDINGS: Patients in accelerated phase CML (CML-AP) and blast phase CML (CML-BP) showed lower expressions of MEG3 and miR-147 and higher expressions of DNMT1, DNMT3B, MBD2, MECP2 and HDAC1 compared to the controls. These patients also showed a higher degree of methylation of MEG3 and miR-147 while there was a reduction after chidamide treatment. Furthermore, the overexpression of MEG3 and miR-147 inhibited cell proliferation both in vivo and in vitro, promoted apoptosis and decreased the expressions of DNMT1, DNMT3A, DNMT3B, MBD2, HDAC1 and MECP2. We also found MEG3 interacted with DNMT1, JAK2, STAT3, HDAC1, and TYK2, and JAK2 was bound to STAT3, STAT5 and MYC. More interestingly, JAK2 was bound to TYK2 by the bridge of MEG3. INTERPRETATION: LncRNA MEG3 and its target miR-147 may serve as a novel therapeutic target for CML blast crisis, and chidamide might have a potential clinical application in treating CML blast crisis.
Subject(s)
Janus Kinase 2/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , MicroRNAs/metabolism , RNA, Long Noncoding/metabolism , STAT3 Transcription Factor/metabolism , STAT5 Transcription Factor/metabolism , Adolescent , Adult , Aged , Animals , Cell Line, Tumor , Child , Female , Humans , Janus Kinase 2/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Male , Mice, Nude , Middle Aged , RNA, Long Noncoding/genetics , STAT3 Transcription Factor/genetics , STAT5 Transcription Factor/genetics , Signal Transduction , Young AdultABSTRACT
The main treatment model for differentiated thyroid cancer is surgery -based individualized treatment .Due to the in-ert cancer characteristics of DTC , drug therapies such as thyrotropin suppressive therapy , molecular targeted therapy, neoadjuvant chemotherapy and Chinese medicine treatment have become the current research hotspots .Here, we reviewed the progress of clinical medication for DTC to improve the understanding of DTC drug therapy .
