Dataset Information

Exosomal miR-200c suppresses chemoresistance of docetaxel in tongue squamous cell carcinoma by suppressing TUBB3 and PPP2R1B.

ABSTRACT: BACKGROUND:Chemoresistance is the main challenge for treating tongue squamous cell carcinoma (TSCC). MiR-200c is an important regulator of chemoresistance. Exosomes are a promising molecule-delivery system for cancer treatment. Thus, this study aimed to investigate the role of miR-200c in chemoresistance of TSCC and whether exosomes could effectively deliver miR-200c to chemo-resistant cells and regulate cellular activities. RESULTS:The results showed that the downregulation of miR-200c increased resistance to DTX, migration, and invasion and decreased apoptosis, which was reversed by the overexpression of miR-200c. The NTECs-derived exosomes transported miR-200c to HSC-3DR, increasing the sensitivity to DTX in vitro and in vivo. Also, epithelial-to-mesenchymal transition (EMT) and DNA damage responses were involved in DTX resistance. Furthermore, miR-200c regulated DTX resistance by targeting TUBB3 and PPP2R1B. CONCLUSION:Exosome-mediated miR-200c delivery may be an effective and promising strategy to treat chemoresistance in TSCC. METHODS:Docetaxel (DTX) resistant HSC-3 cells (HSC-3DR) were transfected with miR-200c lentivirus and cocultured with exosomes derived from normal tongue epithelial cells (NTECs) that were overexpressed with miR-200c. The roles of miR-200c and exosomal miR-200c in vitro and in vivo were determined by RNA-Seq, qRT-PCR, western blots, transmission electron microscopy, and flow cytometry, fluorescence, CCK8, Transwell, and wound healing assays.

SUBMITTER: Cui J

PROVIDER: S-EPMC7202518 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Exosomal miR-200c suppresses chemoresistance of docetaxel in tongue squamous cell carcinoma by suppressing TUBB3 and PPP2R1B.

Cui Jun J Wang Haiyan H Zhang Xiaohe X Sun Xiaodong X Zhang Jin J Ma Jinji J

Aging 20200420 8

<h4>Background</h4>Chemoresistance is the main challenge for treating tongue squamous cell carcinoma (TSCC). MiR-200c is an important regulator of chemoresistance. Exosomes are a promising molecule-delivery system for cancer treatment. Thus, this study aimed to investigate the role of miR-200c in chemoresistance of TSCC and whether exosomes could effectively deliver miR-200c to chemo-resistant cells and regulate cellular activities.<h4>Results</h4>The results showed that the downregulation of mi ...[more]

PMID: 32310826

Similar Datasets

Project description:BackgroundMicroRNA27b-3p (miR-27b) has been reported to be dysregulated in multiple types of human cancer. However, the expression levels, biological roles, and underlying mechanism of miR-27b in tongue squamous cell carcinoma (TSCC) remain to be elucidated.MethodsBioinformatics analyses and quantitative real-time PCR (qRT-PCR) were used to determine miR-27b expression in TSCC tissues and cell lines. The influence of miR-27b overexpression or inhibition on TSCC cell proliferation, migration, and invasion in vitro, and on tumor growth in vivo, was explored via CCK8, colony formation, wound healing, and transwell assays, and in xenograft tumors in nude mice, respectively. Luciferase reporter assays, qRT-PCR, and Western blotting were performed to clarify the potential mechanisms involving miR-27b in TSCC cells.ResultsmiR-27b was significantly downregulated in TSCC tissues and cell lines, and its expression was correlated with cancer status. Overexpression of miR-27b led to diminished proliferation, migration, and invasion, and notably reduced tumor growth in vivo. Bioinformatics analysis followed by luciferase reporter assays demonstrated that miR-27b expression was inversely correlated with that of integrin subunit α5 (ITGA5)and that miR-27b directly bound to the 3'-untranslated region of ITGA5 in TSCC cells. The bioinformatics analysis also indicated that ITGA5 was upregulated in TSCC and that its expression was correlated with epithelial-mesenchymal transition (EMT) and poor prognosis. Moreover, we found that miRNA-27b could reverse ITGA5-induced promotion of TSCC cell proliferation and migration. Finally, we demonstrated that regulation of miR-27b expression in TSCC may result in alterations in the expression of ITGA5 and EMT-related marker genes at the mRNA and protein levels.ConclusionThese results indicate that miR-27b hampers TSCC proliferation and migration via suppressing the EMT process by targeting ITGA5. These findings support consideration of miR-27b/ITGA5 as a valuable marker for the metastatic potential of TSCC, or as a therapeutic target for the treatment of TSCC.

Project description:Background:Exosomes are small membrane vesicles that are secreted by most cell types. Circular RNAs (circRNAs) have recently been identified in exosomes, and exosomal circRNAs exert important biological activities in human cancers, including oral squamous cell carcinoma (OSCC). The purpose of this study was to investigate whether circRNA GDP dissociation inhibitor 2 (circGDI2) was transferred by exosomes and how exosomal circGDI2 regulated OSCC cell malignant behaviors. Methods:The levels of circGDI2, miR-424-5p and suppressor of cancer cell invasion (SCAI) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. Cell proliferation was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Transwell assays were performed to detect cell migration and invasion. Measurement of glucose consumption and lactate production were conducted using a corresponding assay kit. Targeted correlations among circGDI2, miR-424-5p and SCAI were confirmed by dual-luciferase reporter assays. Xenograft assays were used to observe the role of circGDI2 in tumor growth in vivo. Results:Our data indicated that circGDI2 was down-regulated in OSCC, and it could be transferred by the exosomes in OSCC cells. The up-regulation of exosomal circGDI2 weakened OSCC cell proliferation, migration, invasion and glycolysis. CircGDI2 functioned as a molecular sponge of miR-424-5p, and SCAI was a direct target of miR-424-5p. MiR-424-5p mediated the repression of exosomal circGDI2 overexpression on OSCC cell malignant behaviors, and miR-424-5p silencing mitigated OSCC cell progression by up-regulating SCAI. Moreover, exosomal circGDI2 regulated SCAI expression through sponging miR-424-5p. Additionally, the overexpression of exosomal circGDI2 inhibited tumor growth in vivo. Conclusion:The present study had led to the identification of exosomal circGDI2 that regulated OSCC cell malignant behaviors through targeting the miR-424-5p/SCAI axis, highlighting circGDI2 as a novel exosome-based cancer biomarker and therapeutic agent for OSCC treatment.

Project description:Oral tongue squamous cell carcinoma (OTSCC) is one of the most common head and neck cancers. Innate or acquired resistance to cisplatin, a standard chemotherapy agent for OTSCC, is common in patients with OTSCC. Understanding the molecular basis for cisplatin chemoresistance in OTSCC cells may serve as a basis for identification of novel therapeutic targets. Podocalyxin (PODXL) has been found critical for malignant progression in a variety of cancers. Bmi1 has recently been found to induce cell apoptosis and cisplatin chemosensitivity in OTSCC cells. In this study, we explored the interaction between PODXL and Bmi1 in OTSCC cells, and assessed its impact on OTSCC cell chemoresistance to cisplatin. PODXL and/or Bmi1 were stably overexpressed or knocked down in SCC-4 and Tca8113 human OTSCC cells. Overexpression of PODXL in both cell lines markedly elevated the expression level of Bmi1 and the half maximal inhibitory concentration (IC50) of cisplain and reduced cisplatin-induced cell apoptosis, which was abolished by knockdown of Bmi1 or a selective focal adhesion kinase (FAK) inhibitor. On the other hand, knockdown of PODXL significantly decreased the Bmi1 expression level and cisplatin IC50 and increased cisplatin-induced cell apoptosis, which was completely reversed by overexpression of Bmi1. While overexpression and knockdown of PODXL respectively increased and decreased the FAK activity, Bmi1 showed no significant effect on the FAK activity in OTSCC cells. In addition, overexpression of PODXL markedly elevated the stability of Bmi1 mRNA, which was abolished by a selective FAK inhibitor. In conclusion, this study provides the first evidence that PODXL up-regulates the expression level of Bmi1 in OTSCC cells by increasing the stability of Bmi1 mRNA through a FAK-dependent mechanism; this effect leads to enhanced cisplatin chemoresistance in OTSCC cells. This study adds new insights into the molecular mechanisms underlying OTSCC chemoresistance.

Project description:Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs is an important hurdle to effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC is an unmet medical need to improve the survival of ESCC. Herein, we demonstrate that ferroptosis triggered by inhibiting high mobility group AT-hook 1 (HMGA1) may provide a novel opportunity to gain an effective therapeutic strategy against chemoresistance in ESCC. HMGA1 is upregulated in ESCC and works as a key driver for cisplatin (DDP) resistance in ESCC by repressing ferroptosis. Inhibition of HMGA1 enhances the sensitivity of ESCC to ferroptosis. With a transcriptome analysis and following-up assays, we demonstrated that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting the accumulation of malondialdehyde (MDA), thereby suppressing cell ferroptosis. HMGA1 acts as a chromatin remodeling factor promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, and hence enhancing the transcription of SLC7A11 and maintaining the redox balance. We characterized that the enhanced chemosensitivity of ESCC is primarily attributed to the increased susceptibility of ferroptosis resulting from the depletion of HMGA1. Moreover, we utilized syngeneic allograft tumor models and genetically engineered mice of HMGA1 to induce ESCC and validated that depletion of HMGA1 promotes ferroptosis and restores the sensitivity of ESCC to DDP, and hence enhances the therapeutic efficacy. Our finding uncovers a critical role of HMGA1 in the repression of ferroptosis and thus in the establishment of DDP resistance in ESCC, highlighting HMGA1-based rewiring strategies as potential approaches to overcome ESCC chemotherapy resistance. Schematic depicting that HMGA1 maintains intracellular redox homeostasis against ferroptosis by assisting ATF4 to activate SLC7A11 transcription, resulting in ESCC resistance to chemotherapy.

Project description:Endometriosis is a common, benign, and estrogen-dependent disease characterized by pelvic pain and infertility. To date, the pathogenesis of endometriosis remains unclear. Recent studies have demonstrated that noncoding RNAs, including microRNAs and long noncoding RNAs, play important roles in the development of endometriosis.Expression profiling of miRNAs in endometrial tissue was characterized using microarrays. The most differentially expressed miRNAs were confirmed using quantitative reverse transcriptase-polymerase chain reaction analysis in additional ectopic endometrial (n?=?27) and normal endometrial (n?=?12) tissues. For in-vitro functional studies, 5-ethynyl-2'-deoxyuridine incorporation assay, Transwell assay, and dual-luciferase reporter assay were used to measure the proliferation, migration, and luciferase activity of miR-200c and the predicted targets of miR-200c in primary endometrial stromal cells (HESCs) derived from human endometrial biopsies, respectively. For in-vivo therapeutic interventions, polymeric nanoparticles of polyethylenimine-polyethylene glycol-arginine-glycine-aspartic acid were used for delivery of miR-200c mimic and inhibitor to determine the therapeutic effect of miR-200c in a rat model of endometriosis.Exogenous overexpression of miR-200c inhibited the proliferation and migration of HESCs, which were mainly regulated by metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). In contrast, inhibition of miR-200c promoted the proliferation and migration of HESCs, while the simultaneous silencing of MALAT1 expression exerted the opposite effects. We demonstrated that expression of MALAT1 in ectopic endometrial specimens was negatively correlated with that of miR-200c and that MALAT1 knockdown increased the level of miR-200c in HESCs. Moreover, the transfection of endometrial stromal cells with the miR-200c mimic or MALAT1 siRNAs decreased the protein levels of mesenchymal markers ZEB1, ZEB2, and N-cadherin and increased the protein levels of the epithelial marker E-cadherin. Furthermore, using a rat endometriosis model, we showed that local delivery of the miR-200c mimic significantly inhibited the growth of ectopic endometriotic lesions.The MALAT1/miR-200c sponge may be a potential therapeutic target for endometriosis.

Dataset Information

Exosomal miR-200c suppresses chemoresistance of docetaxel in tongue squamous cell carcinoma by suppressing TUBB3 and PPP2R1B.

Publications

Exosomal miR-200c suppresses chemoresistance of docetaxel in tongue squamous cell carcinoma by suppressing TUBB3 and PPP2R1B.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets