scholarly journals Double-Targeted Knockdown of miR-21 and CXCR4 Inhibits Malignant Glioma Progression by Suppression of the PI3K/AKT and Raf/MEK/ERK Pathways

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Feijiao Liu ◽  
Bo Yang
Keyword(s):  
Tumor Volume ◽  
Xenograft Model ◽  
Glioma Cells ◽  
Erk Signaling ◽  
Combined Effects ◽  
Inhibition Effect ◽  
Transplanted Tumor ◽  
Tumor Tissues ◽  
Two Factors ◽  
Glioma Progression

Currently, miR-21 and CXCR4 are being extensively investigated as two key regulators in glioma malignancy. In this study, we investigated the combined effects of these two factors on glioma progression. Herein, the expression of miR-21 and CXCR4 was increased in tumor tissues and cell lines. Inhibition of miR-21, CXCR4, and miR-21 and CXCR4 together all reduced the migration, invasiveness, proliferation, and enhanced apoptosis in glioma cells, as well as reduced tumor volume and mass in xenograft model. The inhibition effect was strongest in double-targeted knockdown of miR-21 and CXCR4 group, whose downstream pathways involved in AKT axis and ERK axis activation. In conclusion, our findings reported that double-targeted knockdown of miR-21 and CXCR4 could more effectively inhibit the proliferation, migration, invasion, and growth of transplanted tumor and promote cell apoptosis, which were involved in the PI3K/AKT and Raf/MEK/ERK signaling pathways.

scholarly journals Double-targeted knockdown of miR-21 and CXCR4 inhibits malignant glioma progression by suppression of the PI3K/AKT and Raf/MEK/ERK pathways

2020 ◽  
Author(s):  
Feijiao Liu ◽  
Bo Yang
Keyword(s):  
Malignant Glioma ◽  
Xenograft Model ◽  
Glioma Cells ◽  
Invasion And Migration ◽  
Treatment Groups ◽  
Tumor Tissues ◽  
Two Factors ◽  
Xenograft Mice ◽  
And Migration ◽  
Glioma Progression

AbstractBackgroundCurrently, miR-21 and CXCR4 are being extensively investigated as two unrelated key regulators in glioma malignancy. In this study, we investigated the combined effect of these two factors on glioma progression.MethodsWe confirmed the expression of miR-21 and CXCR4 in malignant glioma tissue and glioma cells with qRT-PCR and western blotting. Single-targeted knockdown of miR-21 and CXCR4, as well as double-targeted knockdown of miR-21 and CXCR4 lentiviral vectors were constructed and they were transfected to U87 and U251 cells. Cell proliferation, apoptosis, invasion, and migration from different treatment groups were assessed by MTT assay, Flow Cytometry analysis, Transwell analysis, and Scratch assay, respectively. U87 xenograft mice were constructed to detect roles and potential mechanisms of miR-21 and CXCR4 in malignant glioma tumor growth.ResultsThe expression of miR-21 and CXCR4 was increased in tumor tissues and cell lines. Inhibition of miR-21, CXCR4, and miR-21 and CXCR4 together all reduced the migration, invasiveness, proliferation and enhanced apoptosis in glioma cells, as well as reduced tumor volume and mass in xenograft model. The inhibition effect was strongest in double-targeted knockdown of miR-21 and CXCR4 group, whose downstream pathways involved in AKT axis and ERK axis activation.ConclusionsOur findings reported that double-targeted knockdown of miR-21 and CXCR4 could more effectively inhibit the proliferation, migration, invasion and growth of transplanted tumor and promote cell apoptosis, which were involved in the PI3K/AKT and Raf/MEK/ERK signaling pathways.

scholarly journals Solanine Inhibits Immune Escape Mediated by Hepatoma Treg Cells via the TGFβ/Smad Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Juwei Gao ◽  
Yinyin Ying ◽  
Jue Wang ◽  
Yiyi Cui
Keyword(s):  
Flow Cytometry ◽  
Liver Cancer ◽  
Tumor Volume ◽  
Immune Escape ◽  
Tumor Model ◽  
Treg Cells ◽  
Inhibitory Effect ◽  
Control Group ◽  
Transplanted Tumor ◽  
Tumor Tissues

Objective. To observe the inhibitory effect of solanine on regulatory T cells (Treg) in transplanted hepatoma mice and to study the mechanism of solanine inhibiting tumor growth. Methods. The levels of Treg cells and IL-2, IL-10, and TGFβ in the blood of patients with liver cancer were detected by flow cytometry and ELISA, respectively. A mouse hepatocellular carcinoma (HCC) graft model was established and randomly divided into four groups: control group, solanine group, TGFβ inhibitor group (SB-431542), and solanine +TGFβ inhibitor combined group. Tumor volume of each group was recorded, tumor inhibition rate was calculated, and tumor metastasis was counted. The proportion of CD4+CD25+Foxp3+ Treg in transplanted tumor tissues was detected by flow cytometry. The expression levels of Foxp3 and TGFβ in transplanted tumor tissues were detected by quantitative fluorescence PCR. Results. Compared with healthy people, Treg cells and IL-2, IL-10, and TGFβ contents in peripheral blood of liver cancer patients were increased. The results of the transplanted tumor model in mice showed that the tumor volume of the transplanted mice in the solanine group and the TGFβ inhibitor mice was reduced compared with the control group. The combined group had the smallest tumor volume. The proportion of CD4+CD25+Foxp3+ Treg in the transplanted tumor tissues of mice in the solanine treatment group was significantly lower than that in the control group. The expressions of Foxp3 and TGFβ in the transplanted tumor tissues of mice in the solanine group were significantly lower than those in the control group. Conclusion. Solanine may enhance the antitumor immune response by downregulating the proportion of CD4+CD25+ Treg and the expression of Foxp3 and TGFβ in tumor tissues.

scholarly journals Gamma-radiated immunosuppressed tumor xenograft mice can be a new ideal model in cancer research

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hamid Khodayari ◽  
Saeed Khodayari ◽  
Solmaz Khalighfard ◽  
Arash Tahmasebifar ◽  
Mahboubeh Tajaldini ◽  
...  
Keyword(s):  
Gamma Radiation ◽  
High Capacity ◽  
Xenograft Model ◽  
Tumor Xenograft ◽  
Whole Body ◽  
Cell Injection ◽  
Tumor Tissues ◽  
Post Radiation ◽  
Xenograft Models ◽  
Xenograft Mice

AbstractTumor xenograft models can create a high capacity to study human tumors and discover efficient therapeutic approaches. Here, we aimed to develop the gamma-radiated immunosuppressed (GIS) mice as a new kind of tumor xenograft model for biomedical studies. First, 144 mice were divided into the control and treated groups exposed by a medical Cobalt-60 apparatus in 3, 4, and 5 Gy based on the system outputs. Then, 144 BALB/c mice were divided into four groups; healthy, xenograft, radiation, and radiation + xenograft groups. The animals in the xenograft and radiation + xenograft groups have subcutaneously received 3 × 106 MCF-7 cells 24 h post-radiation. On 3, 7, 14, and 21 days after cell injection, the animals were sacrificed. Then, the blood samples and the spleen and tumor tissues were removed for the cellular and molecular analyses. The whole-body gamma radiation had a high immunosuppressive effect on the BALB/c mice from 1 to 21 days post-radiation. The macroscopic and histopathological observations have proved that the created clusters' tumor structure resulted in the xenograft breast tumor. There was a significant increase in tumor size after cell injection until the end of the study. Except for Treg, the spleen level of CD4, CD8, CD19, and Ly6G was significantly decreased in Xen + Rad compared to the Xen alone group on 3 and 7 days. Unlike IL-4 and IL-10, the spleen level of TGF-β, INF-γ, IL-12, and IL-17 was considerably decreased in the Xen + Rad than the Xen alone group on 3 and 7 days. The spleen expressions of the VEGF, Ki67, and Bax/Bcl-2 ratio were dramatically increased in the Xen + Rad group compared to the Xen alone on 3, 7, 14, and 21 days. Our results could confirm a new tumor xenograft model via an efficient immune-suppressive potential of the whole-body gamma radiation in mice.

scholarly journals BRMS1 Suppresses Glioma Progression by Regulating Invasion, Migration and Adhesion of Glioma Cells

PLoS ONE ◽  
2014 ◽  
Vol 9 (5) ◽  
pp. e98544 ◽  
Author(s):  
Pengjin Mei ◽  
Jin Bai ◽  
Meilin Shi ◽  
Qinghua Liu ◽  
Zhonglin Li ◽  
...  
Keyword(s):  
Glioma Cells ◽  
Glioma Progression

scholarly journals The MEK/ERK/miR-21 Signaling Is Critical in Osimertinib Resistance in EGFR-Mutant Non-Small Cell Lung Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6005
Author(s):  
Wen-Chien Huang ◽  
Vijesh Kumar Yadav ◽  
Wei-Hong Cheng ◽  
Chun-Hua Wang ◽  
Ming-Shou Hsieh ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Tumor Suppressor ◽  
Growth Inhibition ◽  
Xenograft Model ◽  
Growth Factor Receptor ◽  
Mek Inhibitor ◽  
Small Cell ◽  
Erk Signaling ◽  
Small Cell Lung

Background: The third-generation epidermal growth factor receptor (EGFR) inhibitor, Osimertinib, is used to treat non-small cell lung cancer (NSCLC) patients with tyrosine kinase inhibitor (TKI) resistance caused by acquired EGFR T790M mutation. However, patients eventually develop resistance against Osimertinib with mechanisms not yet fully clarified. Activated alternative survival pathways within the tumor cells and cancer-associated fibroblasts (CAFs) have been proposed to contribute to Osimertinib resistance. MET and MEK inhibitors may overcome EGFR-independent resistance. Another acquired resistance mechanism of EGFR-TKI is the up-regulation of the RAS/RAF/MEK/ERK signaling pathway, which is the key to cell survival and proliferation; this may occur downstream of various other signaling pathways. In this report, we reveal the possible regulatory mechanism and inhibitory effect of the MEK inhibitor trametinib applied to MEK/ERK/miR-21 axis and PDCD4 in Osimertinib resistance. We found a possible regulatory role of PDCD4 in ERK signaling. PDCD4 is a new type of tumor suppressor that has multiple functions of inhibiting cell growth, tumor invasion, metastasis, and inducing apoptosis. Previous bioinformatics analysis has confirmed that PDCD4 contains the binding site of miR-21 and acts as a tumor suppressor in the regulation of various processes associated with the development of cancer, including cell proliferation, invasion, metastasis, and neoplastic transformation. Based on the above analysis, we hypothesized that the tumor suppressor PDCD4 is one of the effective inhibitory targets of miR-21-5p. Methods: The expression between EGFR and ERK2 in lung adenocarcinoma was evaluated from the TCGA database. Osimertinib-sensitive and resistant NSCLC cells obtained from patients were used to co-culture with human lung fibroblasts (HLFs) to generate CAF cells (termed CAF_R1 and CAF_S1), and the functional roles of these CAF cells plus the regulatory mechanisms were further explored. Then, MEK inhibitor Trametinib with or without Osimertinib was applied in xenograft model derived from patients to validate the effects on growth inhibition of Osimertinib-resistant NSCLC tumors. Result: ERK2 expression correlated with EGFR expression and higher ERK2 level was associated with worse prognosis of patients and Osimertinib resistance. CAFs derived from Osimertinib-resistant cells secreted more IL-6, IL-8, and hepatocyte growth factor (HGF), expressed stronger CAF markers including α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP) plus platelet-derived growth factor receptor (PDGFR), and enhanced stemness and Osimertinib resistance in NSCLC cells. Meanwhile, increased MEK/ERK/miR-21 expressions were found in both CAFs and NSCLC cells. MEK inhibitor Trametinib significantly abrogated the abovementioned effects by modulating β-catenin, STAT3, and ERK. The xenograft model showed combining Osimertinib and Trametinib resulted in the most prominent growth inhibition of Osimertinib-resistant NSCLC tumors. Conclusions: Our results suggested that MEK/ERK/miR-21 signaling is critical in Osimertinib resistance and CAF transformation of NSCLC cells, and MEK inhibitor Trametinib significantly suppressed Osimertinib-resistant NSCLC tumor growth by abolishing both processes.

scholarly journals SorCS3 Promotes the Internalization of p75NTR to Inhibit Glioma Progression

2021 ◽  
Author(s):  
Yanqiu Zhang ◽  
Yue Li ◽  
Yuhua Fan ◽  
Baoshan Zhao ◽  
Huan Liang ◽  
...  
Keyword(s):  
Glioma Cells ◽  
Tissue Microarrays ◽  
Cell Receptor ◽  
Receptor Internalization ◽  
Cellular Signal ◽  
Proliferation And Metastasis ◽  
The Impact ◽  
Glioma Progression

Abstract Background: Glioma is a fatal malignancy caused by dysregulation of cellular signal transduction. Internalization plays a key role in maintaining signalling balance. SorCS3 is involved in nerve cell receptor internalization. However, the impact of SorCS3 on the biological processes involved in glioma has not yet been reported. Here, we highlight the potential of SorCS3-mediated regulation of signalling receptor internalization as a rational target for therapeutic intervention in glioma.Methods: SorCS3 expression was analysed in the TCGA and CGGA databases and in tissue microarrays. The effects of SorCS3 on the proliferation and metastasis of glioma cells were examined in vitro and in vivo with Transwell, wound healing, EdU incorporation and nude mouse tumorigenicity assays. Fluorescent 5-FAM, SE-labelled proteins were used to detect the internalization of SorCS3 in glioma cells. Immunofluorescence and Co-IP assays were conducted to investigate the downstream effector of SorCS3. Moreover, Dynasore and Ro 08-2750, inhibitors of internalization and NGF binding to p75NTR, respectively, were used to validate the biological functions of SorCS3 in glioma.Results: Our data demonstrated that SorCS3 was downregulated in glioma tissues and closely related to favourable prognosis. Overexpression of SorCS3 inhibited the proliferation and metastasis of glioma cells in vitro and in vivo, while silencing of SorCS3 exerted the opposite effects. Mechanistic investigations showed that SorCS3 bound to p75NTR, which subsequently increased the internalization of p75NTR, and then transported p75NTR to the lysosome for degradation, ultimately contributing to inhibition of glioma progression.Conclusions: Our work suggests that SorSC3 is a marker of promising prognosis in glioma patients and suggests that SorCS3 regulates internalization, which plays an important role in inhibiting glioma progression.

Development of orally bioavailable prodrugs of fulvestrant for the treatment of metastatic/advanced breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13027-e13027
Author(s):  
Parva Purohit ◽  
Pathik Brahmkshatriya ◽  
Vishalgiri Goswami
Keyword(s):  
Breast Cancer ◽  
Oral Delivery ◽  
Tumor Volume ◽  
Estrogen Therapy ◽  
Xenograft Model ◽  
Fold Increase ◽  
Tumor Growth Inhibition ◽  
Pharmacokinetic Studies ◽  
Hormone Receptor Positive ◽  
Mcf 7

e13027 Background: Fulvestrant, a potent, selective estrogen receptor degrader, is a primary drug of choice for treating advanced metastatic hormone receptor-positive breast cancer in postmenopausal women following anti-estrogen therapy. However, the existing therapy limits to inconvenient intramuscular injections due to low solubility, weak permeation, high metabolism, and poor pharmacokinetics profile. Additionally, it takes 30 days to reach maximal steady-state plasma concentration, limiting clinical efficacy. To overcome these issues, we modulated physicochemical properties of fulvestrant, enabling its oral delivery to improve bioavailability. Methods: Structurally diverse pro-moieties were appended on fulvestrant to improve solubility and ADME profile. Thermodynamic solubility, plasma/liver microsomal stability, and Caco-2 permeability studies were performed to identify lead molecules. Pharmacokinetic studies were performed for selected molecules in mice. Antitumor activity of once-daily oral dose of three molecules was evaluated in female nude mice using the MCF-7 xenograft model. The efficacy of lead molecules was compared with subcutaneously administered faslodex in terms of percentage tumor growth inhibition. Results: Several prodrugs of fulvestrant were synthesized and evaluated for their intrinsic properties suitable for increasing bioavailability of fulvestrant. Remarkable improvements (̃500 to 2000-fold increase) were achieved in solubility and permeability. The PoC established an increase in systemic plasma exposure of fulvestrant upon oral administration of prodrugs in mice with enhanced bioavailability (1.5-8.7-fold) as compared to fulvestrant given subcutaneously (Table). Herewith, we report the identification of KSHN001022, KSHN001075, and KSHN001126, the prodrugs of fulvestrant, which showed enhanced efficacy with better tumor volume reduction (̃48-88% regression in tumor volume) as compared to that of fulvestrant (78%) in the estrogen-dependent MCF-7 xenograft model. Conclusions: KSHN001 lead candidates demonstrated significantly higher bioavailability, hence, provides a novel strategy to deliver fulvestrant orally to pursue the potential benefits in patients with advanced metastatic disease.[Table: see text]

scholarly journals INNV-13. SYNERGISTIC EFFECT OF COLD ATMOSPHERIC PLASMA IN COMBINATION WITH TEMOZOLOMIDE TO TREAT GLIOBLASTOMA IN A NON-INVASIVE MOUSE XENOGRAFT MODEL

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii119-ii119
Author(s):  
Manish Adhikari ◽  
Vikas Soni ◽  
Simonyan Hayk ◽  
Colin Young ◽  
Jonathan Sherman ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Tumor Volume ◽  
Bioluminescence Imaging ◽  
Xenograft Model ◽  
Atmospheric Plasma ◽  
Minimal Effect ◽  
Cold Atmospheric Plasma ◽  
Mouse Xenograft Model ◽  
In Vivo Bioluminescence Imaging

Abstract INTRODUCTION A primary limitation in anti-cancer therapy is the resistance of cancer cells to chemotherapeutic drugs. However, combination therapy may be an effective approach for reducing drug derived toxicity and evading drug resistance, resulting in improved clinical treatment of cancer. Our prior work demonstrated effective treatment of glioblastoma (GBM) with cold atmospheric plasma (CAP) technology with minimal effect to normal cells. Consequently, CAP may serve as a strong candidate for combination therapy with the classical antineoplastic alkylating agent Temozolomide (TMZ) to treat GBM. OBJECTIVES To determine the in vivo co-efficacy of CAP and TMZ to “sensitize” GBM. METHODS An in vivo study was performed using the CAP jet device (He-gas) to determine the effect of combined CAP–TMZ treatment. U87MG-luc glioblastoma cells were implanted intracranially in athymic nude NU(NCr)-Foxn1nu/immunodeficient mice. He-CAP (or control He alone) was non-invasively applied over the skin for 60sec to developed tumors on the first day of the treatment followed with 6.5 mg/kg TMZ or vehicle control treatment for 5 days for two weeks (n=5/group). In vivo bioluminescence imaging was used to monitor tumor volume on the 6th, 9th and 13th treatment day. RESULTS In vivo bioluminescence imaging revealed a marked 8.0±3.2 fold increase in tumor volume in control animals (He-vehicle). Treatment with He-TMZ (6.7±2.5 fold) or CAP-vehicle (4.8±1.7 fold) in isolation had minimal effect in preventing tumor growth. However, combined CAP-TMZ co-treatment virtually prevented increases in tumor volume over 2 weeks (1.8±0.2 fold). CONCLUSIONS Collectively, these findings indicate an effective synergistic treatment method for GBM combining CAP with TMZ. Future investigations look to incorporate radiation into the treatment regimen as well as primary GBM cell models.

scholarly journals TMIC-58. THE CELLULAR AND MOLECULAR BASIS FOR MESENCHYMAL TRANSFORMATION IN GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi260-vi260
Author(s):  
Andrea Comba ◽  
Patrick J Dunn ◽  
Anna E Argento ◽  
Padma Kadiyala ◽  
Sebastien Motsch ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Tumor Cells ◽  
Smooth Muscle Actin ◽  
Glioma Cells ◽  
Time Lapse ◽  
Mesenchymal Cells ◽  
Genetically Engineered ◽  
Normal Brain ◽  
Mesenchymal Transformation ◽  
Glioma Progression

Abstract Mesenchymal gliomas are the most aggressive tumors that carry the worst prognosis. The origins of mesenchymal cells within brain tumors, remains poorly understood. They could originate either from invading mesenchymal cells, from perivascular smooth muscle actin+ cells, or from a mesenchymal transformation of tumor cells. Identifying the origin and function of mesenchymal cells within gliomas is essential as these cells contribute to increased glioma aggressiveness and tumor progression. In this study we used human biopsies and implantable and genetically engineered mouse models (GEMM) of GBM to study tumor mesenchymal transformation. GBM implantable models were used to analyze the molecular landscape by laser microdissection followed by RNA-Seq and bioinformatics analysis. Time lapse confocal imagining was implemented to analyze GBM cells dynamics. Our results indicate the existence of a complex intratumoral and peritumoral dynamic organization of glioma cells (i.e., Oncostreams). Multicellular structures of elongated cells compatible with mesenchymal differentiation. These structures play important roles in intratumoral movements, peritumoral invasion of normal brain, and overall glioma progression. We also show that oncostreams are molecularly distinct and display increased expression of mesenchymal genes such as Col1a1. Knocking down of Col1a1 in a GEMM of aggressive gliomas reduced tumor progression and significantly increased animal survival. Histological examination confirmed absence of Col1a1, and absence of morphologically identifiable oncostreams. Our results show that tumor cells, especially within oncostreams, display a fibroblastic-like morphology and express proteins typical of mesenchymal cells. The knockout of Col1a1 from tumoral cells eliminated oncostreams from tumors and delayed tumor progression. These data suggest that tumor cells expressing mesenchymal genes regulate the organization of mesenchymal multicellular structures, and determine glioma progression. We propose that inhibiting mesenchymal transformation of glioma cells will assist in the treatment of glioblastoma.

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