The Modulation of miR-195-TGF-β/Smad3 Pathway on Proliferation, Apoptosis and Invasion of Glioma Cells

2020 ◽  
Vol 10 (4) ◽  
pp. 500-506
Author(s):  
Gang Wang ◽  
Wenjun Zhao ◽  
Hailin Chen ◽  
Ruobin Bai ◽  
Boru Hou ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Biology ◽  
Tumor Tissue ◽  
Malignant Tumors ◽  
Glioma Cells ◽  
High Incidence ◽  
The Central Nervous System ◽  
Flow Detection ◽  
Complementary Binding

Glioma is one of the most common malignant tumors of the central nervous system with the high incidence. The abnormal expression of Smad3 is related to the occurrence, progression, metastasis, and drug resistance of various kinds of tumors. It was reported that the decreased expression of miR-195 was related to the onset of glioma. This study aims to explore whether miR-195 plays an important role in regulating Smad3 and influencing the cell biology of glioma. Bioinformatics analysis was performed to determine the target complementary binding site between miR-195 and Smad3. The expressions of miR-195 and Smad3 mRNA were measured in tumor tissue of patients with glioma.In vitro culture, SHG-44 cells were divided into 2 groups: miR-NC group, miR-195 mimic group. The expression of miR-195 was detected by qRT-PCR, and expression of Smad3 was measured by western blot. Apoptosis was detected by flow detection. Cell proliferation and cell invasion ability was detected by Ed U staining and Transwell experiments respectively. Our result showed that, compared with that of the carcinoma tissue, the expressions of miR-195 and Smad3 in glioma tissue were decreased significantly. Compared with normal glial cells HEB, the expression of miR-195 was decreased significantly, whereas the expression of Smad3 was increased significantly. The transfection of miR-195 mimic significantly reduced the expression Smad3 and p-Smad3, which significantly reduced the ability of cell proliferation, and increased apoptosis. In conclusion, miR195 can target regulate proliferation, apoptosis and invasion of glioma cells through TGF-β /Smad3 pathway.

scholarly journals Curcumol inhibits malignant biological behaviors and TMZ-resistance of glioma cells via reducing long noncoding RNA FoxD2-As1 promoted EZH2 activation

2021 ◽  
Author(s):  
Xuyang Lv ◽  
Jiangchuan Sun ◽  
Linfeng Hu ◽  
Ying Qian ◽  
Chunlei Fan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Noncoding Rna ◽  
Glioma Cell ◽  
Glioma Cells ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Self Renewal

Abstract Background: Although curcumol has been shown to possess antitumor effects in several cancers, its effects on glioma are largely unknown. Recently, lncRNAs have been reported to play an oncogenic role through epigenetic modifications. Therefore, here, we investigated whether curcumol inhibited glioma progression by reducing FOXD2-AS1-mediated enhancer of zeste homolog 2 (EZH2) activation.Methods: MTT, colony formation, flow cytometry, Transwell, and neurosphere formation assays were used to assess cell proliferation, cell cycle, apoptosis, the percentage of CD133+ cells, the migration and invasion abilities, and the self-renewal ability. qRT-PCR, western blotting, immunofluorescence, and immunohistochemical staining were used to detect mRNA and protein levels. Isobologram analysis and methylation-specific PCR were used to analyze the effects of curcumol on TMZ resistance in glioma cells. DNA pull-down and Chip assays were employed to explore the molecular mechanism underlying the functions of curcumol in glioma cells. Tumorigenicity was determined using a xenograft formation assay. Results: Curcumol inhibited the proliferation, metastasis, self-renewal ability, and TMZ resistance of glioma cells in vitro and in vivo. FOXD2-AS1 was highly expressed in glioma cell lines, and its expression was suppressed by curcumol treatment in a dose- and time-dependent manner. The forced expression of FOXD2-AS1 abrogated the effect of curcumol on glioma cell proliferation, metastasis, self-renewal ability, and TMZ resistance. Moreover, the forced expression of FOXD2-AS1 reversed the inhibitory effect of curcumol on EZH2 activation.Conclusions: We showed for the first time that curcumol is effective in inhibiting malignant biological behaviors and TMZ-resistance of glioma cells by suppressing FOXD2-AS1-mediated EZH2 activation on anti-oncogenes. Our findings offer the possibility of exploiting curcumol as a promising therapeutic agent for glioma treatment and may provide an option for the clinical application of this natural herbal medicine.

scholarly journals KIF23 Promotes Gastric Cancer by Stimulating Cell Proliferation

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Xiao-Long Li ◽  
Ya-Ming Ji ◽  
Rui Song ◽  
Xiao-Ning Li ◽  
Lan-Shuan Guo
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Malignant Tumors ◽  
Vital Role ◽  
Gastric Cancer Cells ◽  
Vitro Assay ◽  
Multiple Tumor ◽  
Axon Elongation ◽  
Underlying Mechanisms

Gastric cancer (GC) is one of the most aggressive malignant tumors with low early diagnosis and high metastasis. Despite progress in treatment, to combat this disease, a better understanding of the underlying mechanisms and novel therapeutic targets is needed. KIF23, which belongs to the KIF family, plays a vital role in various cell processes, such as cytoplasm separation and axon elongation. Nowadays, KIF23 has been found to be highly expressed in multiple tumor tissues and cells, suggesting a potential link between KIF23 and tumorigenesis. Herein, we reported that KIF23 expression was correlated with poor prognosis of gastric cancer and found an association between KIF23 and pTNM stage. An in vitro assay proved that the proliferation of gastric cancer cells was significantly inhibited, which is caused by KIF23 depletion. Additionally, knockdown of KIF23 resulted in a marked inhibition of cell proliferation of gastric cancer in mice, with significant downregulation of Ki67 and PCNA expression. In conclusion, these data indicate that KIF23 is a potential therapeutic target for gastric cancer treatment.

scholarly journals VEGF-and EGF-mediated cooperation of eosinophilic granulocytes and tumor cells in gastric and colon cancer

2019 ◽  
Vol 18 (1) ◽  
pp. 211-219
Author(s):  
Yu. V. Kolobovnikova ◽  
K. I. Yankovich ◽  
E. V. Romanova ◽  
A. I. Dmitrieva ◽  
O. I. Urazova ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Colon Cancer ◽  
Growth Factor ◽  
Tumor Cells ◽  
Tumor Tissue ◽  
Malignant Tumors ◽  
Tissue Eosinophilia ◽  
Eosinophilic Granulocytes ◽  
Blood Eosinophils

Aim of the research – to analyze secretion of vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) by blood eosinophilic granulocytes in vitro, together with an expression of VEGFR and EGFR in tumor tissue in gastric and colon cancer in association with tissue eosinophilia.Materials and methods. A total of 52 patients with gastric cancer and 50 patients with colon cancer were examined. The material of the research included supernatants of eosinophil cultures and samples of malignant tumors tissues of the stomach and colon. Enzyme-linked immunosorbent assay was used to determine the contents of VEGF and EGF in the eosinophil culture supernatants in vitro. The expression of VEGFR and EGFR in tumor tissue was evaluated by immunohistochemistry. The results were analyzed by statistical methods.Results. An increase in basal and r-IL-5-induced secretion of VEGF by eosinophilic granulocytes of blood in vitro was found in patients with gastric cancer accompanied by tissue eosinophilia. The concentration of EGF in the culture of blood eosinophils in vitro with the addition of r-IL-5 increased in patients with eosinophilic infiltration of tumor tissue, regardless of the localization of the pathological process,both in patients with gastric cancer and colon cancer. Eosinophilic infiltration of the tumor tissue in gastric cancer and colon cancer was combined with hypo-expression of EGFR by tumor cells; VEGFR receptor expression was not dependent on the presence of eosinophilic granulocytes in the tissue of tumors.Conclusion. Hypersecretion of vascular endothelial growth factor VEGF and epidermal growth factor EGF (upon stimulation with r-IL-5) by blood eosinophils in vitro in patients with gastric and colon cancer with tissue eosinophilia indicates an increase in the activity of these cells. Deficiency of expression of VEGF and EGFR receptors in tumor tissue causes violation of cooperative interaction of eosinophilic granulocytes and tumor cells in malignant tumors of the stomach and large intestine.

scholarly journals EXTH-54. ENHANCED SENSITIVITY OF HUMAN GLIOMA CELLS FOR TEMOZOLOMIDE (TMZ) BY COMBINING THERAPY WITH HEAT SHOCK PROTEIN 90

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii99-ii99
Author(s):  
Pratibha Sharma ◽  
Lakshmi Shree K Mahadevan ◽  
Aaron Argall ◽  
Jihong Xu ◽  
Deepa Sampath ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Blood Brain Barrier ◽  
Glioma Cell ◽  
Glioma Cells ◽  
Heat Shock Protein 90 ◽  
Brain Barrier ◽  
Client Proteins

Abstract BACKGROUND Heat-shock protein 90 (HSP90) is a molecular chaperone involved in the conformational maturation of many client proteins that regulate cell proliferation, survival, and apoptosis. Due to the limited solubility of natural Hsp90 inhibitors, synthetic inhibitors with a more potent impact are being developed. In this study we examined the biological activity of a potent synthetic small molecule Hsp90 inhibitor, SNX-5422 (PF-04929113)and assessed its ability of to inhibit the growth of glioma and to synergize with temozolomide. We also examined the ability of SNX-5422 to cross the blood brain barrier (BBB) and to achieve target inhibition in vivo. METHODS Using a combination of in vitro techniques, the effect of SNX-5422 on the biological impact and HSP90 client protein signaling were studied in glioma lines and patient-derived glioma stem like cells. Its efficacy as a single agent or in combination with TMZ was also assessed in vitro. To assess SNX-5422 ability to cross blood brain barrier, brain and plasma pharmacokinetics was performed in non-tumor bearing mice. RESULTS SNX-5422 exhibited potent growth inhibition in both glioma cells and GSCs with an IC50 range of 100-500nM, and inhibited pro-survival signal kinases, phospho-Akt, p-ERK1/2 and p-S6 following treatment in GSC262 and GSC811. This was accompanied by accumulation of apoptotic cells following SNX-5422 exposure. Combination studies with TMZ showed a synergestic impact on glioma cell proliferation. Pharmacokinetics studies showed a significant drug penetrance into the intact brain further supported by elevated levels of HSP70 (molecular maker for HSP90 inhibition) by IHC. CONCLUSIONS SNX-5422 is effective in downregulating Hsp90 client proteins required for glioma cell survival. In addition, SNX-5422 inhibits tumor growth by promoting apoptosis through modulation of several key signaling pathways and sensitizes glioma cells to TMZ. Given also that SNX-5422 crosses BBB, it warrants further investigation as a clinical agent for treatment of gliomas.

scholarly journals Cannabinoid WIN 55,212-2 Inhibits Human Glioma Cell Growth by Triggering ROS-Mediated Signal Pathways

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Kun Wang ◽  
Qian Wang ◽  
Qinghao Li ◽  
Zhaoqiang Zhang ◽  
Jing Gao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Ex Vivo ◽  
Underlying Mechanism ◽  
Migration And Invasion ◽  
Signal Pathways ◽  
Human Glioma ◽  
U251 Cell ◽  
The Central Nervous System

Glioblastoma is a highly invasive primary malignant tumor of the central nervous system. Cannabinoid analogue WIN 55,212-2 (WIN) exhibited a novel anticancer effect against human tumors. However, the anticancer potential and underlying mechanism of WIN against human glioma remain unclear. Herein, the anticancer efficiency and mechanism of WIN in U251 human glioma cells were investigated. The results showed that WIN dose-dependently inhibited U251 cell proliferation, migration, and invasion in vitro. WIN treatment also effectively suppressed U251 tumor spheroids growth ex vivo. Further studies found that WIN induced significant apoptosis as convinced by the caspase-3 activation and release of cytochrome C. Mechanism investigation revealed that WIN triggered ROS-mediated DNA damage and caused dysfunction of VEGF-AKT/FAK signal axis. However, ROS inhibition effectively attenuated WIN-induced DNA damage and dysfunction of VEGF-AKT/FAK signal axis and eventually improved U251 cell proliferation, migration, and invasion. Taken together, our findings validated that WIN had the potential to inhibit U251 cell proliferation, migration, and invasion and induce apoptosis by triggering ROS-dependent DNA damage and dysfunction of VEGF-AKT/FAK signal axis.

Improved In Vitro Biocompatibility of Bicarbonate-Buffered Peritoneal Dialysis Fluid

2006 ◽  
Vol 26 (6) ◽  
pp. 664-670 ◽  
Author(s):  
Nicolas Grossin ◽  
Marie-Paule Wautier ◽  
Jean-Luc Wautier ◽  
Pierre Gane ◽  
Redouane Taamma ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Peritoneal Dialysis ◽  
Growth Factor ◽  
Cell Biology ◽  
Transforming Growth Factor ◽  
Mesothelial Cell ◽  
Long Term Treatment ◽  
Peritoneal Dialysis Fluid ◽  
New Generation

Background Conventional peritoneal dialysis fluids (PDFs) have been shown to damage the mesothelial layer and are associated with the development of peritoneal fibrosis and neoangiogenesis. New-generation PDFs have therefore been developed with physiological pH and reduced levels of glucose degradation products (GDPs), precursors of advanced glycation end products (AGEs). In this work, we evaluated and compared the improved biocompatibility of two new-generation PDFs (Balance and bicaVera) using mesothelial cell biology; we also compared them to a standard PDF (stay·safe) (all PDFs by Fresenius Medical Care, Fresnes, France). Methods stay·safe, Balance, and bicaVera were tested for their effect on human peritoneal mesothelial cell (HPMC) viability by measuring cell proliferation and apoptosis, and oncosis induction. The formation of AGEs was evaluated by immunoassay. Transforming growth factor beta-1 and vascular endothelial growth factor (VEGF) were immunoassayed in HPMC supernatants exposed to the above PDFs. Results At 15 g/L glucose concentration, HPMC exposure to bicaVera resulted in higher cell proliferation compared to Balance ( p < 0.001) and stay·safe ( p < 0.001). Compared to the lactate-buffered PDFs (Balance and stay·safe), oncosis was significantly lower in cells exposed to bicaVera ( p < 0.05). bicaVera, containing lower amounts of GDPs, generated less AGE formation ( p < 0.05) and VEGF production ( p < 0.05) than either Balance or stay·safe. Conclusions New-generation PDFs with physiological pH and lower GDP levels, especially if bicarbonate-buffered (bicaVera), have fewer in vitro toxic effects on mesothelial cells and may contribute to peritoneal preservation, thus improving long-term treatment of PD patients.

Induction of prostaglandin E2 synthesis and microsomal prostaglandin E synthase–1 expression in murine microglia by glioma-derived soluble factors

2008 ◽  
Vol 108 (2) ◽  
pp. 311-319 ◽  
Author(s):  
Yoshiteru Nakano ◽  
Etsushi Kuroda ◽  
Tomohiro Kito ◽  
Satoshi Uematsu ◽  
Shizuo Akira ◽  
...  
Keyword(s):  
Glioma Cells ◽  
Peritoneal Macrophages ◽  
Prostaglandin E ◽  
Soluble Factors ◽  
Arachidonate Cascade ◽  
Cox Inhibitor ◽  
Murine Microglia ◽  
The Central Nervous System

Object Microglia are one of the members of monocyte/macrophage lineage in the central nervous system (CNS) and exist as ramified microglia in a normal resting state, but they are activated by various stimuli, such as tumors. Activated microglia induce immune responses in the CNS, but the precise functions of microglia in glioma microenvironments are not clear. It has been reported that glioma cells produce prostaglandin (PG)E2, which promotes the growth of tumor cells and possesses immunosuppressive activity. The authors previously reported that PGE2 production by peritoneal macrophages was enhanced by glioma-derived soluble factors, which induce an immunosuppressive state. In this study, they investigated PGE2 production by microglia treated with glioma cells and assessed the role of microglia in glioma microenvironments in the mouse. Methods Microglia and peritoneal macrophages were cultured in vitro with or without lipopolysaccharide, and tumor necrosis factor (TNF) and PGE2 in the culture supernatant were measured using L929 bioassay and enzyme immunoassay. The expression of mRNA was measured using reverse transcriptase polymerase chain reaction, and the protein expression was assayed with Western blotting. In some experiments glioma cells and conditioned glioma medium were added to the microglia cultures. Results Glioma cells studied in this report did not produce a significant amount of PGE2. However, the coculture of microglia with glioma cells or conditioned glioma medium led to the production of a large amount of PGE2. The enhancement of PGE2 production by microglia was more significant than that by peritoneal macrophages. The expression of cyclooxygenase (COX)–2 and particularly the expression of microsomal PGE synthase (mPGES)–1 (a terminal enzyme of the arachidonate cascade) in microglia were enhanced by conditioned glioma medium. The enhancement of mPGES-1 expression in microglia was more significant than that in peritoneal macrophages. The production of TNF was suppressed when culturing microglia with conditioned glioma medium, but this suppression was abrogated by the addition of a COX inhibitor (NS-398) and a PGE2 receptor (EP4) antagonist. Furthermore, TNF production was not suppressed in microglia from mPGES-1–deficient mice. Conclusions These results indicate that PGE2 production by microglia is enhanced by conditioned glioma medium, which induces an immunosuppressive state in the CNS. Therefore, the manipulation of microglia, from the standpoint of PGE2, provides investigators with an important strategy to induce an effective antiglioma immune response.

scholarly journals MiR-218 inhibits malignant phenotypes of glioma by targeting TNC/AKT/AP-1/TGFβ1 feedback signaling loop

2020 ◽  
Author(s):  
Siwen Dang ◽  
Rui Zhang ◽  
Sijia Tian ◽  
Banjun Ruan ◽  
Peng Hou ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Malignant Tumors ◽  
Glioma Cells ◽  
Luciferase Reporter ◽  
Normal Brain ◽  
Reporter System ◽  
Control Subjects ◽  
Luciferase Reporter System

Abstract Background: Gliomas are the most common and malignant tumors in the brain of humans, and the prognosis of glioma patient is very poor. MicroRNAs (miRNAs) play critical roles in different types of cancer by regulating gene expression at the posttranscriptional levels. Although miR-218 has been reported to be downregulated in gliomas, its role in gliomas still remains largely unknown. Methods: MiR-218 expression in gliomas and normal brain tissues (control subjects) were analyzed using TCGA dataset. The biological roles of miR-218 in glioma cells were determined by a series of in vitro and in vivo studies. The dual-luciferase reporter system was performed to identify potential targets of miR-218. The regulatory effect of miR-218 on TNC/AKT/AP-1/TGFβ1 pathway was evaluated by dual-luciferase reporter system and western blot.Results: We demonstrated miR-218 was significantly downregulated in gliomas compared to control subjects, and exerted a potent tumor suppressor in glioma cells by inhibiting cell proliferation, colony formation, migration, invasion and tumorigenic potential in nude mice, as well as inducing cell cycle arrest and apoptosis.Mechanistically, miR-218 inhibited malignant phenotypes of glioma cells by binding to the 3’ UTR of its target TNC and subsequently repressing its expression. As a result, it could reduce AKT phosphorylation and subsequently inhibit transcriptional activity of AP-1 by reducing JNK phosphorylation, downregulating the expression of TGFβ1, while TGFβ1 is able to, in turn, activate the TNC/AKT/AP-1 signaling axis.Conclusions: Our data uncover a previously unknown tumor suppressor role of miR-218 in glioma by blocking the TNC/AKT/AP-1/TGFβ1 positive feedback loop.

scholarly journals Curcumol inhibits malignant biological behaviors and TMZ-resistance of glioma cells via reducing long noncoding RNA FoxD2-As1 promoted EZH2 activation

2021 ◽  
Author(s):  
Xuyang Lv ◽  
Jiangchuan Sun ◽  
Linfeng Hu ◽  
Ying Qian ◽  
Chunlei Fan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Noncoding Rna ◽  
Glioma Cell ◽  
Glioma Cells ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Self Renewal

Abstract Background: Although curcumol has been shown to possess antitumor effects in several cancers, its effects on glioma are largely unknown. Recently, lncRNAs have been reported to play an oncogenic role through epigenetic modifications. Therefore, here, we investigated whether curcumol inhibited glioma progression by reducing FOXD2-AS1-mediated enhancer of zeste homolog 2 (EZH2) activation.Methods: MTT, colony formation, flow cytometry, Transwell, and neurosphere formation assays were used to assess cell proliferation, cell cycle, apoptosis, the percentage of CD133+ cells, the migration and invasion abilities, and the self-renewal ability. qRT-PCR, western blotting, immunofluorescence, and immunohistochemical staining were used to detect mRNA and protein levels. Isobologram analysis and methylation-specific PCR were used to analyze the effects of curcumol on TMZ resistance in glioma cells. DNA pull-down and Chip assays were employed to explore the molecular mechanism underlying the functions of curcumol in glioma cells. Tumorigenicity was determined using a xenograft formation assay. Results: Curcumol inhibited the proliferation, metastasis, self-renewal ability, and TMZ resistance of glioma cells in vitro and in vivo. FOXD2-AS1 was highly expressed in glioma cell lines, and its expression was suppressed by curcumol treatment in a dose- and time-dependent manner. The forced expression of FOXD2-AS1 abrogated the effect of curcumol on glioma cell proliferation, metastasis, self-renewal ability, and TMZ resistance. Moreover, the forced expression of FOXD2-AS1 reversed the inhibitory effect of curcumol on EZH2 activation.Conclusions: We showed for the first time that curcumol is effective in inhibiting malignant biological behaviors and TMZ-resistance of glioma cells by suppressing FOXD2-AS1-mediated EZH2 activation on anti-oncogenes. Our findings offer the possibility of exploiting curcumol as a promising therapeutic agent for glioma treatment and may provide an option for the clinical application of this natural herbal medicine.

scholarly journals IL-10 Promotes Glioma Cell Growth and Invasion via Upregulation of KPNA2 In vitro

2019 ◽  
Author(s):  
Zihao Zhang ◽  
Xiaoming Huang ◽  
Jie Li ◽  
Haitao Fan ◽  
Fan Yang ◽  
...  
Keyword(s):  
Cell Growth ◽  
Glioma Cell ◽  
Causes Of Death ◽  
Glioma Cells ◽  
Primary Brain Tumor ◽  
Dual Function ◽  
Quantitative Real Time Pcr ◽  
High Incidence ◽  
Important Significance

Abstract Background: Glioma is one of the leading causes of death worldwide with high incidence, recurrence and mortality. IL-10 is a cytokine with dual function in many types of tumors. Although IL-10 is overexpressed and promotes tumor progression in human primary brain tumor, the mechanisms are largely unknown. Methods: Glioma cells were treated with different dosages of IL-10. The cell growth was detected by CCK8, and the invasion was measured by Transwell. The relative expression of mRNAs was detected by Quantitative real-time PCR (q-PCR). Results: We found that IL-10 treatment significantly enhanced glioma cell growth and invasion. And KPNA2 was significantly upregulated after treatment with IL-10. By performing knockdown experiments, we found that the glioma cell growth and invasion were significantly declined. Conclusions: The results indicated that knockdown of KPNA2 significantly inhibited the growth and invasion of glioma cells. And IL-10 promotes glioma progression via upregulation of KPNA2. This study will be of important significance and provides a potential target for treatment of patients with glioma. Keywords: Cell growth, cell invasion, glioma, IL-10, KPNA2.

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