FKBP10 promotes proliferation of glioma cells via activating AKT-CREB-PCNA axis

Abstract Background Although the availability of therapeutic options including temozolomide, radiotherapy and some target agents following neurosurgery, the prognosis of glioma patients remains poor. Thus, there is an urgent need to explore possible targets for clinical treatment of this disease. Methods Tissue microarrays and immunohistochemistry were used to detect FKBP10, Hsp47, p-AKT (Ser473), p-CREB (Ser133) and PCNA expression in glioma tissues and xenografts. CCK-8 tests, colony formation assays and xenograft model were performed to test proliferation ability of FKBP10 in glioma cells in vitro and in vivo. Quantitative reverse transcriptase-PCR, western-blotting, GST-pull down, co-immunoprecipitation and confocal-immunofluorescence staining assay were used to explore the molecular mechanism underlying the functions of overexpressed FKBP10 in glioma cells. Results FKBP10 was highly expressed in glioma tissues and its expression was positively correlates with grade, poor prognosis. FKBP10-knockdown suppressed glioma cell proliferation in vitro and subcutaneous/orthotopic xenograft tumor growth in vivo. Silencing of FKBP10 reduced p-AKT (Ser473), p-CREB (Ser133), PCNA mRNA and PCNA protein expression in glioma cells. FKBP10 interacting with Hsp47 enhanced the proliferation ability of glioma cells via AKT-CREB-PCNA cascade. In addition, correlation between these molecules were also found in xenograft tumor and glioma tissues. Conclusions We showed for the first time that FKBP10 is overexpressed in glioma and involved in proliferation of glioma cells by interacting with Hsp47 and activating AKT-CREB-PCNA signaling pathways. Our findings suggest that inhibition of FKBP10 related signaling might offer a potential therapeutic option for glioma patients.

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SorCS3 Promotes the Internalization of p75NTR to Inhibit Glioma Progression

10.21203/rs.3.rs-548754/v1 ◽

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.

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Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma

Cancers ◽

10.3390/cancers12030672 ◽

2020 ◽

Vol 12 (3) ◽

pp. 672 ◽

Cited By ~ 5

Author(s):

Roberta Affatato ◽

Laura Carrassa ◽

Rosaria Chilà ◽

Monica Lupi ◽

Valentina Restelli ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

High Throughput Screening ◽

Therapeutic Option ◽

Xenograft Model ◽

Antimitotic Drugs ◽

M Phase ◽

Sirna Library

Mucinous epithelial ovarian cancer (mEOC) is a rare subset of epithelial ovarian cancer. When diagnosed at a late stage, its prognosis is very poor, as it is quite chemo-resistant. To find new therapeutic options for mEOC, we performed high-throughput screening using a siRNA library directed against human protein kinases in a mEOC cell line, and polo-like kinase1 (PLK1) was identified as the kinase whose downregulation interfered with cell proliferation. Both PLK1 siRNA and two specific PLK1 inhibitors (onvansertib and volasertib) were able to inhibit cell growth, induce apoptosis and block cells in the G2/M phase of the cell cycle. We evaluated, in vitro, the combinations of PLK1 inhibitors and different chemotherapeutic drugs currently used in the treatment of mEOC, and we observed a synergistic effect of PLK1 inhibitors and antimitotic drugs. When translated into an in vivo xenograft model, the combination of onvansertib and paclitaxel resulted in stronger tumor regressions and in a longer mice survival than the single treatments. These effects were associated with a higher induction of mitotic block and induction of apoptosis, similarly to what was observed in vitro. These data suggest that the combination onvansertib/paclitaxel could represent a new active therapeutic option in mEOC.

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Mesenchymal stem cells promote glioma neovascularization in vivo by fusing with cancer stem cells

BMC Cancer ◽

10.1186/s12885-019-6460-0 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 5

Author(s):

Chao Sun ◽

Xingliang Dai ◽

Dongliang Zhao ◽

Haiyang Wang ◽

Xiaoci Rong ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Tumor Growth ◽

Glioma Cells ◽

Stem Cell Markers ◽

Xenograft Tumor ◽

Angiogenic Effect

Abstract Background and objective Tumor angiogenesis is vital for tumor growth. Recent evidence indicated that bone marrow-derived mesenchymal stem cells (BMSCs) can migrate to tumor sites and exert critical effects on tumor growth through direct and/or indirect interactions with tumor cells. However, the effect of BMSCs on tumor neovascularization has not been fully elucidated. This study aimed to investigate whether fusion cells from glioma stem cells and BMSCs participated in angiogenesis. Methods SU3-RFP cells were injected into the right caudate nucleus of NC-C57Bl/6 J-GFP nude mice, and the RFP+/GFP+ cells were isolated and named fusion cells. The angiogenic effects of SU3-RFP, BMSCs and fusion cells were compared in vivo and in vitro. Results Fusion cells showed elevated levels of CD31, CD34 and VE-Cadherin (markers of VEC) as compared to SU3-RFP and BMSCs. The MVD-CD31 in RFP+/GFP+ cell xenograft tumor was significantly greater as compared to that in SU3-RFP xenograft tumor. In addition, the expression of CD133 and stem cell markers Nanog, Oct4 and Sox2 were increased in fusion cells as compared to the parental cells. Fusion cells exhibited enhanced angiogenic effect as compared to parental glioma cells in vivo and in vitro, which may be related to their stem cell properties. Conclusion Fusion cells exhibited enhanced angiogenic effect as compared to parental glioma cells in vivo and in vitro, which may be related to their stem cell properties. Hence, cell fusion may contribute to glioma angiogenesis.

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S100A11 Promotes Glioma Cell Proliferation and Predicts Grade-Correlated Unfavorable Prognosis

Technology in Cancer Research & Treatment ◽

10.1177/15330338211011961 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110119

Author(s):

Haopeng Wang ◽

Mengyuan Yin ◽

Lei Ye ◽

Peng Gao ◽

Xiang Mao ◽

...

Keyword(s):

Glioma Cell ◽

Xenograft Model ◽

Clinical Information ◽

The Public ◽

Potential Biomarker ◽

Glioma Cell Proliferation ◽

Glioma Growth

The prognosis of glioma is significantly correlated with the pathological grades; however, the correlations between the prognostic biomarkers with pathological grades have not been elucidated. S100A11 is involved in a variety of malignant biological processes of tumor, whereas its biological and clinicopathological features on glioma remain unclear. In this study, the S100A11 expression and clinical information were obtained from the public databases (TCGA, GEPIA2) to analyze its correlations with the pathological grade and the prognosis of glioma patients. We then verified the expression of S100A11 by immunohistochemistry staining. The effects of S100A11 on the proliferation of glioma cells were confirmed by cytological function assays (CCK-8, Flow cytometry, Clone formation assay) in vitro, the role of S100A11 in regulation of glioma growth was determined by xenograft model assay. We observed that S100A11 expression positively correlated with the pathological grades, while negatively correlated with the survival time of patients. In cytological analysis, we found the proliferations of glioma cell lines were significantly inhibited in vitro ( P < 0.05) after interfering S100A11 expression via shRNAs. The cell cycle was blocked at G0/G1 stage. The ability of clone formation was significantly decreased, and the tumorigenicity in vivo was weakened ( P < 0.05). In summary, S100A11 was over-expressed in gliomas and positively correlated with the pathological grades. Interfering the expression of S100A11 significantly inhibited the proliferation of glioma in vitro and the tumorigenicity in vivo ( P < 0.05). In conclusion, S100A11 might be considered as a potential biomarker in glioma.

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A Novel Strategy Conjugating PD-L1 Polypeptide With Doxorubicin Alleviates Chemotherapeutic Resistance and Enhances Immune Response in Colon Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.737323 ◽

2021 ◽

Vol 11 ◽

Author(s):

Maolin Wang ◽

Xing-sheng Shu ◽

Meiqi Li ◽

Yilin Zhang ◽

Youli Yao ◽

...

Keyword(s):

Drug Delivery ◽

Colon Cancer ◽

Binding Affinity ◽

Therapeutic Option ◽

Xenograft Model ◽

Combination Regimen ◽

Tumor Tissues ◽

Mouse Xenograft Model

BackgroundModifying the structure of anti-tumor chemotherapy drug is of significance to enhance the specificity and efficacy of drug-delivery. A novel proteolysis resistant PD-L1-targeted peptide (PPA1) has been reported to bind to PD-L1 and disrupt the PD-1/PD-L1 interaction, thus appearing as an outstanding tumor-targeting modification of synergistic drug conjugate for effective anti-tumor treatment. However, the combination regimen of coupling PD-L1 polypeptide with chemotherapeutic drug in tumoricidal treatment has not been reported thus far.MethodsWe developed a novel synergistic strategy by conjugating PPA1 to doxorubicin (DOX) with a pH sensitive linker that can trigger the release of DOX near acidic tumor tissues. The binding affinity of PPA1-DOX with PD-L1 and the acid-sensitive cleavage of PPA1-DOX were investigated. A mouse xenograft model of colon cancer was used to evaluate the biodistribution, cytotoxicity and anti-tumor activity of PPA1-DOX.ResultsPPA1-DOX construct showed high binding affinity with PD-L1 in vitro and specifically enriched within tumor when administered in vivo. PPA1-DOX exhibited a significantly lower toxicity and a remarkably higher antitumor activity in vivo, as compared with free PPA1, random polypeptide-DOX conjugate, DOX, or 5-FU, respectively. Moreover, increased infiltration of both CD4+ and CD8+ T cells was found in tumors from PPA1-DOX treated mice.ConclusionsWe describe here for the first time that the dual-functional conjugate PPA1-DOX, which consist of the PD-L1-targeted polypeptide that renders both the tumor-specific drug delivery and inhibitory PD-1/PD-L1 immune checkpoint inhibition, and a cytotoxic agent that is released and kills tumor cells once reaching tumor tissues, thus representing a promising therapeutic option for colon cancer with improved efficacy and reduced toxicity.

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Establishment of Primary Xenograft Model From Newly Characterized Patient Extrauterine Carcinosarcoma

International Journal of Gynecological Cancer ◽

10.1097/01.igc.0000434105.98035.c7 ◽

2013 ◽

Vol 23 (9) ◽

pp. 1552-1560 ◽

Cited By ~ 1

Author(s):

Hyun Joo Lee ◽

Hye-Jung Choi ◽

Heung-Mo Yang ◽

You Min Kim ◽

Jeeyun Lee ◽

...

Keyword(s):

Anticancer Drug ◽

Kinase Inhibitors ◽

Xenograft Model ◽

Drug Susceptibility ◽

Primary Cells ◽

Xenograft Tumor ◽

Facs Analysis ◽

Therapeutic Model

Background and ObjectiveThe aim of this study was to characterize primary cells from extrauterine carcinosarcoma (CS) and to establish a primary CS xenograft mouse model.MethodsPrimary cells were isolated from a patient with CS and cultured in vitro. Primary CS cells were verified for their ability to consecutively generate tumorigenesis in NOD/SCID mice. The properties of xenograft tumor and explants cells were investigated by immunohistochemistry, cytogenetic, and FACS analysis. Anticancer drug susceptibility of primary CS was analyzed using CCK-8.ResultsPrimary CS cells greater than 27 passages in vitro showed an ability of a series of xenograft tumorigenesis in vivo having the same marker expression and cytogenetic character as that of original tumor. In addition, explants of xenograft tumors retained their original characteristics in the in vitro culture system. Finally, the analysis of the susceptibility to anticancer drug revealed that primary CS cells were susceptible to both doxorubicin and nilotinib, which are tyrosine kinase inhibitors.ConclusionsThe primary CS cells and the primary CS xenograft tumorigenesis introduce a new therapeutic model for targeting cancer and also explore a deeper understanding of generation of the tumor itself.

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Downregulation of TET1 Promotes Glioma Cell Proliferation and Invasion by Targeting Wnt/β-Catenin Pathway

Analytical Cellular Pathology ◽

10.1155/2021/8980711 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Jianwen Ji ◽

Qiuxiang You ◽

Jidong Zhang ◽

Yutao Wang ◽

Jing Cheng ◽

...

Keyword(s):

Cell Proliferation ◽

Glioma Cell ◽

Molecular Mechanisms ◽

Glioma Cells ◽

Adult Brain ◽

Migration And Invasion ◽

Downstream Targets ◽

Glioma Cell Proliferation

Glioma is the most common malignant tumor in adult brain characteristic with poor prognosis and low survival rate. Despite the application of advanced surgery, chemotherapy, and radiotherapy, the patients with glioma suffer poor treatment effects due to the complex molecular mechanisms of pathological process. In this paper, we conducted the experiments to prove the critical roles TET1 played in glioma and explored the downstream targets of TET1 in order to provide a novel theoretical basis for clinical glioma therapy. RT-qPCR was adopted to detect the RNA level of TET1 and β-catenin; Western blot was taken to determine the expression of proteins. CCK8 assay was used to detect the proliferation of glioma cells. Flow cytometry was used to test cell apoptosis and distribution of cell cycle. To detect the migration and invasion of glioma cells, wound healing assay and Transwell were performed. It was found that downregulation of TET1 could promote the proliferation migration and invasion of glioma cells and the concomitant upregulation of β-catenin, and its downstream targets like cyclinD1 and c-myc were observed. The further rescue experiments were performed, wherein downregulation of β-catenin markedly decreases glioma cell proliferation in vitro and in vivo. This study confirmed the tumor suppressive function of TET1 and illustrated the underlying molecular mechanisms regulated by TET1 in glioma.

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Effect of hnRNPA2/B1 on the proliferation and apoptosis of glioma U251 cells via the regulation of AKT and STAT3 pathways

Bioscience Reports ◽

10.1042/bsr20190318 ◽

2020 ◽

Vol 40 (7) ◽

Author(s):

Decheng Yin ◽

Chengxiang Kong ◽

Muhu Chen

Keyword(s):

Signaling Pathways ◽

Xenograft Model ◽

Glioma Cells ◽

B Cell Lymphoma ◽

Tumor Xenograft ◽

Nuclear Antigen ◽

Proliferation And Apoptosis ◽

Nuclear Ribonucleoprotein

Abstract Glioma is the most common malignant tumor in the human central nervous system. Although heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) was previously presumed to be a tumor-promoting gene, the relationship between hnRNPA2/B1 and glioma is unclear. Targeting hnRNPA2/B1 interference in glioma cells can significantly inhibit proliferation and increase apoptosis of human glioma cells in vitro. In a tumor xenograft model, knockdown of hnRNPA2/B1 suppressed tumor growth in glioma cells in vivo. In terms of a mechanism, the knockdown of hnRNPA2/B1 led to inactivation of the AKT and STAT3 signaling pathways, which ultimately reduced the expression of B-cell lymphoma-2 (Bcl-2), CyclinD1 and proliferating cell nuclear antigen (PCNA). Collectively, these data suggest that the inhibition of hnRNPA2/B1 can reduce the growth of gliomas through STAT3 and AKT signaling pathways, and this inhibition is expected to be a therapeutic target for gliomas.

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Ribosomal Protein S27-Like is overexpressed in glioma cells and inhibition of RPS27L expression suspends the tumorigenesis

10.21203/rs.3.rs-49193/v2 ◽

2020 ◽

Author(s):

Zhongzheng Sun ◽

Hao Xue ◽

Yan Wei ◽

Shaobo Wang ◽

Jianye Xu ◽

...

Keyword(s):

Ribosomal Protein ◽

Xenograft Model ◽

Glioma Cells ◽

Tumor Grade ◽

Migration And Invasion ◽

Normal Brain ◽

Orthotopic Xenograft Model ◽

High Expression Group

Abstract Background: Ribosomal Protein S27-Like is an evolutionarily conserved ribosomal protein and the role of RPS27L influencing the malignance of several cancers has been reported. However, its effects on glioma were still unknown. This investigation aims to characterize the clinical significance and the biological functions of RPS27L in gliomas.Methods: TCGA databases were explored to analyze the correlation between RPS27L expression and the clinical characteristics of glioma patients. Immunohistochemical staining was performed on glioma cases and normal brain tissues. The function of RPS27L in glioma was further explored using U87MG and A172 cell lines and a orthotopic xenograft model of nude mice.Results: Data obtained from TCGA database showed higher expression of RPS27L in glioma than normal, and the overall survival was lower in the high expression group. Immunohistochemistry showed the expression levels of RPS27L were increased with the tumor grade rising in gliomas. Functional assays showed knockdown of RPS27L inhibited proliferation, cell cycle transition, migration and invasion, while promoted apoptosis. Data of western blot indicated that knockdown of RPS27L increased the level of p21，Bax and Cleaved Caspase-3 while decreased the level of CDK4, cyclinD1, cyclinE1, Bcl-2 and MMP2, MMP9 in glioma cells. In vivo, the growth of orthotopic glioma xenografts was suppressed by expression of RPS27L shRNA, and the tumors with RPS27L shRNA showed less aggressiveness and reduced expression of Ki67, Bcl-2 and MMP2. Conclusions: RPS27L is overexpressed in glioma cells. Knockdown of RPS27L could inhibit the proliferation, migration and invasion while promote apoptosis of glioma cells in vitro and in vivo. RPS27L might be a potential prognostic biomarker and possible target for future therapy in glioma.

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