scholarly journals Temozolomide-Acquired Resistance Is Associated with Modulation of the Integrin Repertoire in Glioblastoma, Impact of α5β1 Integrin

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 369
Author(s):  
Saidu Sani ◽  
Nikita Pallaoro ◽  
Mélissa Messe ◽  
Chloé Bernhard ◽  
Nelly Etienne-Selloum ◽  
...  
Keyword(s):  
Cell Model ◽  
Acquired Resistance ◽  
Standard Of Care ◽  
Recurrent Glioblastoma ◽  
Therapy Failure ◽  
And Migration ◽  
High Level ◽  
Tumoral Cells ◽  
Α5β1 Integrin ◽  
Proliferation And Migration

Despite extensive treatment, glioblastoma inevitably recurs, leading to an overall survival of around 16 months. Understanding why and how tumours resist to radio/chemotherapies is crucial to overcome this unmet oncological challenge. Primary and acquired resistance to Temozolomide (TMZ), the standard-of-care chemotherapeutic drug, have been the subjects of several studies. This work aimed to evaluate molecular and phenotypic changes occurring during and after TMZ treatment in a glioblastoma cell model, the U87MG. These initially TMZ-sensitive cells acquire long-lasting resistance even after removal of the drug. Transcriptomic analysis revealed that profound changes occurred between parental and resistant cells, particularly at the level of the integrin repertoire. Focusing on α5β1 integrin, which we proposed earlier as a glioblastoma therapeutic target, we demonstrated that its expression was decreased in the presence of TMZ but restored after removal of the drug. In this glioblastoma model of recurrence, α5β1 integrin plays an important role in the proliferation and migration of tumoral cells. We also demonstrated that reactivating p53 by MDM2 inhibitors concomitantly with the inhibition of this integrin in recurrent cells may overcome the TMZ resistance. Our results may explain some integrin-based targeted therapy failure as integrin expressions are highly switchable during the time of treatment. We also propose an alternative way to alter the viability of recurrent glioblastoma cells expressing a high level of α5β1 integrin.

Exosomal miR-214-5p Released from Glioblastoma Cells Modulates Inflammatory Response of Microglia after Lipopolysaccharide Stimulation through Targeting CXCR5

2019 ◽  
Vol 18 (1) ◽  
pp. 78-87 ◽  
Author(s):  
Jian-kai Yang ◽  
Hong-jiang Liu ◽  
Yuanyu Wang ◽  
Chen Li ◽  
Ji-peng Yang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Critical Role ◽  
Luciferase Reporter ◽  
Clinical Prognosis ◽  
Direct Target ◽  
And Migration ◽  
High Level ◽  
Cxcr5 Expression ◽  
Proliferation And Migration

Background and Objective: Exosomes communicate inter-cellularly and miRNAs play critical roles in this scenario. MiR-214-5p was implicated in multiple tumors with diverse functions uncovered. However, whether miR-214-5p is mechanistically involved in glioblastoma, especially via exosomal pathway, is still elusive. Here we sought to comprehensively address the critical role of exosomal miR-214-5p in glioblastoma (GBM) microenvironment.Methods:The relative expression of miR-214-5p was determined by real-time PCR. Cell viability and migration were measured by MTT and transwell chamber assays, respectively. The secretory cytokines were measured with ELISA kits. The regulatory effect of miR-214-5p on CXCR5 expression was interrogated by luciferase reporter assay. Protein level was analyzed by Western blot.Results:We demonstrated that miR-214-5p was aberrantly overexpressed in GBM and associated with poorer clinical prognosis. High level of miR-214-5p significantly contributed to cell proliferation and migration. GBM-derived exosomal miR-214-5p promoted inflammatory response in primary microglia upon lipopolysaccharide challenge. We further identified CXCR5 as the direct target of miR-214- 5p in this setting.Conclusion:Overexpression of miR-214-5p in GBM modulated the inflammatory response in microglia via exosomal transfer.

scholarly journals FLT3 Inhibitor Quizartinib Facilitates Proliferation and CXCL12-Induced Chemotaxis in Quizartinib Resistant FLT3/ITD + Hematopoietic Cells By Increasing RUNX1

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3324-3324
Author(s):  
Seiji Fukuda ◽  
Nozomi Matsuda
Keyword(s):  
Protein Expression ◽  
Acquired Resistance ◽  
Cxcr4 Expression ◽  
Expression Level ◽  
Expression Levels ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors ◽  
And Migration ◽  
Runx1 Expression ◽  
Proliferation And Migration

Abstract RUNX1 generally functions as a tumor suppressor in the hematopoietic system. However, RUNX1 expression is significantly elevated in human AML cells with FLT3/ITD mutations, promotes leukemogenesis induced by FLT3/ITD (Behrens et al. JEM 2017) and enhances the resistance of FLT3/ITD + cells to type-II FLT3 inhibitor quizartinib (Hirade et al IJH 2016). We previously reported that RUNX1 expression is higher in CXCR4-low FLT3/ITD + cells compared to Cxcr4-high FLT3/ITD + cells, even though Cxcr4 expression is trans-activated by RUNX1. This difference in RUNX1 expression level was associated with divergent response to CXCL12 in FLT3/ITD + cells harboring different CXCR4 expression levels that were exposed to quizartinib (Fukuda S. et al. ASH 2019). Our data also demonstrated that RUNX1 expression is down-regulated following withdrawal of quizartinib in FLT3/ITD + cells that became refractory to quizartinib (Hirade et al. IJH 2016), suggesting that RUNX1 expression may be up-regulated by quizartinib in FLT3/ITD + cells. Since RUNX1 regulates proliferation of FLT3/ITD + AML cells, the present study investigated association between RUNX1 expression levels and proliferation of quizartinib resistant FLT3/ITD + cells that are exposed to quizartinib. In the sensitive FLT3/ITD + Ba/F3 cells, RUNX1 protein expression was transiently up-regulated but eventually down-regulated by 5 nM quizartinib, coincident with decline in the viable cells. In contrast, RUNX1 expression was up-regulated by quizartinib and remained elevated in the resistant FLT3/ITD + Ba/F3 cells. Since RUNX1 enhances proliferation of FLT3/ITD + cells, we next examined whether proliferation FLT3/ITD + cells that acquired resistance to quizartinib is facilitated by quizaritinib as a result from quizartinib-mediated up-regulation of RUNX1, using the Cxcr4-low and Cxcr4-high FLT3/ITD + cells that acquired resistance to quizartinib. Although CXCL12 barely enhanced the proliferation of refractory FLT3/ITD + Ba/F3 cells, 5 nM quizartinib significantly increased the proliferation of both Cxcr4-low and Cxcr4-high FLT3/ITD + Ba/F3 cells that acquired resistance to quizartinib compared to those without quizartinib. This increase in the proliferation of Cxcr4-low and Cxcr4-high FLT3/ITD + Ba/F3 cells coincided with the elevation in RUNX1 and CXCR4 protein expression. Moreover, the resistant Cxcr4-low FLT3/ITD + Ba/F3 cells proliferated significantly faster than Cxcr4-high FLT3/ITD + cells, with concomitant higher expression of RUNX1 in Cxcr4-low FLT3/ITD + cells than in Cxcr4-high FLT3/ITD + cells. Likewise, type-I FLT3 inhibitor gilteritinib significantly enhanced proliferation of Cxcr4-low and Cxcr4-high FLT3/ITD + Ba/F3 cells that acquired resistance to gilteritinib. Knocking down Runx1 using shRNAs significantly decreased the enhanced proliferation induced by quizartinib in refractory FLT3/ITD + Ba/F3 cells, coincident with reduction in CXCR4 expression. Since CXCR4 expression level was elevated by quizartinib in the FLT3/ITD + cells refractory to quizartinib, we next examined CXCL12-induced migration in quizartinib-resistant FLT3/ITD + cells following exposure to quzartinib. Pre-incubating the quizartinib resistant Cxcr4-low or Cxcr4-high FLT3/ITD + Ba/F3 cells with 5 nM quizartinib for 72 hours significantly enhanced their migration to 100 ng/ml of Cxcl12 compared to those without quizartinib, coincident with elevation in RUNX1 levels. Surprisingly, migration of CXCR4-low FLT3/ITD + cells to CXCL12 was significantly elevated compared to CXCR4-high cells, with concomitant higher expression of RUNX1 in Cxcr4-low FLT3/ITD + cells than in Cxcr4-high FLT3/ITD + cells. Silencing Runx1 using shRNAs significantly decreased migration to CXCL12 in refractory Cxcr4-low FLT3/ITD + Ba/F3 cells. These data indicate that the FLT3 inhibitor itself can facilitate the proliferation and migration to CXCL12 in FLT3/ITD + cells that are refractory to FLT3 inhibitors by up-regulating RUNX1. The results implicate that FLT3 inhibitors may worsen the disease progression in the patients that became refractory to FLT3 inhibitors by facilitating proliferation and migration to CXCL12 of the resistant FLT3/ITD + AML cells. In this regard, targeting RUNX1 may represent additional strategy to eradicate resistant FLT3/ITD + AML cells, in which their proliferation and migration are supported by FLT3 inhibitors. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Association of Aberrant Expression of FGF1 and mTOR-S6K1 in Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Tinghui Duan ◽  
Diyuan Zhou ◽  
Yizhou Yao ◽  
Xinyu Shao
Keyword(s):  
Colorectal Cancer ◽  
Malignant Neoplasms ◽  
Aberrant Expression ◽  
Protein Levels ◽  
And Migration ◽  
High Level ◽  
Proliferation And Migration

Colorectal cancer (CRC) is one of the most frequent malignant neoplasms worldwide, and the effect of treatments is limited. Fibroblast growth factor 1 (FGF1) has been involved in a wide variety of several malignant diseases and takes part in the tumorigenesis of CRC. However, the function and mechanism of FGF1 in CRC remains elusive. In this study, the results indicated that FGF1 is elevated in CRC tissues and linked with poor prognosis (P < 0.001). In subgroup analysis of FGF1 in CRC, regardless of any clinic-factors except gender, high level FGF1 expression was associated with markedly shorter survival (P < 0.05). In addition, the expression of p-S6K1 and FGF1 was not associated in normal tissue (P = 0.781), but their expression was closely related in tumor tissue (P = 0.010). The oncogenic role of FGF1 was determined using in vitro and in vivo functional assays. FGF1 depletion inhibited the proliferation and migration of CRC cells in vitro and vivo. FGF1 was also significantly correlated with mTOR-S6K1 pathway on the gene and protein levels (P < 0.05). In conclusion, FGF1 acts as a tumor activator in CRC, and against FGF1 may provide a new visual field on treating CRC, especially for mTORC1-targeted resistant patients.

scholarly journals KCNQ1OT1 promotes the proliferation and migration of psoriatic keratinocytes by regulating miR-183-3p/GAB1

2021 ◽  
Vol 49 (5) ◽  
pp. 125-130
Author(s):  
Ting Liu ◽  
Xi Duan ◽  
Jia He ◽  
Chuan Yang
Keyword(s):  
Cell Viability ◽  
Cell Model ◽  
Growth Factor Receptor ◽  
Keratinocyte Proliferation ◽  
Tnf Α ◽  
Keratinocyte Cell Line Hacat ◽  
Gated Channel ◽  
And Migration ◽  
Proliferation And Migration

Background: Differentially expressed lncRNAs have been reported to be involved in keratinocyte proliferation and migration, and participate in the development of psoriasis. Potassium voltage-gated channel subfamily Q member 1 overlapping transcript 1 (KCNQ1OT1) was implicated in the pathogenesis of various diseases, including cancer, sepsis, diabetic cardiomyopathy, and atherosclerosis. The influence of KCNQ1OT1 on proliferation and migration of psoriatic keratinocytes was unfolded in this study. Methods: Human keratinocyte cell line (HaCaT) was incubated with TNF-α to establish in vitro cell model of psoriasis. Cell viability and migration were assessed by MTT and wound healing, respectively. Target miRNA of KCNQ1OT1 was identified by luciferase activity and RNA immunoprecipitation (RIP) assays. Results: KCNQ1OT1 was up-regulated in TNF-α-induced HaCaT, and knockdown of KCNQ1OT1 reduced cell viability and suppressed migration of TNF-α-induced HaCaT. KCNQ1OT1 bind to miR-183-3p and negatively regulated expression of miR-183-3p. Over-expression of GAB1 (growth factor receptor binding 2-associated binding protein 1) counteracted with the suppressive effects of KCNQ1OT1 silence on cell viability and migration of TNF-α-induced HaCaT. Conclusion: Silence of KCNQ1OT1 suppressed proliferation and migration of TNF-α-induced HaCaT through regulation of miR-183-3p/GAB1, providing potential strategy for psoriasis.

scholarly journals Involvement of F-Actin in Chaperonin-Containing t-Complex 1 Beta Regulating Mouse Mesangial Cell Functions in a Glucose-Induction Cell Model

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Jin-Shuen Chen ◽  
Li-Chien Chang ◽  
Chia-Chao Wu ◽  
Lai-King Yeung ◽  
Yuh-Feng Lin
Keyword(s):  
Mesangial Cell ◽  
Cell Model ◽  
Cell Contraction ◽  
Small Interference Rna ◽  
Cell Functions ◽  
T Complex ◽  
Glucose Induction ◽  
And Migration ◽  
Proliferation And Migration

The aim of this study is to investigate the role of chaperonin-containing t-complex polypeptide 1 beta (CCT2) in the regulation of mouse mesangial cell (mMC) contraction, proliferation, and migration with filamentous/globular-(F/G-) actin ratio under high glucose induction. A low CCT2 mMC model induced by treatment of small interference RNA was established. Groups with and without low CCT2 induction examined in normal and high (H) glucose conditions revealed the following major results: (1) low CCT2 or H glucose showed the ability to attenuate F/G-actin ratio; (2) groups with low F/G-actin ratio all showed less cell contraction; (3) suppression of CCT2 may reduce the proliferation and migration which were originally induced by H glucose. In conclusion, CCT2 can be used as a specific regulator for mMC contraction, proliferation, and migration affected by glucose, which mechanism may involve the alteration of F-actin, particularly for cell contraction.

scholarly journals Ionizing Radiation Induces Resistant Glioblastoma Stem-Like Cells by Promoting Autophagy via the Wnt/β-Catenin Pathway

Life ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 451
Author(s):  
Cheng-Yu Tsai ◽  
Huey-Jiun Ko ◽  
Chi-Ying F. Huang ◽  
Ching-Yi Lin ◽  
Shean-Jaw Chiou ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Cell Model ◽  
Therapy Resistance ◽  
Vital Role ◽  
Recurrent Glioblastoma ◽  
Recurrent Glioblastoma Multiforme ◽  
Poor Overall Survival ◽  
A Cell ◽  
Field Lines ◽  
High Level

Therapeutic resistance in recurrent glioblastoma multiforme (GBM) after concurrent chemoradiotherapy (CCRT) is a challenging issue. Although standard fractionated radiation is essential to treat GBM, it has led to local recurrence along with therapy-resistant cells in the ionizing radiation (IR) field. Lines of evidence showed cancer stem cells (CSCs) play a vital role in therapy resistance in many cancer types, including GBM. However, the molecular mechanism is poorly understood. Here, we proposed that autophagy could be involved in GSC induction for radioresistance. In a clinical setting, patients who received radiation/chemotherapy had higher LC3II expression and showed poor overall survival compared with those with low LC3 II. In a cell model, U87MG and GBM8401 expressed high level of stemness markers CD133, CD44, Nestin, and autophagy marker P62/LC3II after receiving standard fractionated IR. Furthermore, Wnt/β-catenin proved to be a potential pathway and related to P62 by using proteasome inhibitor (MG132). Moreover, pharmacological inhibition of autophagy with BAF and CQ inhibit GSC cell growth by impairing autophagy flux as demonstrated by decrease Nestin, CD133, and SOX-2 levels. In conclusion, we demonstrated that fractionated IR could induce GSCs with the stemness phenotype by P62-mediated autophagy through the Wnt/β-catenin for radioresistance. This study offers a new therapeutic strategy for targeting GBM in the future.

scholarly journals KIF15 is involved in development and progression of Burkitt lymphoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zhao Wang ◽  
Meiting Chen ◽  
Xiaojie Fang ◽  
Huangming Hong ◽  
Yuyi Yao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Burkitt Lymphoma ◽  
Cell Model ◽  
Human Cancer ◽  
Cell Activity ◽  
Normal Tissues ◽  
Through Flow ◽  
And Migration ◽  
Related Proteins ◽  
Proliferation And Migration

Abstract Background Burkitt lymphoma (BL) is a highly aggressive, fast-growing B-cell non-Hodgkin's lymphoma, manifested in several subtypes, including sporadic, endemic, and immunodeficiency-related forms, the mechanism of which is still not clear. Abundant evidence reported that KIF15 was involved in the progression of human cancer. The emphasis of this study is to explore the functions of KIF15 in the development of BL. Methods Firstly, tumor and normal tissues were collected for detecting expression of KIF15 in BL. Lentivirus-mediated shRNA knockdown of KIF15 was used to construct BL cell model, which was verified by qRT-PCR and Western Blot. The cell proliferation was detected by CCK8 assay, cell apoptosis and cell cycle were measured through flow cytometry. Transwell assay was conducted to detect the migration. Results We first found that KIF15 is highly expressed in BL. Knockdown of KIF15 can inhibit proliferation and migration, promote apoptosis and arrest the cell cycle. Moreover, KIF15 is involved in BL cell activity through regulating expression of apoptosis-related proteins (Caspase3, Caspase8, HTRA, IGFBP-6, p53, SMAC, sTNF-R1, TNF-β and Bcl-2) and downstream pathways, such as p-Akt, CCND1, CDK6 and PIK3CA. Conclusions These findings justify the search for small molecule inhibitors targeting KIF15 as a novel therapeutic strategy in BL.

scholarly journals shRNA Glut-1 inhibits cell viability, apoptosis and migration of laryngeal carcinoma HEp-2 cells through regulating Beclin-1-mediated autophagy

2020 ◽  
Author(s):  
Wen-Dong Wang ◽  
Jin-Long Zhu ◽  
Shui-Hong Zhou ◽  
Jun Fan ◽  
Yang-Yang Bao
Keyword(s):  
Cell Viability ◽  
Laryngeal Carcinoma ◽  
Migration Rate ◽  
Caspase 3 ◽  
Cell Model ◽  
Beclin 1 ◽  
Glut 1 ◽  
And Migration ◽  
Proliferation And Migration

AbstractObjectiveGlut-1 is a key regulator in the process of glucose uptake. Previous studies have shown that Glut-1 affects autophagy. However, it is unclear whether there is a correlation between Glut-1 and autophagy in the progression of laryngeal carcinoma. This study was performed to investigate the role of Glut-1 in the development of laryngeal carcinoma.MethodsA stable HEp-2 cell model was constructed by Glut-1 and Beclin-1 shRNA lentiviral infection. The autophagosome was measured by transmission electron microscopy. Protein levels of LC3, ATG5, CyclinD1, Bcl-2, Caspase-3, and c-Myc were determined by Western blotting. CCK8 assay and Transwell assays were used to determine cell viability and migration rate of HEp-2 cells, respectively. Flow cytometry was performed to analyze the rate of apoptosis. Immunofluorescence was performed to determine the expression distribution of LC3.ResultsGlut-1 knockdown significantly promoted autophagosome formation by upregulating the ratio of LC3-II/LC3-I as well as the role of rapamycin (RAP) and Beclin-1 overexpression on autophagy flux in HEp-2 cells. Glut-1 inhibition also reduced the viability of HEp-2 cells followed by the decreases in expression of cyclinD1 and c-Myc. In addition, Glut-1 depletion increased the number of apoptotic HEp-2 cells accompanied by activation of caspase-3 and downregulation of Bcl-2. Glut-1 knockdown also reduced the migration rate of HEp-2 cells by promoting the expression of N-cadherin and inhibiting the expression of E-cadherin. Beclin-1 consumption significantly reversed Gult-1 knockdown-mediated autophagy activation, resulting in promotion of both proliferation and migration and inhibition of apoptosis.ConclusionsGlut-1 knockdown-induced autophagy inhibits the proliferation and migration of HEp-2 cells, and promotes apoptosis of HEp-2 cells partly by regulating autophagy.

scholarly journals The long noncoding RNA TINCR promotes breast cancer cell proliferation and migration by regulating OAS1

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Die Lu ◽  
Shihao Di ◽  
Shuaishuai Zhuo ◽  
Linyan Zhou ◽  
Rumeng Bai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Cancer Tissue ◽  
Breast Cancer Patients ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
High Level ◽  
Proliferation And Migration

AbstractBreast cancer is the leading cause of cancer-related death in women around the world. It is urgently needed to identify genes associated with tumorigenesis and prognosis, as well as to elucidate the molecular mechanisms underlying the oncogenic process. Long noncoding RNAs (lncRNAs) are widely involved in the pathological and physiological processes of organisms and play an important role as oncogenes or tumor suppressor genes, affecting the development and progression of tumors. In this study, we focused on terminal differentiation-induced non-coding RNA (TINCR) (GeneID:257000) and explore its role in the pathogenesis of breast cancer. The results showed that TINCR was increased in breast cancer tissue, and high expression level of TINCR was associated with older age, larger tumor size, and advanced TNM stage. High level of TINCR can promote proliferation and metastasis of breast cancer cells, while downregulation of TINCR induces G1-G0 arrest and apoptosis. Mechanismly, TINCR can bind to staufen1 (STAU1) and then guide STAU1 (GeneID:6780) to bind to OAS1 mRNA (NM_016816.4) to mediate its stability. Thus low level of OAS1(GeneID:4938) can lead to cell proliferation and migration. This result elucidates a new mechanism for TINCR in breast cancer development and provides a survival indicator and potential therapeutic target for breast cancer patients.

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