COL5A1 Serves as a Biomarker of Tumor Progression and Poor Prognosis and May Be a Potential Therapeutic Target in Gliomas

Glioma is the most common malignancy of the central nervous system. Although advances in surgical resection, adjuvant radiotherapy, and chemotherapy have been achieved in the last decades, the prognosis of gliomas is still dismal. COL5A1 is one of the collagen members with minor content but prominent functions. The present study examined the biological functions, prognostic value, and gene-associated tumor-infiltrating immune cells of COL5A1 through experiments and bioinformatics analysis. We found that the overexpression of COL5A1 was positively correlated with the increasing tumor malignancies and indicated poor prognosis in gliomas. Moreover, downregulation of COL5A1 could inhibit proliferation and migration of glioma cells and enhance their temozolomide sensitivities in vitro. Further bioinformatic analysis revealed that COL5A1 and its co-expressed genes participated in a number of pathways and biological processes involved in glioma progression. Finally, we evaluated the tumor-infiltrating immune cells of gliomas depending on COL5A1 and found that the percentages of the dendritic cells, which were known as the central mediator of tumor microenvironment in gliomas, were positively associated with the expression levels of COL5A1. Taken together, COL5A1 is an important biomarker and potential therapeutic target of gliomas.

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Novel LncRNA OXCT1-AS1 Indicates Poor Prognosis and Contributes to Tumorigenesis by Regulating miR-195/CDC25A Axis in Glioblastoma

10.21203/rs.3.rs-130876/v1 ◽

2020 ◽

Author(s):

Chen Zhong ◽

Qian Yu ◽

Shengjun Zhou ◽

Yucong Peng ◽

Zhendong Liu ◽

...

Keyword(s):

Therapeutic Target ◽

Poor Prognosis ◽

Cell Clone ◽

Glioma Cells ◽

The Cancer Genome Atlas ◽

Migration And Invasion ◽

Potential Mechanism ◽

Potential Therapeutic Target ◽

Tissue Samples

Abstract BackgroundIt’s well known that long noncoding RNAs (lncRNAs) contribute to multiple biological processes of human glioblastoma (GBM). However, identifying a specific lncRNA target is still the major difficulty. In this study, bioinformatics methods and competing endogenous RNA network (ceRNA) regulatory rules was used to identify GBM related lncRNAs, and found OXCT1 antisense RNA 1 (OXCT1-AS1) may acted as a potential therapeutic target for treatment of glioma.MethodsBased on the Gene Expression Omnibus (GEO) date set, we identified differential lncRNAs, microRNAs and mRNAs and constructed a lncRNA associated ceRNA network.Novel lncRNA OXCT1-AS1 was proposed to exercise its function as a ceRNA, and its potential targeted miRNAs was predicted through the database LncBase Predicted v.2. The expression pattern of OXCT1-AS1 was measured in glioma and normal tissue samples. Effect of OXCT1-AS1 on glioma cells were checked by cell count kit 8 assay, cell clone formation assay, transwell assay and flow cytometry in vitro, respectively. The dual-luciferase activity assay was performed to investigate the potential mechanism of ceRNA network. Finally, orthotopic mouse models of glioma was created to evaluate the influence of OXCT1-AS1 on tumor growth in vivo.ResultsIn this study, it was found that the expression of lncRNA OXCT1-AS1 is upregulated in both The Cancer Genome Atlas (TCGA) GBM cases and GBM tissue samples we collected, and a high expression of OXCT1-AS1 predicts poor prognosis of gliomas. Suppressing OXCT1-AS1 expression significantly decreased the proliferation of GBM cells and inhibited cell migration and invasion. We further investigated the potential mechanism and found OXCT1-AS1 may acted as a ceRNA of miR-195 to enhance CDC25A expression and attenuate glioma cells progression. Finally, knocking down of OXCT1-AS1 notably attenuated the severity of glioma in vivo.ConclusionOXCT1-AS1 inhibited glioma progression by regulating miR-195-5p/ CDC25A axis and can be a specific tumor marker and a novel potential therapeutic target for glioma treatment.

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Phospholipase A2: A Potential Therapeutic Target in Inflammation and Cancer (In silico, In vitro, In vivo and Clinical Approach)

Journal of Cancer Science & Therapy ◽

10.4172/1948-5956.1000357 ◽

2015 ◽

Vol 07 (08) ◽

Cited By ~ 2

Author(s):

Nagendra sastry Yarla ◽

Koduri Satyakumar ◽

Duppalapudi Srinivasu ◽

Kaladhar DSVGK

Keyword(s):

Phospholipase A2 ◽

Therapeutic Target ◽

In Silico ◽

Clinical Approach ◽

Potential Therapeutic Target

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SHP2 promotes NETosis through ERK5 pathway and mediates the development of psoriasis

10.1101/2021.11.10.21266198 ◽

2021 ◽

Author(s):

Yang Sun ◽

Yan Ding ◽

Jiao Qu ◽

Chenyang Zhang ◽

Yuyu Zhu ◽

...

Keyword(s):

Immune Cells ◽

Experimental Verification ◽

Inflammatory Disease ◽

Therapeutic Target ◽

Tyrosine Phosphatase ◽

Skin Lesions ◽

Chronic Inflammatory Disease ◽

Potential Therapeutic Target ◽

Single Cell Rna Sequencing

Psoriasis is a chronic inflammatory disease which infiltrated a large number of neutrophils among skin lesions. Here, we investigated the contribution of tyrosine phosphatase SHP2 in neutrophils, as well as its pathogenesis in psoriasis. We combined single-cell RNA sequencing with experimental verification to declare that SHP2 in neutrophils could promote the NETs formation through the ERK5 pathway, and resulted in the infiltration of inflammatory immune cells, which leads to psoriasis. Our study provides evidence for the role of SHP2 in NETosis in the progression of psoriasis, and SHP2 may be a potential therapeutic target for the treatment of psoriasis.

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Crosstalk between microglia and patient-derived glioblastoma cells inhibit invasion in a three-dimensional gelatin hydrogel model

10.1101/2020.08.06.238345 ◽

2020 ◽

Author(s):

Jee-Wei Emily Chen ◽

Jan Lumibao ◽

Sarah Leary ◽

Jann N. Sarkaria ◽

Andrew J. Steelman ◽

...

Keyword(s):

Immune Cells ◽

Molecular Mechanisms ◽

Three Dimensional ◽

Bioinformatic Analysis ◽

The United States ◽

Study Patient ◽

Valuable Insight ◽

Glioblastoma Cells ◽

Contact Patterns ◽

The Central Nervous System

ABSTRACTBackgroundGlioblastoma is the most common and deadly form of primary brain cancer, accounting for more than thirteen thousand new diagnoses annually in the United States alone. Microglia are the innate immune cells within the central nervous system, acting as a front-line defense against injuries and inflammation via a process that involves transformation from a quiescent to an activated phenotype. Crosstalk between GBM cells and microglia represents an important axis to consider in the development of tissue engineering platforms to examine pathophysiological processes underlying GBM progression and therapy.MethodsThis work used a brain-mimetic hydrogel system to study patient-derived glioblastoma specimens and their interactions with microglia. Here, glioblastoma cells were either cultured alone in 3D hydrogels or in co-culture with microglia in a manner that allowed secretome-based signaling but prevented direct GBM-microglia contact. Patterns of GBM cell invasion were quantified using a three-dimensional spheroid assay. Secretome and transcriptome (via RNAseq) were used to profile the consequences of GBM-microglia interactions.ResultsMicroglia displayed an activated phenotype as a result of GBM crosstalk. Three-dimensional migration patterns of patient derived glioblastoma cells showed invasion was significantly decreased in response to microglia paracrine signaling. Potential molecular mechanisms underlying with this phenotype were identified from bioinformatic analysis of secretome and RNAseq data.ConclusionThe data demonstrate a tissue engineered hydrogel platform can be used to investigate crosstalk between immune cells of the tumor microenvironment related to GBM progression. Such multidimensional models may provide valuable insight to inform therapeutic innovations to improve GBM treatment.

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MMP12 is a potential therapeutic target for Adamantinomatous craniopharyngioma: Conclusions from bioinformatics analysis and in vitro experiments

Oncology Letters ◽

10.3892/ol.2021.12797 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Minde Li ◽

Lin Zhou ◽

Shaoyang Li ◽

Linchun Fang ◽

Le Yang ◽

...

Keyword(s):

Therapeutic Target ◽

Bioinformatics Analysis ◽

In Vitro Experiments ◽

Potential Therapeutic Target ◽

Adamantinomatous Craniopharyngioma

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Global Genomic Analysis of Newly Diagnosed t(4 ;14) Multiple Myeloma Reveals a Specific Mutational Spectrum and Identifies PKD2 As a Potential Therapeutic Target

Blood ◽

10.1182/blood.v128.22.4462.4462 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4462-4462

Author(s):

Xiu Ly Song ◽

Raphaël Szalat ◽

Alexis Talbot ◽

HaiVu Nguyen ◽

Mehmet K. Samur ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Lines ◽

Therapeutic Target ◽

Plasma Cells ◽

Genomic Analysis ◽

Sequencing Analysis ◽

Newly Diagnosed ◽

Potential Therapeutic Target ◽

Mutational Landscape

Abstract In Multiple Myeloma (MM), the t(4;14) translocation is associated with a poor outcome. However, beside this translocation, the genetic events which determine the adverse evolution of the disease and the resistance to treatments remain elusive. In this study we performed whole exome or RNA sequencing analysis of samples from 65 newly diagnosed t(4;14) MM. We found that NRAS, KRAS, MAPK and FGFR3 are frequently mutated (12%, 9%, 13.8%, and 20% respectively). Overall, the FGFR3/RAS/BRAF/MAPK genes were mutated in 36 cases (54%). There was a negative correlation between mutations in FGFR3 and those occurring in NRAS, KRAS and BRAF as expected from the mutually exclusive occurrence of mutations in these genes. In addition to alterations in TP53 and DIS3, we found marked elevated frequency of mutations in PRKD2 (10.7%), ATM/ATR (10.7%) and MYCBP2 (7.6%), reduced frequency in FAM46C (1.5%) and no mutation in TRAF3 and CCND1. Mutations in ATM/ATR were strongly associated with the MB4-2 breakpoint (Bp) (p = 1.62 10-4) and significantly correlated with mutations affecting genes coding for members of the MAPK family. We observed a positive correlation between non-silent mutations in PRKD2 and the MB4-1 or MB4-3 Bp (p = 1.3 10-2). Of note, PRKD2 mutations are exclusively found in 3 t(4;14) MM cell lines and among the 84 MM sequenced by Bolli et al. (1), none of the non t(4;14) patient were mutated in PRKD2, indicating that this genetic lesion is associated with t(4;14) MM. In the NCI-H929 t(4;14) MM cell line, which is mutated for PRKD2, encoding the PKD2 serine/threonine kinase, we observed elevated levels of phosphorylated PKD2. Furthermore, inhibition of PKD, decreased PKD2 phosphorylation and triggered reduced proliferation and apoptosis of MM cell lines and fresh plasma cells from patients in vitro. These results define a specific mutational landscape for t(4;14) MM and identify PKD2 as a potential therapeutic target in MM patients. Altogether, these results define a specific mutational landscape for t(4;14) MM and identify PKD2 as a potential therapeutic target in MM patients. Reference 1. Bolli, N., Avet-Loiseau, H., Wedge, D.C., Van Loo, P., Alexandrov, L.B., Martincorena, I., Dawson, K.J., Iorio, F., Nik-Zainal, S., Bignell, G.R., et al. (2014). Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun 5, 2997. Disclosures Munshi: Janssen: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Oncopep: Patents & Royalties.

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GNG5 is a novel oncogene associated with cell migration, proliferation, and poor prognosis in glioma

10.21203/rs.3.rs-49192/v2 ◽

2021 ◽

Author(s):

Wang Zhang ◽

Zhendong Liu ◽

Binchao Liu ◽

Miaomiao Jiang ◽

Shi Yan ◽

...

Keyword(s):

Signaling Pathways ◽

Clinical Data ◽

Poor Prognosis ◽

Glioma Cells ◽

Diagnosis And Treatment ◽

And Migration ◽

The Relationship ◽

Proliferation And Migration

Abstract Background: Although many biomarkers have been reported for detecting glioma, the prognosis for the disease remains poor, and therefore, new biomarkers need to be identified. GNG5, which is part of the G-protein family, has been associated with different malignant tumors, though the role of GNG5 in glioma has not been studied. Therefore, we aimed to identify the relationship between GNG5 and glioma prognosis and identify a new biomarker for the diagnosis and treatment of gliomas.Methods: We used data on more than a thousand gliomas from multiple databases and clinical data to determine the expression of GNG5 in glioma. Based on clinical data and CGGA database, we identified the correlation between GNG5 and multiple molecular and clinical features and prognosis using various analytical methods. Co-expression analysis and GSEA were performed to detect GNG5-related genes in glioma and possible signaling pathways involved. ESTIMATE, ssGSEA, and TIMER were used to detect the relationship between GNG5 and the immune microenvironment. Functional experiments were performed to explore the function of GNG5 in glioma cells.Results: GNG5 is highly expressed in gliomas, and its expression level is positively correlated with pathological grade, histological type, age, and tumor recurrence and negatively correlated with isocitrate dehydrogenase mutation, 1p/19 co-deletion, and chemotherapy. Moreover, GNG5 as an independent risk factor was negatively correlated with the overall survival time. GSEA revealed the potential signaling pathways involved in GNG5 function in gliomas, including cell adhesion molecules signaling pathway. The ssGSEA, ESTIMATE, and TIMER based analysis indicated a correlation between GNG5 expression and various immune cells in glioma. In vivo and in vitro experiments showed that GNG5 could participate in glioma cell proliferation and migration.Conclusions: Based on the large data platform and the use of different databases to corroborate results obtained using various datasets, as well as in vitro and in vivo experiments, our study reveals for the first time that GNG5, as an oncogene, is overexpressed in gliomas and can inhibit the proliferation and migration of glioma cells and lead to poor prognosis of patients. Thus, GNG5 is a potential novel biomarker for the clinical diagnosis and treatment of gliomas.

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SET Protein in Cancer: A Potential Therapeutic Target

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557521666210114163318 ◽

2021 ◽

Vol 21 ◽

Author(s):

Xinjie Liang ◽

Xuefei Bao ◽

Guoliang Chen

Keyword(s):

Drug Resistance ◽

Clinical Trials ◽

Cancer Therapy ◽

Tumor Cells ◽

Strong Correlation ◽

Therapeutic Target ◽

Poor Prognosis ◽

Therapeutic Options ◽

Potential Therapeutic Target ◽

Bona Fide

: SET protein is a multi-functional oncoprotein that is ubiquitously expressed in most tumor cells. Dysregulation of SET has been associated with many types of cancer. Due to ever-accumulating evidence of its strong correlation with both poor prognosis and drug resistance, the targeting of SET is starting to be explored. SET is currently regarded as a potential target for cancer therapy, and several inhibitors are being developed for clinical trials. In this review, the physiological and pathological functions of SET, as well as its antagonists, will be discussed along with the prospects and challenges involved with translating SET inhibitors into bona fide therapeutic options.

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P11.17 Splicing dysregulation drives glioblastoma malignancy: SRSF3 as a potential therapeutic target to impair glioblastoma progression

Neuro-Oncology ◽

10.1093/neuonc/noz126.163 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii46-iii46

Author(s):

A C Fuentes-Fayos ◽

M C Vázquez-Borrego ◽

J M Jiménez-Vacas ◽

L Bejarano ◽

C Blanco-Acevedo ◽

...

Keyword(s):

Therapeutic Target ◽

Tumor Development ◽

Microarray Dataset ◽

Oncogenic Signaling ◽

Potential Therapeutic Target ◽

Induced Apoptosis ◽

Perfect Discrimination ◽

Control Samples

Abstract Glioblastomas (GBMs) remain the deadliest human brain tumors, with poor prognosis despite years of research. Currently, standard therapeutic strategies to treat GBM are not efficient and common survival from diagnosis is ~12–16 months. Thus, identification of new diagnostic/prognostic/therapeutic tools to tackle GBMs is crucial. Emerging evidence indicates that the cellular machinery controlling alternative splicing is altered in tumor pathologies, leading to oncogenic splicing events linked to tumor progression. Accordingly, we aimed to determine the expression pattern of the spliceosome components (SCs) and splicing factors (SFs) in high-grade astrocytomas (HGAs), mostly GBMs, and to ascertain the potential consequences of its dysregulation on GBM development. To this end, expression levels of SCs core and selected SFs were measured using a customized-microfluidic qPCR array in a well-characterized cohort of HGAs (n=33). Our results unveiled a profound alteration in the expression of multiple SCs and SFs in HGAs compared to healthy brain control-samples, wherein levels of particular elements (SRSF3/RBM22/PTBP1/RBM3) enabled perfect discrimination between non-pathological vs. tumor human-tissues, and between proneural and mesenchymal-like GBMs vs. control samples in mouse-models. Results were confirmed in an independent validation-cohort (n=49) and available Microarray dataset (Murat), which revealed that the expression of these splicing elements was correlated with relevant tumor markers and with survival. Remarkably, SRSF3/RBM22/PTBP1/RBM3 silencing (using specific siRNAs) decreased several aggressiveness parameters in vitro (e.g. proliferation, migration, tumorsphere formation, VEGFA secretion, etc.) and induced apoptosis, being SRSF3 the most relevant element affecting these parameters. Hence, a preclinical mouse model (U87MG-xenografts) with SRSF3 silencing drastically decreased in vivo tumor development/progression (i.e. tumor size, %MKI67, mitosis number, etc.) likely through a molecular/cellular mechanism involving the regulation of PDGFRB expression and its associated oncogenic signaling pathways. Overall, our results demonstrate that there is a profound dysregulation of the splicing machinery (spliceosome core and SFs) in HGAs/GBMs, which is directly associated to the development/progression of GBMs. Furthermore, this study reveals that SRSF3 can be a novel biomarker of malignancy and a potential therapeutic target to impair GBMs progression.

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