Characteristic mTOR activity in Hodgkin-lymphomas offers a potential therapeutic target in high risk disease – a combined tissue microarray, in vitro and in vivo study

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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Integrin α10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival

Cancers ◽

10.3390/cancers11040587 ◽

2019 ◽

Vol 11 (4) ◽

pp. 587 ◽

Cited By ~ 8

Author(s):

Matilda Munksgaard Thorén ◽

Katarzyna Chmielarska Masoumi ◽

Cecilia Krona ◽

Xiaoli Huang ◽

Soumi Kundu ◽

...

Keyword(s):

Cell Death ◽

Therapeutic Target ◽

Functional Role ◽

Treatment Strategies ◽

Antibody Drug Conjugate ◽

Potential Therapeutic Target ◽

Sphere Formation

New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody–drug conjugate (ADC), an integrin α10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10β1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin α10β1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.

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EXTH-29. GALECTIN-3 AS A POTENTIAL THERAPEUTIC TARGET IN RECURRENT ATYPICAL AND MALIGNANT MENINGIOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.361 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi88-vi88

Author(s):

Arabinda Das ◽

Jaime Martinez Santos ◽

Indira Kanginakudru ◽

Daniel G McDonald ◽

Libby Kosnik Infinger ◽

...

Keyword(s):

Therapeutic Target ◽

Survival Rates ◽

Laboratory Data ◽

Standard Of Care ◽

Potential Therapeutic Target ◽

Protein Levels ◽

Signaling Transduction Pathway ◽

Galectin 3

Abstract Atypical and malignant meningiomas are rare tumors that unlike WHO I meningiomas are characteristically more aggressive in nature and are associated with higher recurrence risks of recurrence. In fact despite aggressive treatment of malignant meningiomas, the average 5-year survival rates are in the range of 30% to 60%. Still the standard of care for atypical and malignant meningiomas (AM and MM) has yet to be established. Our laboratory data demonstrated that galectin-3 (Gal-3), a multifunctional β-galactoside-binding protein, is highly expressed in AM and MM as compared to normal tissue. However, the biological functions of Gal-3 in meningioma cells are not fully understood. To address this, we used either small interfering RNA (siRNA) to knock down Gal-3 expression or Gal-3 inhibitor, TD139 to suppress Gal-3 expression in in vitro cell culture model. Silencing or inhibiting of Gal-3 expression significantly decreased the protein levels of urokinase-type plasminogen activator receptor (uPAR) as well as uPAR’s downstream signaling transduction pathway, including phosphorylation of AKT. In both cases, we found that silencing of Gal-3 or inhibiting Gal-3 expression decreased the proliferative activity, and migratory potential of AM and MM cells. Furthermore, we demonstrated that TD139 inhibits MM growth in an in vivo xenograft MM model. Taken together, our results suggest that Gal-3 modulates uPAR expression and that Gal-3 may be a potential therapeutic target for the treatment of atypical and malignant meningiomas.

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GdCl3 reduces hyperglycaemia through Akt/FoxO1-induced suppression of hepatic gluconeogenesis in Type 2 diabetic mice

Clinical Science ◽

10.1042/cs20130670 ◽

2014 ◽

Vol 127 (2) ◽

pp. 91-100 ◽

Cited By ~ 15

Author(s):

Qian Wang ◽

Ning Wang ◽

Mei Dong ◽

Fang Chen ◽

Zhong Li ◽

...

Keyword(s):

Therapeutic Target ◽

Diabetic Mice ◽

Hepatic Gluconeogenesis ◽

Potential Therapeutic Target ◽

Hepatocarcinoma Cells ◽

Type 2 Diabetic

In the present study, we demonstrate that GdCl3 reduces hyperglycaemia via the Akt/FoxO1-induced suppression of hepatic gluconeogenesis, both in Type 2 diabetic mice (in vivo) and in hepatocarcinoma cells (in vitro), suggesting that GdCl3 may be a potential therapeutic target for diabetes.

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SYT7 acts as an oncogene and a potential therapeutic target and was regulated by ΔNp63α in HNSCC

Cancer Cell International ◽

10.1186/s12935-021-02394-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

You Fu ◽

Guocai Tian ◽

Zhiyuan Zhang ◽

Xiao Yang

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Therapeutic Target ◽

Carcinoma Cells ◽

Potential Therapeutic Target ◽

Differential Expression Genes

Abstract Background Head and neck squamous cell carcinoma (HNSCC) are one of the most common types of head and neck cancer, and it is urgent to find effective treatment for advanced patients. Exploring developing and progressing mechanisms of HNSCC could provide a theoretical basis to find new therapeutic targets. Methods In our research, we performed a whole-gene expression profile microarray analysis to identify differential expression genes between squamous cell carcinoma cells and ΔNp63 alpha (ΔNp63α) knockdown cells. As a result, an important gene Synaptotagmin VII (SYT7) was screened out. Results SYT7 knockdown affected the proliferation, apoptosis and cell cycle of squamous cell carcinoma cells. The rescue experiment in vitro with ΔNp63α and SYT7 double knockdown resulted in partial reversion of ΔNp63α-induced phenotypes. This was also confirmed by experiments in vivo. Conclusions Taken together, we found that ΔNp63α could inhibit the occurrence and progression of HNSCC throughout downregulating the expression of SYT7. Therefore, SYT7/ΔNp63α axis could be a potential therapeutic target for clinical treatment of HNSCC.

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Caveolin-1 regulation of disrupted-in-schizophrenia-1 as a potential therapeutic target for schizophrenia

Journal of Neurophysiology ◽

10.1152/jn.00481.2016 ◽

2017 ◽

Vol 117 (1) ◽

pp. 436-444 ◽

Cited By ~ 10

Author(s):

Adam Kassan ◽

Junji Egawa ◽

Zheng Zhang ◽

Angels Almenar-Queralt ◽

Quynh My Nguyen ◽

...

Keyword(s):

Stem Cells ◽

Synaptic Plasticity ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Therapeutic Target ◽

Potential Therapeutic Target ◽

Caveolin 1 ◽

Induced Pluripotent

Schizophrenia is a debilitating psychiatric disorder manifested in early adulthood. Disrupted-in-schizophrenia-1 ( DISC1) is a susceptible gene for schizophrenia (Hodgkinson et al. 2004; Millar et al. 2000; St Clair et al. 1990) implicated in neuronal development, brain maturation, and neuroplasticity (Brandon and Sawa 2011; Chubb et al. 2008). Therefore, DISC1 is a promising candidate gene for schizophrenia, but the molecular mechanisms underlying its role in the pathogenesis of the disease are still poorly understood. Interestingly, caveolin-1 (Cav-1), a cholesterol binding and scaffolding protein, regulates neuronal signal transduction and promotes neuroplasticity. In this study we examined the role of Cav-1 in mediating DISC1 expression in neurons in vitro and the hippocampus in vivo. Overexpressing Cav-1 specifically in neurons using a neuron-specific synapsin promoter ( SynCav1) increased expression of DISC1 and proteins involved in synaptic plasticity (PSD95, synaptobrevin, synaptophysin, neurexin, and syntaxin 1). Similarly, SynCav1-transfected differentiated human neurons derived from induced pluripotent stem cells (hiPSCs) exhibited increased expression of DISC1 and markers of synaptic plasticity. Conversely, hippocampi from Cav-1 knockout (KO) exhibited decreased expression of DISC1 and proteins involved in synaptic plasticity. Finally, SynCav1 delivery to the hippocampus of Cav-1 KO mice and Cav-1 KO neurons in culture restored expression of DISC1 and markers of synaptic plasticity. Furthermore, we found that Cav-1 coimmunoprecipitated with DISC1 in brain tissue. These findings suggest an important role by which neuron-targeted Cav-1 regulates DISC1 neurobiology with implications for synaptic plasticity. Therefore, SynCav1 might be a potential therapeutic target for restoring neuronal function in schizophrenia. NEW & NOTEWORTHY The present study is the first to demonstrate that caveolin-1 can regulate DISC1 expression in neuronal models. Furthermore, the findings are consistent across three separate neuronal models that include rodent neurons ( in vitro and in vivo) and human differentiated neurons derived from induced pluripotent stem cells. These findings justify further investigation regarding the modulatory role by caveolin on synaptic function and as a potential therapeutic target for the treatment of schizophrenia.

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The long non-coding RNA lnc-HLX-2-7 is oncogenic in group 3 medulloblastomas

10.1101/2020.06.08.140251 ◽

2020 ◽

Author(s):

Keisuke Katsushima ◽

Bongyong Lee ◽

Haritha Kunhiraman ◽

Cuncong Zhong ◽

Rabi Murath ◽

...

Keyword(s):

Rna Sequencing ◽

Therapeutic Target ◽

Rna Seq ◽

Potential Therapeutic Target ◽

Non Coding Rna ◽

Group 3 ◽

Induced Apoptosis ◽

Long Non Coding Rna

AbstractBackgroundMedulloblastoma (MB) is an aggressive brain tumor that predominantly affects children. Recent high-throughput sequencing studies suggest that the non-coding RNA genome, in particular long non-coding RNAs (lncRNAs), contributes to MB sub-grouping. Here we report the identification of a novel lncRNA, lnc-HLX-2-7, as a potential molecular marker and therapeutic target in group 3 MBs.MethodsPublicly available RNA sequencing (RNA-seq) data from 175 MB patients were interrogated to identify lncRNAs that differentiate between MB subgroups. After characterizing a subset of differentially expressed lncRNAs in vitro and in vivo, the group 3-enriched lncRNA lnc-HLX2-7 was deleted by CRISPR/Cas9 in the MB cell line D425 Med. Intracranially injected tumors were further characterized by bulk and single-cell RNA-sequencing.Resultslnc-HLX-2-7 is highly upregulated in group 3 MB cell lines, patient-derived xenografts, and primary MBs compared to other MB sub-groups as assessed by qRT-PCR, RNA-seq, and RNA fluorescence in situ hybridization (FISH). Depletion of lnc-HLX-2-7 with antisense oligonucleotides or CRISPR/Cas9 significantly reduced cell proliferation and 3D colony formation and induced apoptosis. lnc-HLX-2-7-deleted D425 Med cells injected into mouse cerebella produced smaller tumors than those derived from parental cells. Pathway analysis revealed that lnc-HLX2-7 modulated oxidative phosphorylation, mitochondrial dysfunction, and sirtuin signaling pathways. The MYC oncogene regulated lnc-HLX-2-7, and the small molecule BET-bromodomain (BRD4) inhibitor JQ1 reduced lnc-HLX2-7 expression.Conclusionslnc-HLX-2-7 is oncogenic in MB and represents a promising novel molecular marker and a potential therapeutic target in group 3 MBs in children.Key pointslnc-HLX-2-7 is highly upregulated in group 3 medulloblastomas compared to other sub-groups.In vitro and in vivo studies strongly support an oncogenic role for lnc-HLX2-7 in group 3 medulloblastoma.lnc-HLX-2-7 may be a novel biomarker and a potential therapeutic target in group 3 medulloblastoma.Importance of the studyGroup 3 medulloblastomas are associated with poor clinical outcomes, are difficult to subtype clinically, and their biology is poorly understood. In an effort to address these problems, we identified a group 3-specific long non-coding RNA, lnc-HLX-2-7, in an in silico analysis of 175 medulloblastomas and confirmed its expression in group 3 medulloblastoma cell lines, patient-derived xenografts, and FFPE samples. CRISPR/Cas9 deletion and antisense oligonucleotide knockdown of lnc-HLX-2-7 significantly reduced cell growth and 3D colony formation and induced apoptosis. Deletion of lnc-HLX-2-7 in cells injected into mouse cerebellums reduced tumor growth compared to parental cells, and RNA sequencing of these tumors revealed lnc-HLX-2-7-associated modulation of cell viability and cell death signaling pathways. The oncogene MYC regulates lnc-HLX-2-7, and its expression can be controlled by the BET-bromodomain (BRD4) inhibitor JQ1. lnc-HLX-2-7 is a candidate biomarker and a potential therapeutic target in group 3 medulloblastomas in children.

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AnnexinA7 promotes epithelial–mesenchymal transition by interacting with Sorcin and contributes to aggressiveness in hepatocellular carcinoma

Cell Death and Disease ◽

10.1038/s41419-021-04287-2 ◽

2021 ◽

Vol 12 (11) ◽

Author(s):

Fei Ling ◽

Huan Zhang ◽

Yunliang Sun ◽

Jinyi Meng ◽

Jaceline Gislaine Pires Sanches ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

High Mortality ◽

Therapeutic Target ◽

Epithelial Mesenchymal Transition ◽

Interacting Proteins ◽

Potential Therapeutic Target ◽

Mesenchymal Transition ◽

Hcc Cells

AbstractHepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and metastasis is the major cause of the high mortality of HCC. In this study, we identified that AnnexinA7 (ANXA7) and Sorcin (SRI) are overexpressed and interacting proteins in HCC tissues and cells. In vitro functional investigations revealed that the interaction between ANXA7 and SRI regulated epithelial–mesenchymal transition (EMT), and then affected migration, invasion, and proliferation in HCC cells. Furthermore overexpression/knockdown of ANXA7 was remarkably effective in promoting/inhibiting tumorigenicity and EMT in vivo. Altogether, our study unveiled a mechanism that ANXA7 promotes EMT by interacting with SRI and further contributes to the aggressiveness in HCC, which provides a novel potential therapeutic target for preventing recurrence and metastasis in HCC.

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Drp-1 as Potential Therapeutic Target for Lipopolysaccharide-Induced Vascular Hyperpermeability

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/5820245 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Xu Luo ◽

Shumin Cai ◽

Yunfeng Li ◽

Guicheng Li ◽

Yuanyuan Cao ◽

...

Keyword(s):

Therapeutic Target ◽

Mitochondrial Fission ◽

Critical Role ◽

Protective Effects ◽

Caspase 9 ◽

Potential Therapeutic Target ◽

Mitochondrial Mass ◽

Mitochondrial Homeostasis

Mitochondria-dependent apoptotic signaling has a critical role in the pathogenesis of vascular hyperpermeability (VH). Dynamin-related protein-1- (Drp-1-) mediated mitochondrial fission plays an important role in mitochondrial homeostasis. In the present study, we studied the involvement of Drp-1 in resistance to VH induced by lipopolysaccharide (LPS). To establish the model of LPS-induced VH, LPS at 15 mg/kg was injected into rats in vivo and rat pulmonary microvascular endothelial cells were exposed to 500 ng/ml LPS in vitro. We found that depletion of Drp-1 remarkedly exacerbated the mitochondria-dependent apoptosis induced by LPS, as evidenced by reduced apoptosis, mitochondrial membrane potential (MMP) depolarization, and activation of caspase-3 and caspase-9. Increased FITC-dextran flux indicated endothelial barrier disruption. In addition, overexpression of Drp-1 prevented LPS-induced endothelial hyperpermeability and upregulated mitophagy, as evidenced by the loss of mitochondrial mass and increased PINK1 expression and mitochondrial Parkin. However, the mitophagy inhibitor, 3-Methyladenine, blocked these protective effects of Drp-1. Furthermore, inhibition of Drp-1 using mitochondrial division inhibitor 1 markedly inhibited LPS-induced mitophagy and aggravated LPS-induced VH, as shown by increased FITC-dextran extravasation. These findings implied that Drp-1 strengthens resistance to mitochondria-dependent apoptosis by regulating mitophagy, suggesting Drp-1 as a possible therapeutic target in LPS-induced VH.

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