scholarly journals SEMA6D, Negatively Regulated by miR-7, Contributing to Chondrocyte Catabolic and Anabolic Activities via p38 Signaling Pathway

2020 ◽  
Author(s):  
Xindie Zhou ◽  
Yi Zhang ◽  
Junjie Zhang ◽  
Zhicheng Yang ◽  
Haoyu Yang ◽  
...  
Keyword(s):  
Target Gene ◽  
Regulatory Mechanism ◽  
Regulatory Factor ◽  
Regulatory Relation ◽  
Direct Target Gene ◽  
Direct Target ◽  
Novel Therapeutic ◽  
P38 Pathway

Abstract Background: MiR-7 has been recognized as a promoting factor of osteoarthritis (OA), but the specific down-stream pathway of miR-7 still remains unknown. Further investigation of the molecular regulatory mechanism of miR-7 might help develop a novel therapeutic method for OA.Results: Here we revealed that Semaphorin 6D (SEMA6D) was a direct target gene of miR-7, of which presented a negatively regulatory relation in vitro and in vivo. Lucubration of SEMA6D suggested that SEMA6D is validated to promote the anabolic metabolism and reduce the catabolism of chondrocytes via inhibiting the activation of p38 pathway.Conclusions: Present research illustrated that SEMA6D is a negatively regulatory factor of miR-7 and a pivotal mediator of the catabolism and anabolism of chondrocytes. SEMA6D exerts its function via inhibiting the activation of p38 pathway.

scholarly journals WSB1 Regulates c-Myc Expression Through β-catenin Signaling and Forms a Feedforward Circuit Promoting the Development of Cancer

2020 ◽  
Author(s):  
Xiaomeng Gao ◽  
Yanling Gong ◽  
Jieqiong You ◽  
Meng Yuan ◽  
Haiying Zhu ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Target Gene ◽  
Regulatory Mechanism ◽  
Intervention Strategy ◽  
E3 Ubiquitin Ligase ◽  
Promoting Effect ◽  
Direct Target Gene ◽  
Direct Target

AbstractThe dysregulation of transcription factors is widely associated with tumorigenesis. As the most well-defined transcription factor in multiple types of cancer, c-Myc can directly transform cells by transactivating various downstream genes. Given that there is no effective way to directly inhibit c-Myc, c-Myc targeting strategies based on its regulatory mechanism hold great potential for cancer therapy. In this study, we found that WSB1, a direct target gene of c-Myc, can positively regulate c-Myc expression, which forms a feedforward circuit promoting cancer development. Luciferase-based promoter activity assays and RNA sequencing results confirmed that WSB1 promoted c-Myc expression through the β-catenin pathway. Mechanistically, WSB1 affected β-catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptor β-TRCP recruitment, which inhibited the ubiquitination of β-catenin and subsequently transactivated c-Myc. Of interest, the promoting effect of WSB1 on c-Myc was independent of its E3 ligase activity. Moreover, co-expression of WSB1 and c-Myc strongly enhanced the initiation and progression of tumours both in vitro and in vivo. Thus, our findings revealed a novel mechanism involved in tumorigenesis in which the WSB1/c-Myc feedforward circuit played an essential role, highlighting a potential c-Myc intervention strategy in cancer treatment.

scholarly journals MicroRNA-346 inhibits the growth of glioma by directly targeting NFIB

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Yangyang Li ◽  
Jia Xu ◽  
Jiale Zhang ◽  
Jie Zhang ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Target Gene ◽  
Glioma Cells ◽  
Downstream Target ◽  
Downstream Target Gene ◽  
Direct Target ◽  
Proliferation Assays ◽  
The Relationship ◽  
Proliferation In Vitro

Abstract Background Glioma is considered one of the most common tumors and has a poor prognosis. Recently, microRNAs (miRNAs) have been reported to be strongly linked to various human tumors including glioma. In this study, we investigated a new anticancer miRNA, miR-346, to determine the effects and mechanism of miR-346 and its downstream target gene NFIB on tumors. Methods Lentivirus transfection, real-time PCR, western blotting, immunohistochemistry, cell proliferation assays, and mouse experiments were used to examine the relationship between miR-346 and its regulation of NFIB in glioma cells. Results The expression of miR-346 was downregulated in glioma cells. Overexpression of miR-346 arrested the cell cycle of glioma cells and inhibited their proliferation in vitro and in vivo. NFIB was a direct target of miR-346, whose expression was reduced by the miRNA. Overexpression of NFIB reversed all tested functions of miR-346. Conclusion miR-346 inhibited the growth of glioma cells by targeting NFIB and may be a new prognostic and diagnostic biomarker for glioma.

Clinical significance of serum miR-101-3p expression in patients with neonatal sepsis

2021 ◽  
Author(s):  
Juan Zhang ◽  
Xinwei Xu ◽  
Min Wang
Keyword(s):  
Neonatal Sepsis ◽  
Target Gene ◽  
Operating Characteristic ◽  
Characteristic Curve ◽  
Quantitative Real Time Pcr ◽  
Tnf Α ◽  
Direct Target Gene ◽  
Direct Target ◽  
Operating Characteristic Curve

Aim: This study aimed to evaluate the levels and functions of miR-101-3p in neonatal sepsis (NS). Materials & methods: Quantitative real-time PCR was conducted to investigate the expression of miR-101-3p and the receiver operating characteristic curve was applied to manifest its diagnostic effects. Results: MiR-101-3p was increased in the NS patients and the dysregulation of miR-101-3p was associated with levels of procalcitonin, CRP, IL-8 and TNF-α. The combination of miR-101-3p and procalcitonin could function as a promising indicator in distinguishing NS patients. The silenced miR-101-3p reversed the increased levels of TNF-α and IL-8 caused by lipopolysaccharide in vitro. DUSP1 was identified as a direct target gene of miR-101-3p in NS. Conclusion: The abundance of miR-101-3p facilitated the inflammation in NS by targeting DUSP1.

scholarly journals MiR-429 Determines Poor Outcome and Inhibits Pancreatic Ductal Adenocarcinoma Growth by Targeting TBK1

2015 ◽  
Vol 35 (5) ◽  
pp. 1846-1856 ◽  
Author(s):  
Bin Song ◽  
Kailian Zheng ◽  
Hongyun Ma ◽  
Anan Liu ◽  
Wei Jing ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Lines ◽  
Target Gene ◽  
Target Genes ◽  
Ductal Adenocarcinoma ◽  
Direct Target Gene ◽  
Direct Target ◽  
Sw1990 Cell ◽  
High Level

Background: Pancreatic ductal adenocarcinoma (PDAC) ranks fourth on the list of cancer-related causes of death and its prognosis has not improved significantly over the past decades. Deregulation or dysfunction of miRNAs contribute to cancer development. Previous data indicates that miR-429 is involved in the pathogenesis of PDAC. However, the role of miR-429 in PDAC remained unknown. Methods: MiR-429 levels in sample tissues of 78 patients and in PANC1 and SW1990 cell lines were quantified by real-time PCR. MiR-429 expression was modulated using specific pre- and anti-miRNAs and cell growth was assayed by MTT analysis. Bioinformatics prediction of the miR-429 putative target genes was performed and luciferase assays confirmed TBK1 as a direct target gene. TBK1 levels in PDAC tissues were analyzed by immunohistochemistry. Results: MiR-429 was remarkably decreased in PDAC tissues and cell lines. Lower miR-429 expression in PDAC tissues significantly correlated with shorter survival of PDAC patients. Overexpression of miR-429 inhibited PDAC cell lines growth in vitro and vice versa. TBK1 was found to be the direct target gene of miR-429. Higher TBK1 protein level in PDAC tissues correlated with shorter survival of PDAC patients. Overexpression of TBK1 partly restored cell proliferation. Conclusions: Low level of miR-429 and high level of TBK1 in PDAC promoted PDAC cells growth which might be related to the low survival rate of PDAC patients. MiR-429 play its role in PDAC by targeting TBK1.

Regulation of Ci-tropomyosin-like, a Brachyury target gene in the ascidian, Ciona intestinalis

Development ◽  
1999 ◽  
Vol 126 (24) ◽  
pp. 5599-5609 ◽  
Author(s):  
A. Di Gregorio ◽  
M. Levine
Keyword(s):  
Target Gene ◽  
Target Genes ◽  
Ciona Intestinalis ◽  
Subtractive Hybridization ◽  
Flanking Sequence ◽  
Binding Assays ◽  
Specific Staining ◽  
Direct Target Gene ◽  
Direct Target

Brachyury is a sequence-specific transcriptional activator that is essential for notochord differentiation in a variety of chordates. In vertebrates, Brachyury is expressed throughout the presumptive mesoderm, but becomes restricted to the notochord at later stages of development. In ascidians, such as Ciona intestinalis, Brachyury is expressed exclusively in the notochord and does not exhibit an early pan-mesodermal pattern. Subtractive hybridization screens were recently used to identify potential Ciona Brachyury (Ci-Bra) target genes (Takahashi, H., Hotta, K., Erives, A., Di Gregorio, A., Zeller, R. W., Levine, M. and Satoh, N. (1999). Genes Dev. 13, 1519–1523). Of the genes that were identified in this screen, one corresponds to a new member of the tropomyosin superfamily, Ciona tropomyosin (Ci-trop). Here we show that Ci-trop is specifically expressed in the developing notochord beginning at gastrulation, and expression persists in the notochord during tailbud and tadpole stages. A 3 kb region of the Ci-trop 5′-flanking sequence was characterized via electroporation of lacZ fusion genes into fertilized Ciona eggs. A minimal, 114 bp enhancer was identified that is sufficient to direct the expression of a heterologous promoter in the notochord. DNA binding assays indicate that this enhancer contains two sets of low-affinity Brachyury half-sites, which are bound in vitro by a GST/Ci-Bra fusion protein. Deletion of the distal sites inactivates the notochord-specific staining pattern mediated by an otherwise normal Ci-trop/lacZ transgene. These results suggest that Ci-trop is a direct target gene of Ci-Bra and that Brachyury plays an immediate role in the cellular morphogenesis of the notochord.

scholarly journals Proanthocyanidins Induce miR-133b Expression to Promote Ischemic Skeletal Muscle Regeneration by Targeting MKP1

2020 ◽  
Author(s):  
Shi Chen ◽  
Chao Du ◽  
Lilong Pan ◽  
Qian Yang ◽  
Peihe Yu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Target Gene ◽  
Myogenic Differentiation ◽  
Limb Ischemia ◽  
Skeletal Muscle Regeneration ◽  
Aberrant Expression ◽  
Direct Target Gene ◽  
Direct Target

Abstract Background: Limb ischemic necrosis is mainly attributed to peripheral arterial disease (PAD). Reducing oxidative stress and promoting damaged skeletal muscle regeneration may be benefit for ischemic limb treatment. Proanthocyanidins (PC) is a powerful antioxidant and free radical scavenger, but little is known about its role and related molecular mechanism in limb ischemic injury. The current study was undertaken to explore its role in the damaged skeletal muscle regeneration both in vitro and vivo, and whether MicroRNAs (miRNAs) involved in this process. Methods: The potential effects of PC on the damaged muscle regeneration were explored in human skeletal muscle satellite cells (HSKMSCs) under hypoxic-ischemic condition and in mice limb ischemia model, then, aberrant expression of miRNAs in ischemic skeletal muscles were determined by microarray analysis, and regulatory mechanism of the specific miRNA on HSKMSCs myogenic differentiation was further investigated by gain and loss of functional experiments. Additionally, the direct target gene was examined by luciferase reporter assay.Results: In mice limb ischemia model, our results revealed that PC reduced oxidative stress level, significantly promoted ischemic limb damaged muscle regeneration and motor function recovery, then, aberrant expression of miRNAs in ischemic skeletal muscles were determined by microarray analysis, combine with the results of the RT-qPCR, the miR-133b-3p was proved to be the specific miRNA. In vitro, our results revealed that PC induced the overexpression of miR-133b to activate the p38-MAPK signal pathway and increased the myogenic differentiation-related molecules expression, which eventually promoted myotubes formation. Furthermore, MKP1 was confirmed a direct target gene of miR-133b.Conclusion: Our results suggest that PC display skeletal muscle protective properties that are mediated by miR-133b /MKP1/ p38-MAPK signal axis, offering a novel therapeutic opportunity for limb ischemic injury.

scholarly journals EphA2 super-enhancer promotes tumor progression by recruiting FOSL2 and TCF7L2 to activate the target gene EphA2

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Shuang Cui ◽  
Qiong Wu ◽  
Ming Liu ◽  
Mu Su ◽  
ShiYou Liu ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Tumor Cells ◽  
Target Gene ◽  
Super Enhancer ◽  
Proliferation And Metastasis ◽  
Active Transcription ◽  
Hct 116 ◽  
Large Clusters

AbstractSuper-enhancers or stretch enhancers (SEs) consist of large clusters of active transcription enhancers which promote the expression of critical genes that define cell identity during development and disease. However, the role of many super-enhancers in tumor cells remains unclear. This study aims to explore the function and mechanism of a new super-enhancer in various tumor cells. A new super-enhancer that exists in a variety of tumors named EphA2-Super-enhancer (EphA2-SE) was found using multiple databases and further identified. CRISPR/Cas9-mediated deletion of EphA2-SE results in the significant downregulation of its target gene EphA2. Mechanistically, we revealed that the core active region of EphA2-SE comprises E1 component enhancer, which recruits TCF7L2 and FOSL2 transcription factors to drive the expression of EphA2, induce cell proliferation and metastasis. Bioinformatics analysis of RNA-seq data and functional experiments in vitro illustrated that EphA2-SE deletion inhibited cell growth and metastasis by blocking PI3K/AKT and Wnt/β-catenin pathway in HeLa, HCT-116 and MCF-7 cells. Overexpression of EphA2 in EphA2-SE−/− clones rescued the effect of EphA2-SE deletion on proliferation and metastasis. Subsequent xenograft animal model revealed that EphA2-SE deletion suppressed tumor proliferation and survival in vivo. Taken together, these findings demonstrate that EphA2-SE plays an oncogenic role and promotes tumor progression in various tumors by recruiting FOSL2 and TCF7L2 to drive the expression of oncogene EphA2.

scholarly journals MBRS-48. IDENTIFICATION OF NOVEL THERAPEUTIC APPROACHES FOR MYC-DRIVEN MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii406-iii406
Author(s):  
Kübra Taban ◽  
David Pauck ◽  
Mara Maue ◽  
Viktoria Marquardt ◽  
Hua Yu ◽  
...  
Keyword(s):  
New Drugs ◽  
Current Therapy ◽  
Cancer Drug ◽  
Mrna Levels ◽  
Cell Models ◽  
Therapeutic Approaches ◽  
Group 3 ◽  
Novel Therapeutic

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children and is frequently metastatic at diagnosis. Treatment with surgery, radiation and multi-agent chemotherapy may leave survivors of these brain tumors with long-term deficits as a consequence. One of the four consensus molecular subgroups of MB is the MYC-driven group 3 MB, which is the most malignant type and has a poor prognosis under current therapy. Thus, it is important to discover more effective targeted therapeutic approaches. We conducted a high-throughput drug screening to identify novel compounds showing efficiency in group 3 MB using both clinically established inhibitors (n=196) and clinically-applicable compounds (n=464). More than 20 compounds demonstrated a significantly higher anti-tumoral effect in MYChigh (n=7) compared to MYClow (n=4) MB cell models. Among these compounds, Navitoclax and Clofarabine showed the strongest effect in inducing cell cycle arrest and apoptosis in MYChigh MB models. Furthermore, we show that Navitoclax, an orally bioavailable and blood-brain barrier passing anti-cancer drug, inhibits specifically Bcl-xL proteins. In line, we found a significant correlation between BCL-xL and MYC mRNA levels in 763 primary MB patient samples (Data source: “R2 https://hgserver1.amc.nl”). In addition, Navitoclax and Clofarabine have been tested in cells obtained from MB patient-derived-xenografts, which confirmed their specific efficacy in MYChigh versus MYClow MB. In summary, our approach has identified promising new drugs that significantly reduce cell viability in MYChigh compared to MYClow MB cell models. Our findings point to novel therapeutic vulnerabilities for MB that need to be further validated in vitro and in vivo.

scholarly journals TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Qingxia Wei ◽  
Olivia Singh ◽  
Can Ekinci ◽  
Jaspreet Gill ◽  
Mira Li ◽  
...  
Keyword(s):  
Critical Role ◽  
Gene Expression Signature ◽  
Endothelial Activation ◽  
Tumor Vascularization ◽  
Angiogenic Therapy ◽  
Mouse Glioma ◽  
Novel Therapeutic ◽  
Tumor Area

AbstractOne of the most prominent features of glioblastoma (GBM) is hyper-vascularization. Bone marrow-derived macrophages are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs) which are thought to provide a critical role in tumor neo-vascularization. However, the mechanisms by which GAMs regulate endothelial cells (ECs) in the process of tumor vascularization and response to anti-angiogenic therapy (AATx) is not well-understood. Here we show that GBM cells secrete IL-8 and CCL2 which stimulate GAMs to produce TNFα. Subsequently, TNFα induces a distinct gene expression signature of activated ECs including VCAM-1, ICAM-1, CXCL5, and CXCL10. Inhibition of TNFα blocks GAM-induced EC activation both in vitro and in vivo and improve survival in mouse glioma models. Importantly we show that high TNFα expression predicts worse response to Bevacizumab in GBM patients. We further demonstrated in mouse model that treatment with B20.4.1.1, the mouse analog of Bevacizumab, increased macrophage recruitment to the tumor area and correlated with upregulated TNFα expression in GAMs and increased EC activation, which may be responsible for the failure of AATx in GBMs. These results suggest TNFα is a novel therapeutic that may reverse resistance to AATx. Future clinical studies should be aimed at inhibiting TNFα as a concurrent therapy in GBMs.

scholarly journals The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy

Oncogene ◽  
2021 ◽  
Author(s):  
Jian Chen ◽  
Risi Na ◽  
Chao Xiao ◽  
Xiao Wang ◽  
Yupeng Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Patient Survival ◽  
Serine Hydroxymethyltransferase ◽  
First Line ◽  
Xenograft Models ◽  
Potential Opportunity ◽  
First Line Treatment ◽  
Novel Therapeutic

Abstract5-Fluorouracil (5-FU)-based chemotherapy is the first-line treatment for colorectal cancer (CRC) but is hampered by chemoresistance. Despite its impact on patient survival, the mechanism underlying chemoresistance against 5-FU remains poorly understood. Here, we identified serine hydroxymethyltransferase-2 (SHMT2) as a critical regulator of 5-FU chemoresistance in CRC. SHMT2 inhibits autophagy by binding cytosolic p53 instead of metabolism. SHMT2 prevents cytosolic p53 degradation by inhibiting the binding of p53 and HDM2. Under 5-FU treatment, SHMT2 depletion promotes autophagy and inhibits apoptosis. Autophagy inhibitors decrease low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, the lethality of 5-FU treatment to CRC cells was enhanced by treatment with the autophagy inhibitor chloroquine in patient-derived and CRC cell xenograft models. Taken together, our findings indicate that autophagy induced by low SHMT2 levels mediates 5-FU resistance in CRC. These results reveal the SHMT2–p53 interaction as a novel therapeutic target and provide a potential opportunity to reduce chemoresistance.

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