scholarly journals P2X7 receptor: the regulator of glioma tumor development and survival

2021 ◽  
Author(s):  
Damian Matyśniak ◽  
Vira Chumak ◽  
Natalia Nowak ◽  
Artur Kukla ◽  
Lilya Lehka ◽  
...  
Keyword(s):  
P2x7 Receptor ◽  
Glioma Cell ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Development ◽  
Enrichment Analysis ◽  
Membrane Pore ◽  
Mesenchymal Transition ◽  
Wide Range ◽  
Glioma Tumor

Abstract P2X7 is an ionotropic nucleotide receptor, forming the cation channel upon ATP stimulation. It can also function as a large membrane pore as well as transmit ATP-dependent signal without forming a channel at all. P2X7 activity in somatic cells is well-known, but remains poorly studied in glioma tumors. The current paper presents the comprehensive study of P2X7 activity in C6 and glioma cell line showing the wide range of effects the receptor has on glioma biology. We observed that P2X7 stimulation boosts glioma cell proliferation and increases cell viability. P2X7 activation promoted cell adhesion, mitochondria depolarization, and reactive oxygen species overproduction in C6 cells. P2X7 receptor also influenced glioma tumor growth in vivo via activation of pro-survival signaling pathways and ATP release. Treatment with Brilliant Blue G, a selective P2X7 antagonist, effectively inhibited glioma tumor development; decreased the expression of negative prognostic cancer markers pro-survival and epithelial-mesenchymal transition (EMT)-related proteins; and modulated the immune response toward glioma tumor in vivo. Finally, pathway-specific enrichment analysis of the microarray data from human patients also showed an upregulation of P2X7 receptor in gliomas from grades I to III. The presented results shed more light on the role of P2X7 receptor in the biology of this disease.

scholarly journals Linc00426 accelerates lung adenocarcinoma progression by regulating miR-455-5p as a molecular sponge

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Hongli Li ◽  
Qingjie Mu ◽  
Guoxin Zhang ◽  
Zhixin Shen ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Tumor Development ◽  
Biological Significance ◽  
Mesenchymal Transition

AbstractIncreasing lines of evidence indicate the role of long non-coding RNAs (LncRNAs) in gene regulation and tumor development. Hence, it is important to elucidate the mechanisms of LncRNAs underlying the proliferation, metastasis, and invasion of lung adenocarcinoma (LUAD). We employed microarrays to screen LncRNAs in LUAD tissues with and without lymph node metastasis and revealed their effects on LUAD. Among them, Linc00426 was selected for further exploration in its expression, the biological significance, and the underlying molecular mechanisms. Linc00426 exhibits ectopic expression in LUAD tissues and cells. The ectopic expression has been clinically linked to tumor size, lymphatic metastasis, and tumor differentiation of patients with LUAD. The deregulation of Linc00426 contributes to a notable impairment in proliferation, invasion, metastasis, and epithelial–mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the deregulation of Linc00426 could reduce cytoskeleton rearrangement and matrix metalloproteinase expression. Meanwhile, decreasing the level of Linc00426 or increasing miR-455-5p could down-regulate the level of UBE2V1. Thus, Linc00426 may act as a competing endogenous RNA (ceRNA) to abate miR-455-5p-dependent UBE2V1 reduction. We conclude that Linc00426 accelerates LUAD progression by acting as a molecular sponge to regulate miR-455-5p, and may be a potential novel tumor marker for LUAD.

scholarly journals HCK promotes glioblastoma progression by TGFβ signaling

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Zhenlin Wang ◽  
Chenting Ying ◽  
Anke Zhang ◽  
Houshi Xu ◽  
Yang Jiang ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
B Lymphocyte ◽  
Epithelial Mesenchymal Transition ◽  
Enrichment Analysis ◽  
Underlying Mechanism ◽  
Gene Set Enrichment Analysis ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition

Abstract The hematopoietic cell kinase (HCK), a member of the Src family protein-tyrosine kinases (SFKs), is primarily expressed in cells of the myeloid and B lymphocyte lineages. Nevertheless, the roles of HCK in glioblastoma (GBM) remain to be examined. Thus, we aimed to investigate the effects of HCK on GBM development both in vitro and in vivo, as well as the underlying mechanism. The present study found that HCK was highly expressed in both tumor tissues from patients with GBM and cancer cell lines. HCK enhanced cell viability, proliferation, and migration, and induced cell apoptosis in vitro. Tumor xenografts results also demonstrated that HCK knockdown significantly inhibited tumor growth. Interestingly, gene set enrichment analysis (GSEA) showed HCK was closed associated with epithelial mesenchymal transition (EMT) and TGFβ signaling in GBM. In addition, we also found that HCK accentuates TGFβ-induced EMT, suggesting silencing HCK inhibited EMT through the inactivation of Smad signaling pathway. In conclusion, our findings indicated that HCK is involved in GBM progression via mediating EMT process, and may be served as a promising therapeutic target for GBM.

scholarly journals Long non-coding RNA linc00645 promotes TGF-β-induced epithelial–mesenchymal transition by regulating miR-205-3p-ZEB1 axis in glioma

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Chenlong Li ◽  
Hongshan Zheng ◽  
Weiliang Hou ◽  
Hongbo Bao ◽  
Jinsheng Xiong ◽  
...  
Keyword(s):  
Cell Lines ◽  
Glioma Cell ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Glioma Cells ◽  
Vital Role ◽  
Migration And Invasion ◽  
Poor Overall Survival ◽  
Mesenchymal Transition

Abstract Accumulating evidence indicates long noncoding RNAs (lncRNA) play a vital role in tumor progression. However, the role of linc00645-induced accelerated malignant behavior in glioblastoma (GBM) remains unknown. In the present study, linc00645 expression was significantly upregulated in GBM tissues and cell lines. High level of linc00645 was associated with poor overall survival in GBM patients. Knockdown of linc00645 suppressed the proliferation, stemness, migration, invasion, and reversed transforming growth factor (TGF)-β-induced motility of glioma cell lines. Furthermore, linc00645 directly interacted with miR-205-3p and upregulated of miR-205-3p impeded efficiently the increase of ZEB1 induced by linc00645 overexpression. Moreover, knockdown of linc00645 significantly suppressed the progression of glioma cells in vivo. miR-205-3p was a target of linc00645 and linc00645 modulates TGF-β-induced glioma cell migration and invasion via miR-205-3p. Taken together, our findings identified the linc00645/miR-205-3p/ZEB1 signaling axis as a key player in EMT of glioma cells triggered by TGF-β. These data elucidated that linc00645 plays an oncogenic role in glioma and it may serve as a prognostic biomarker and a potential therapeutic target for the treatment of glioma in humans.

scholarly journals Mechanism and Molecular Network of RBM8A-Mediated Regulation of Oxaliplatin Resistance in Hepatocellular Carcinoma

2021 ◽  
Vol 10 ◽  
Author(s):  
Rong Liang ◽  
Jinyan Zhang ◽  
Zhihui Liu ◽  
Ziyu Liu ◽  
Qian Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Binding Motif ◽  
Mesenchymal Transition ◽  
Regulatory Pathways ◽  
Wide Range

RNA-binding motif protein 8A (RBM8A) is abnormally overexpressed in hepatocellular carcinoma (HCC) and involved in the epithelial-mesenchymal transition (EMT). The EMT plays an important role in the development of drug resistance, suggesting that RBM8A may be involved in the regulation of oxaliplatin (OXA) resistance in HCC. Here we examined the potential involvement of RBM8A and its downstream pathways in OXA resistance using in vitro and in vivo models. RBM8A overexpression induced the EMT in OXA-resistant HCC cells, altering cell proliferation, apoptosis, migration, and invasion. Moreover, whole-genome microarrays combined with bioinformatics analysis revealed that RBM8A has a wide range of transcriptional regulatory capabilities in OXA-resistant HCC, including the ability to regulate several important tumor-related signaling pathways. In particular, histone deacetylase 9 (HDAC9) emerged as an important mediator of RBM8A activity related to OXA resistance. These data suggest that RBM8A and its related regulatory pathways represent potential markers of OXA resistance and therapeutic targets in HCC.

scholarly journals Protein arginine methyltransferase 5 promotes metastasis via enhancing EGFR transcription and modulating AKT1 activation by methylation

2020 ◽  
Author(s):  
Lei Huang ◽  
Xiao-Ou Zhang ◽  
Odette Verdejo-Torres ◽  
Kim Wigglesworth ◽  
Xiaomei Sun ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Metastatic Cancer ◽  
Growth Factor Receptor ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Mesenchymal Transition ◽  
Molecule Inhibitor ◽  
Wide Range ◽  
Protein Arginine Methyltransferase 5

AbstractProtein arginine methyltransferase 5 (PRMT5) regulates a wide range of physiological processes, including cancer cell proliferation and metastasis, by generating symmetric di-methyl-arginine marks on histones and non-histone proteins. Here, we report that PRMT5 directly regulates epidermal growth factor receptor (EGFR) transcription to control EGF stimulated EGFR signaling. Furthermore, PRMT5 modulates protein kinase B (AKT) activation by methylation of AKT1 Arg 15, which is required for its subsequent phosphorylation at AKT1 Thr 308 and Ser 473. The PRMT5/EGFR/AKT axis converges to regulate transcription factors ZEB1, SNAIL, and TWIST1 to promote the epithelial-mesenchymal transition (EMT), in the manner that EGFR and AKT1 compensate each other to support tumor cell invasion and metastasis. Inhibiting PRMT5 methyltransferase activity with a small molecule inhibitor attenuated primary tumor growth and prevented hepatic metastasis in aggressive in vivo tumor models. Collectively, our results support the use of PRMT5 based therapies for metastatic cancer.

scholarly journals Kras activation in endometrial organoids drives cellular transformation and epithelial-mesenchymal transition

Oncogenesis ◽  
2021 ◽  
Vol 10 (6) ◽  
Author(s):  
Yoshiaki Maru ◽  
Naotake Tanaka ◽  
Yasutoshi Tatsumi ◽  
Yuki Nakamura ◽  
Makiko Itami ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Development ◽  
Cellular Transformation ◽  
In Vivo Models ◽  
Mesenchymal Transition ◽  
Endometrial Cells ◽  
Immunodeficient Mice ◽  
Organ Type

AbstractKRAS, an oncogene, is frequently activated by mutations in many cancers. Kras-driven adenocarcinoma development in the lung, pancreas, and biliary tract has been extensively studied using gene targeting in mice. By taking the organoid- and allograft-based genetic approach to these organs, essentially the same results as in vivo models were obtained in terms of tumor development. To verify the applicability of this approach to other organs, we investigated whether the combination of Kras activation and Pten inactivation, which gives rise to endometrial tumors in mice, could transform murine endometrial organoids in the subcutis of immunodeficient mice. We found that in KrasG12D-expressing endometrial organoids, Pten knockdown did not confer tumorigenicity, but Cdkn2a knockdown or Trp53 deletion led to the development of carcinosarcoma (CS), a rare, aggressive tumor comprising both carcinoma and sarcoma. Although they originated from epithelial cells, some CS cells expressed both epithelial and mesenchymal markers. Upon inoculation in immunodeficient mice, tumor-derived round organoids developed carcinoma or CS, whereas spindle-shaped organoids formed monophasic sarcoma only, suggesting an irreversible epithelial-mesenchymal transition during the transformation of endometrial cells and progression. As commonly observed in mutant Kras-driven tumors, the deletion of the wild-type Kras allele was identified in most induced tumors, whereas some epithelial cells in CS-derived organoids were unexpectedly negative for KrasG12D. Collectively, we showed that the oncogenic potential of KrasG12D and the histological features of derived tumors are context-dependent and varies according to the organ type and experimental settings. Our findings provide novel insights into the mechanisms underlying tissue-specific Kras-driven tumorigenesis.

COL11A1 acted as a downstream of Mist1 to promote the EMT in pancreatic cancer

2020 ◽  
Author(s):  
Yang Li ◽  
Zhiqiang Liu ◽  
Ying Sun ◽  
Hui Ding ◽  
Dianyun Ren ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Development ◽  
Clinical Prognosis ◽  
Mesenchymal Transition ◽  
Interactive Analysis ◽  
Metastasis Models ◽  
Xenograft Models

Abstract Background Pancreatic cancer remains one of the deadliest cancers worldwide. The tumor microenvironment is closely related to the occurrence, growth, and metastasis of tumors. Collagen type XI alpha 1 chain (COL11A1), as a component of extracellular collagen, has been proven to be responsible for tumor development and drug resistance in various cancers. However, it’s role in pancreatic cancer remains unknown. Method The GEPIA (Gene Expression Profiling Interactive Analysis) web tool was used to clarify the differential expression of COL11A1 and clinical prognosis in pancreatic cancer. Functional experiments were performed to assess the effect of COL11A1 on the state of pancreatic cells in vitro. Mouse xenograft models and pulmonary metastasis models were established to investigate the influence of COL11A1 in vivo. Chromatin immunoprecipitation (ChIP) assays and dual-luciferase assays were applied to assess the relationship between muscle, intestine and stomach expression 1 (Mist1) and COL11A1.Results The upregulated expression of COL11A1 in pancreatic cancer led to a worse prognosis and overall survival for patients with pancreatic cancer. Knockdown of COL11A1 in pancreatic cancer cell lines inhibited their proliferation and invasion, while upregulating COL11A1 increased those abilities. The ChIP and dual-luciferase assays clarified Mist1 could bind to the promoter of COL11A1 as a transcription factor and repress its transcription. Meanwhile, we found that the N-terminal repressor region of Mist1 was capable of inhibiting COL11A1 expression.Conclusion We identified COL11A1 as a carcinogen in pancreatic cancer, and clarified a novel mechanism which Mist1 reverses the Epithelial-Mesenchymal Transition in pancreatic cancer by repressing COL11A1 expression.

scholarly journals Role of Ubiquitin-Specific Peptidase 47 in Cancers and Other Diseases

2021 ◽  
Vol 9 ◽  
Author(s):  
Kailing Pan ◽  
Junhao Fu ◽  
Wenxia Xu
Keyword(s):  
Neuronal Development ◽  
Epithelial Mesenchymal Transition ◽  
Inflammatory Responses ◽  
Tumor Development ◽  
Post Translational Modifications ◽  
Mesenchymal Transition ◽  
Wide Range ◽  
Specific Protease ◽  
Range Of Functions ◽  
Targeted Inhibition

Deubiquitination is the reverse process of ubiquitination, which is catalyzed by deubiquitinase enzymes. More than 100 deubiquitinases have been identified. Ubiquitin-specific peptidase 47 (USP47), a member of the ubiquitin-specific protease family with high homology to USP7, is an active molecule with a wide range of functions and is closely associated with cancer and other diseases. However, no systematic summary exists regarding the functions of USP47. Here, we summarize the functions and expression regulation of USP47. USP47 is highly expressed in many tumors and is widely involved in tumor development, metastasis, drug resistance, epithelial-mesenchymal transition, and other processes. Targeted inhibition of USP47 can reverse malignant tumor behavior. USP47 also plays a role in inflammatory responses, myocardial infarction, and neuronal development. USP47 is involved in multiple levels of expression-regulating mechanisms, including transcriptional, post-transcriptional, and post-translational modifications. Development of targeted inhibitors against USP47 will provide a basis for studying the mechanisms of USP47 and developing therapeutic strategies for cancers and other diseases.

scholarly journals CircRNA PIP5K1A promotes the progression of glioma through upregulation of the TCF12/PI3K/AKT pathway by sponging miR-515-5p

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Kebin Zheng ◽  
Haipeng Xie ◽  
Wensong Wu ◽  
Xichao Wen ◽  
Zhaomu Zeng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Glioma Cell ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Akt Pathway ◽  
Circular Rnas ◽  
Rt Pcr ◽  
Mesenchymal Transition

Abstract Background Increasing studies have revealed that circular RNAs (CircRNAs) make great contributions to regulating tumor progression. Therefore, we intended to explore the expression characteristics, function, and related mechanisms of a novel type of circRNA, PIP5K1A, in glioma. Methods Firstly, reverse transcription-polymerase chain reaction (RT-PCR) was carried out to examine CircPIP5K1A expression in glioma tissues and adjacent normal tissues, and the correlation between CircPIP5K1A level and the clinical-pathological indicators of glioma was analyzed. Then, the CircPIP5K1A expression in various glioma cell lines was detected, and CircPIP5K1A overexpression and knockdown cell models were constructed. Subsequently, cell proliferation and viability were detected by the CCK8 method and BrdU staining. Cell apoptosis was detected by flow cytometry, and cell invasion was examined by Transwell assay. The expression of TCF12, PI3K/AKT pathway apoptotic related proteins (Caspase3, Bax, and Bcl2) and epithelial-mesenchymal transition (EMT) markers (E-cadherin, Vimentin, and N-cadherin) was determined by western blot or RT-PCR. Results The results manifested that CircPIP5K1A was upregulated in glioma tissues (compared with that in normal adjacent tissues), and overexpressed CircPIP5K1A was related to glioma volume and histopathological grade. Functionally, overexpressing CircPIP5K1A notably elevated glioma cell proliferation, invasion, and EMT and inhibited apoptosis both in vivo and in vitro. Besides, CircPIP5K1A upregulated TCF12 and PI3K/AKT activation. Bioinformatics analysis testified that miR-515-5p was a common target of CircPIP5K1A and TCF12, while the dual-luciferase reporter assay and RNA immunoprecipitation (RIP) experiment further confirmed that CircPIP5K1A targeted miR-515-5p, which bound the 3′-untranslated region (UTR) of TCF12. Conclusions Overall, the study illustrated that CircPIP5K1A is a potential prognostic marker in glioma and regulates glioma evolvement by modulating the miR-515-5p-mediated TCF12/PI3K/AKT axis.

scholarly journals Silencing of circRNA circ_0001666 Represses EMT in Pancreatic Cancer Through Upregulating miR-1251 and Downregulating SOX4

2021 ◽  
Vol 8 ◽  
Author(s):  
Rundong Zhang ◽  
Wanli Zhu ◽  
Chenchao Ma ◽  
Kaixing Ai
Keyword(s):  
Pancreatic Cancer ◽  
Cell Invasion ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Development ◽  
Circular Rnas ◽  
Loss Of Function ◽  
Survival Times ◽  
Mesenchymal Transition

BackgroundPancreatic cancer (PC) is an aggressive malignancy and has a poor prognosis. Although emerging research has revealed that circular RNAs (circRNAs) are crucial modulators that control tumor development and metastasis, their functional involvement in PC has not been well characterized. Here, we examined whether and how circRNA circ_0001666 governs epithelial-mesenchymal transition (EMT) in PC.MethodsWe investigated the effects of circ_0001666 on EMT and PC cell invasion by gain- and loss-of-function assays. We also explored the mechanisms underlying the functions of circ_0001666 in PC cells.ResultsWe found that circ_0001666 is highly expressed in PC tissues and PC cell lines. Patients with high circ_0001666 expression had shorter survival times. In vitro and in vivo experiments have demonstrated that upregulation of circ_0001666 facilitates PC cell proliferation, EMT and invasiveness, whereas knockdown of circ_0001666 exhibits opposite functions. Moreover, circ_0001666 is able to bind to miR-1251, thus increasing the expression of SOX4, which is a direct downstream effector of miR-1251. The oncogenic effects of circ_0001666 on EMT and PC cell invasion were rescued by miR-1251 overexpression.ConclusionsThese results suggested that circ_0001666 acts as an oncogenic circRNA to promote EMT and invasion of PC cells through sponging miR-1251, and indicated that circ_0001666 could be explored as a potential therapeutic target for PC.

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