scholarly journals A Novel Six Metastasis-Related Prognostic Gene Signature for Patients With Osteosarcoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Di Zheng ◽  
Kezhou Xia ◽  
Ling Yu ◽  
Changtian Gong ◽  
Yubo Shi ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Epithelial To Mesenchymal Transition ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Gene Signature ◽  
Suppressor Gene ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Osteosarcoma is the most common malignant bone tumor, and although there has been significant progress in its management, metastases often herald incurable disease. Here we defined genes differentially expressed between primary and metastatic osteosarcoma as metastasis-related genes (MRGs) and used them to construct a novel six-MRG prognostic signature for overall survival of patients with osteosarcoma. Validation in internal and external datasets confirmed satisfactory accuracy and generalizability of the prognostic model, and a nomogram based on the signature and clinical variables was constructed to aid clinical decision-making. Of the six MRGs, FHIT is a well-documented tumor suppressor gene that is poorly defined in osteosarcoma. Consistent with tumor suppressor function, FHIT was downregulated in osteosarcoma cells and human osteosarcoma samples. FHIT overexpression inhibited osteosarcoma proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, FHIT overexpression upregulate the epithelial marker E-cadherin while repressing the mesenchymal markers N-cadherin and vimentin. Our six-MRG signature represents a novel and clinically useful prognostic biomarker for patients with osteosarcoma, and FHIT might represent a therapeutic target by reversing epithelial to mesenchymal transition.

scholarly journals CircMTO1 suppresses hepatocellular carcinoma progression via the miR-541-5p/ZIC1 axis by regulating Wnt/β-catenin signaling pathway and epithelial-to-mesenchymal transition

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Dandan Li ◽  
Jiawei Zhang ◽  
Jing Yang ◽  
Jie Wang ◽  
Runling Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Epithelial To Mesenchymal Transition ◽  
Bioinformatic Analysis ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Signal Pathways ◽  
Mesenchymal Transition

AbstractCircRNA mitochondrial tRNA translation optimization 1 (circMTO1) functions as a tumor suppressor usually and is related to the progression of many tumors, including hepatocellular carcinoma (HCC). CircMTO1 is downregulated in HCC as compared to adjacent nontumor tissue, which may suppress the HCC progression by certain signal pathways. However, the underlying signal pathway remains largely unknown. The interactions between circMTO1 and miR-541-5p were predicted through bioinformatics analysis and verified using pull-down and dual-luciferase reporter assays. CCK-8, transwell, and apoptosis assays were performed to determine the effect of miR-541-5p on HCC progression. Using bioinformatic analysis, dual-luciferase reporter assay, RT-qPCR, and western blot, ZIC1 was found to be the downstream target gene of miR-541-5p. The regulatory mechanisms of circMTO1, miR-541-5p, and ZIC1 were investigated using in vitro and in vivo rescue experiments. The results depicted that silencing circMTO1 or upregulating miR-541-5p expression facilitated HCC cell proliferation, migration, and invasion and inhibited apoptosis. CircMTO1 silencing upregulated the expression of downstream ZIC1 regulators of the Wnt/β-catenin pathway markers, β-catenin, cyclin D1, c-myc, and the mesenchymal markers N-cadherin, Vimentin, and MMP2, while the epithelial marker E-cadherin was downregulated. MiR-541-5p knockdown had the opposite effect and reversed the effect of circMTO1 silencing on the regulation of downstream ZIC1 regulators. Intratumoral injection of miR-541-5p inhibitor suppressed tumor growth and reversed the effect of circMTO1 silencing on the promotion of tumor growth in HCC. These findings indicated that circMTO1 suppressed HCC progression via the circMTO1/ miR-541-5p/ZIC1 axis by regulating Wnt/β-catenin signaling and epithelial-to-mesenchymal transition, making it a novel therapeutic target.

scholarly journals Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sabina Di Matteo ◽  
Lorenzo Nevi ◽  
Diletta Overi ◽  
Nadine Landolina ◽  
Jessica Faccioli ◽  
...  
Keyword(s):  
Intrahepatic Cholangiocarcinoma ◽  
Epithelial To Mesenchymal Transition ◽  
Primary Cultures ◽  
Chronic Administration ◽  
Migration And Invasion ◽  
Cytokeratin 19 ◽  
Mesenchymal Transition ◽  
Therapeutic Implications

AbstractIntrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with marked resistance to chemotherapeutics without therapies. The tumour microenvironment of iCCA is enriched of Cancer-Stem-Cells expressing Epithelial-to-Mesenchymal Transition (EMT) traits, being these features associated with aggressiveness and drug resistance. Treatment with the anti-diabetic drug Metformin, has been recently associated with reduced incidence of iCCA. We aimed to evaluate the anti-cancerogenic effects of Metformin in vitro and in vivo on primary cultures of human iCCA. Our results showed that Metformin inhibited cell proliferation and induced dose- and time-dependent apoptosis of iCCA. The migration and invasion of iCCA cells in an extracellular bio-matrix was also significantly reduced upon treatments. Metformin increased the AMPK and FOXO3 and induced phosphorylation of activating FOXO3 in iCCA cells. After 12 days of treatment, a marked decrease of mesenchymal and EMT genes and an increase of epithelial genes were observed. After 2 months of treatment, in order to simulate chronic administration, Cytokeratin-19 positive cells constituted the majority of cell cultures paralleled by decreased Vimentin protein expression. Subcutaneous injection of iCCA cells previously treated with Metformin, in Balb/c-nude mice failed to induce tumour development. In conclusion, Metformin reverts the mesenchymal and EMT traits in iCCA by activating AMPK-FOXO3 related pathways suggesting it might have therapeutic implications.

scholarly journals Knockdown long noncoding RNA SLC8A1-AS1 attenuate cell invasion and migration in glioma via suppression of Wnt-β catenin signaling pathways

2020 ◽  
Author(s):  
Ling He ◽  
Hui Yang ◽  
Xiao-long Zhu ◽  
Yan Zhang ◽  
Kun Lv
Keyword(s):  
Noncoding Rna ◽  
Epithelial To Mesenchymal Transition ◽  
Glioma Cells ◽  
Neural System ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Validation Experiment

Abstract Background: Glioma, as the most common aggressive malignant tumor in the central nervous system, is still an insurmountable disease in neural system. The potential mechanism of its carcinogenesis remains largely unclear. Methods: In the present study, we identified dysregulated lncRNA solute carrier family 8 member A1 antisense RNA 1 (SLC8A1-AS1) as associated with glioma based on The Cancer Genome Atlas （TCGA）data. Validation experiment was conducted to confirm a high expression level of lncRNA SLC8A1-AS1 in glioma tissues. Results: Down-regulation of lncRNA SLC8A1-AS1 suppressed proliferation, clone formation, migration and invasion of glioma cells in vitro and in vivo. Moreover, lncRNA SLC8A1-AS1 silencing decreased the activity of the Wnt/β-catenin pathway and suppressed the epithelial to mesenchymal transition (EMT) in glioma cells. Conclusions: Collectively, these findings provide a novel insights into the function and mechanism of lncRNA SLC8A1-AS1 in the pathogenesis of glioma and highlight its potential as a therapeutic target for glioma intervention.

scholarly journals TDO2 Promotes the EMT of Hepatocellular Carcinoma Through Kyn-AhR Pathway

2021 ◽  
Vol 10 ◽  
Author(s):  
Lei Li ◽  
Tao Wang ◽  
Shanbao Li ◽  
Zhengqian Chen ◽  
Junyi Wu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Aryl Hydrocarbon Receptor ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Aryl Hydrocarbon ◽  
Hcc Cells

Tryptophan 2,3-dioxygenase (TDO2), an enzyme involved in tryptophan (Trp) metabolism has been linked with some malignant traits of various cancers. Kyn, the main product of Trp metabolism pathway catalyzed by TDO2 and indoleamine 2,3-dioxygenase (IDO) in tumor cells, was also demonstrated to activate aryl hydrocarbon receptor (AhR), which may regulate cancer growth and invasion in some malignancies. However, whether TDO2 participates in the metastasis and invasion of HCC has not been explored before. The underlying mechanism played by TDO2 in this process still requires further investigation. Here, we demonstrated that overexpression of TDO2 correlates with advanced stage or malignant traits in HCC patients. Knockdown or inhibition of TDO2 suppressed the migration and invasion of HCC cells in vitro and in vivo. Epithelial to mesenchymal transition (EMT) is an essential program happened in the initial phase of cancer metastasis. We found that in HCC cells, TDO2 promoted the EMT process evidenced by altered levels of biomarkers for EMT. Mechanically, TDO2 regulated the Kyn production in HCC cell via activated aryl hydrocarbon receptor (AhR). Together, these results indicate that TDO2 promotes the EMT of hepatocellular carcinoma through activating Kyn-AhR pathway, thereby participating in the metastasis and invasion of HCC.

scholarly journals Inactivation of p21-Activated Kinase 2 (Pak2) Inhibits the Development of Nf2-Deficient Malignant Mesothelioma

2020 ◽  
Author(s):  
Eleonora Sementino ◽  
Yuwaraj Kadariya ◽  
Mitchell Cheung ◽  
Craig W. Menges ◽  
Yinfei Tan ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Genetic System ◽  
Gene Signature ◽  
Suppressor Gene ◽  
Conditional Knockout ◽  
Negative Regulator ◽  
Mesenchymal Transition ◽  
Group I ◽  
P21 Activated Kinase

AbstractMalignant mesotheliomas (MM) show frequent somatic loss of the NF2 tumor suppressor gene. The NF2 product, Merlin, is implicated in several tumor-related pathways, including p21-activated kinase (PAK) signaling. Merlin is both a phosphorylation target for PAK and a negative regulator of this oncogenic kinase. Merlin loss results in PAK activation, and PAK inhibitors hold promise for the treatment of NF2-deficient tumors. To test this possibility in an in vivo genetic system, Nf2f/f;Cdkn2af/f mice were crossed to mice with conditional knockout of Pak2, a highly expressed group I Pak member. Cohorts of these animals were injected in either the thoracic or peritoneal cavities with adeno-Cre virus to delete floxed alleles in the mesothelial lining. Loss of Pak2 resulted in a markedly decreased incidence and delayed onset and progression of pleural and peritoneal MMs in Nf2;Cdkn2a-deficient (NC) mice, as documented by Kaplan-Meier survival curves and in vivo bioluminescent imaging. RNA-seq revealed that MMs from NC;Pak2-/- mice showed downregulated expression of genes involved in several oncogenic pathways (Wnt, Akt) when compared to MMs from mice retaining Pak2. Kinome profiling showed that, as compared to NC MM cells, NC;Pak2-/- MM cells had multiple kinase changes indicative of an epithelial to mesenchymal transition. Collectively, these findings suggest that NC;Pak2-/- MMs adapt by reprogramming their kinome and gene signature profiles to bypass the need for PAK activity via the activation of other compensatory oncogenic kinase pathways. The identification of such secondary pathways offers opportunities for rational combination therapies to circumvent resistance to anti-PAK drugs.

scholarly journals Deregulated expression of the imprinted DLK1-DIO3 region in glioblastoma stemlike cells: tumor suppressor role of lncRNA MEG3

2020 ◽  
Vol 22 (12) ◽  
pp. 1771-1784 ◽  
Author(s):  
Mariachiara Buccarelli ◽  
Valentina Lulli ◽  
Alessandro Giuliani ◽  
Michele Signore ◽  
Maurizio Martini ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Tumor Suppressor ◽  
Epithelial To Mesenchymal Transition ◽  
Primary Brain Tumor ◽  
Normal Brain ◽  
Potential Candidate ◽  
Iodothyronine Deiodinase ◽  
Mesenchymal Transition

Abstract Background Glioblastoma (GBM) stemlike cells (GSCs) are thought to be responsible for the maintenance and aggressiveness of GBM, the most common primary brain tumor in adults. This study aims at elucidating the involvement of deregulations within the imprinted delta-like homolog 1 gene‒type III iodothyronine deiodinase gene (DLK-DIO3) region on chromosome 14q32 in GBM pathogenesis. Methods Real-time PCR analyses were performed on GSCs and GBM tissues. Methylation analyses, gene expression, and reverse-phase protein array profiles were used to investigate the tumor suppressor function of the maternally expressed 3 gene (MEG3). Results Loss of expression of genes and noncoding RNAs within the DLK1-DIO3 region was observed in GSCs and GBM tissues compared with normal brain. This downregulation is mainly mediated by epigenetic silencing. Kaplan–Meier analysis indicated that low expression of MEG3 and MEG8 long noncoding (lnc)RNAs significantly correlated with short survival in GBM patients. MEG3 restoration impairs tumorigenic abilities of GSCs in vitro by inhibiting cell growth, migration, and colony formation and decreases in vivo tumor growth, reducing infiltrative growth. These effects were associated with modulation of genes involved in cell adhesion and epithelial-to-mesenchymal transition (EMT). Conclusion In GBM, MEG3 acts as a tumor suppressor mainly regulating cell adhesion, EMT, and cell proliferation, thus providing a potential candidate for novel GBM therapies.

scholarly journals NADPH Oxidase 4 Promotes Hypoxia-induced Epithelial-to-mesenchymal Transition via Histone Modification in Pancreatic cancer

2020 ◽  
Author(s):  
Hongzhen Li ◽  
Chunyan Peng ◽  
Chenhui Zhu ◽  
Shuang Nie ◽  
Xuetian Qian ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pancreatic Cancer ◽  
Nadph Oxidase ◽  
Western Blot ◽  
Epithelial To Mesenchymal Transition ◽  
Gene Signature ◽  
Related Gene ◽  
Mesenchymal Transition

Abstract BackgroundHypoxia is a characteristic of the tumor microenvironments within Pancreatic cancer (PC) which has been linked to its malignancy. Oxidative stress, characterized by NADPH oxidase (NOX) activation, and epithelial-to-mesenchymal transition (EMT) could be induced by hypoxia which involved in tumor progression and metastasis. However, the relationship between hypoxia-induced oxidative stress and EMT has not been clarified, and the regulatory mechanism of NADPH oxidase is still unknown. MethodsA hypoxic-related gene signature and its associated pathways in PC were identified by bioinformatics method. Candidate downstream gene (NOX4), responding to hypoxia was validated by RT-PCR and western blot. In vitro and in vivo assays as well as tumor samples from our centre were preformed to explore the phenotype of NOX4 in PC. Immunofluorescence, western blot and chromatin immunoprecipitation assays were further applied to search for detailed mechanism. ResultsWe established a hypoxia-related gene signature within PC which was prognostic and linked with up-regulated EMT pathway. Then we found that hypoxia could induce stable up-regulation of NOX4, which is essential for EMT activation. Elevated expression of NOX4 was observed in PC samples and positively associated with advanced tumor grade and unfavorable prognosis. In vivo and in vitro experiments demonstrated NOX4 overexpress or inhibition in pancreatic cancer cells caused changes of proliferation and invasion ability. Then we found NOX4 could increase the methylation modification of histone H3 and regulated the transcription of EMT-associated gene_ snail family transcriptional repressor 1 (SNAIL1). ConclusionsThis study highlights the prognostic role of hypoxia-related genes in PC and strong correlation with EMT pathway. Our results also creatively discovered that NOX4 was an essential mediator for hypoxia-induced histone methylation modification and EMT in PC cells.

scholarly journals Knockdown long noncoding RNA SLC8A1-AS1 attenuate cell invasion and migration in glioma via suppression of Wnt-β catenin signaling pathways

2020 ◽  
Author(s):  
Ling He ◽  
Hui Yang ◽  
Xiao-long Zhu ◽  
Yan Zhang ◽  
Kun Lv
Keyword(s):  
Noncoding Rna ◽  
Epithelial To Mesenchymal Transition ◽  
Glioma Cells ◽  
Neural System ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Validation Experiment

Abstract Background Glioma, as the most common aggressive malignant tumor in the central nervous system, is still an insurmountable disease in neural system. The potential mechanism of its carcinogenesis remains largely unclear. Methods In the present study, we identified dysregulated lncRNA solute carrier family 8 member A1 antisense RNA 1 (SLC8A1-AS1) as associated with glioma based on The Cancer Genome Atlas (TCGA)data. Validation experiment was conducted to confirm a high expression level of lncRNA SLC8A1-AS1 in glioma tissues. Results Down-regulation of lncRNA SLC8A1-AS1 suppressed proliferation, clone formation, migration and invasion of glioma cells in vitro and in vivo. Moreover, lncRNA SLC8A1-AS1 silencing decreased the activity of the Wnt/β-catenin pathway and suppressed the epithelial to mesenchymal transition (EMT) in glioma cells. Conclusions Collectively, these findings provide a novel insights into the function and mechanism of lncRNA SLC8A1-AS1 in the pathogenesis of glioma and highlight its potential as a therapeutic target for glioma intervention.

scholarly journals LINC02027 / MiR-625-3p /PDLIM5 Axis Inhibits The Proliferation, Migration And Invasion And Promotes Apoptosis of HCC By Inhibiting RAS-MAPK Pathway

2021 ◽  
Author(s):  
Jinyi Wang ◽  
Yong Zhu ◽  
Xiaoming Ai ◽  
Hong Wan ◽  
Wenbo Jia ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Cell Function ◽  
Mapk Pathway ◽  
Underlying Mechanism ◽  
Primary Objective ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Hcc Cells

Abstract Background and Aims: Long non-coding RNAs have been shown to promote or inhibit various cancers, acting as competing endogenous RNAs for specific microRNAs. The primary objective of this research was to investigate the underlying mechanism by which the LINC02027/miR-625-3p/PDLIM5 axis affects proliferation, migration, invasion and apoptosis in hepatocellular carcinoma (HCC). Methods: The level of LINC02027 in HCC tissues and cells and its regulatory effect on the development of HCC were detected. According to the results of database prediction and qRT-PCR, the downstream microRNA and target gene were searched. Finally, HCC cells were transfected with lentivirus and used for cell function assays (in vitro) and subcutaneous tumorigenesis assay in nude mice (in vivo).Results: Downregulation of LINC02027 was detected in HCC tissues and cell lines. The knockdown or overexpression of LINC02027 increased or reduced the proliferation migration and invasion of HCC cells, and the apoptotic ability of HCC cells decreased or increased, respectively. Mechanistically, INC02027 inhibited epithelial-to-mesenchymal transition (EMT). As a ceRNA, LINC02027 inhibited the malignant ability of HCC by competitively binding to miR-625-3p to regulate the expression of PDLIM5 and the activity of RAS-MAPK pathway.Conclusion: LINC02027/miR-625-3p/PDLIM5 axis inhibits the EMT and promotes apoptosis of HCC by regulating RAS-MAPK pathway.

scholarly journals HDAC4 promotes nasopharyngeal carcinoma progression and serves as a therapeutic target

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Chun Cheng ◽  
Jun Yang ◽  
Si-Wei Li ◽  
Guofu Huang ◽  
Chenxi Li ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Tumor Growth ◽  
Therapeutic Target ◽  
Histone Deacetylases ◽  
Migration And Invasion ◽  
Poor Overall Survival ◽  
Mesenchymal Transition ◽  
E Cadherin

AbstractHistone deacetylases (HDACs) are involved in tumor progression, and some have been successfully targeted for cancer therapy. The expression of histone deacetylase 4 (HDAC4), a class IIa HDAC, was upregulated in our previous microarray screen. However, the role of HDAC4 dysregulation and mechanisms underlying tumor growth and metastasis in nasopharyngeal carcinoma (NPC) remain elusive. Here, we first confirmed that the HDAC4 levels in primary and metastatic NPC tissues were significantly increased compared with those in normal nasopharyngeal epithelial tissues and found that high HDAC4 expression predicted a poor overall survival (OS) and progression-free survival (PFS). Functionally, HDAC4 accelerated cell cycle G1/S transition and induced the epithelial-to-mesenchymal transition to promote NPC cell proliferation, migration, and invasion in vitro, as well as tumor growth and lung metastasis in vivo. Intriguingly, knockdown of N-CoR abolished the effects of HDAC4 on the invasion and migration abilities of NPC cells. Mechanistically, HDAC3/4 binds to the E-cadherin promoter to repress E-cadherin transcription. We also showed that the HDAC4 inhibitor tasquinimod suppresses tumor growth in NPC. Thus, HDAC4 may be a potential diagnostic marker and therapeutic target in patients with NPC.

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