scholarly journals Comprehensive Analysis of The Significance of Hypoxia-Related Genes in Ovarian Cancer

2021 ◽  
Author(s):  
Wancheng Zhao ◽  
Lili Yin
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Principal Component ◽  
Vital Role ◽  
The Cancer Genome Atlas ◽  
Consensus Clustering ◽  
Mesenchymal Transition ◽  
Cancer Genome Atlas ◽  
Pca Algorithm

Abstract Background: Hypoxia-related genes have been reported to play important roles in a variety of cancers. However, their roles in ovarian cancer (OC) have remained unknown. The aim of our research was to explore the significance of hypoxia-related genes in OC patients.Methods: In this study, 15 hypoxia-related genes were screened from The Cancer Genome Atlas (TCGA) database to group the ovarian cancer patients using the consensus clustering method. Principal component analysis (PCA) was performed to calculate the hypoxia score for each patient to quantify the hypoxic status. Results: The OC patients from TCGA-OV dataset were divided into two distinct hypoxia statuses (cluster.A and cluster.B) based on the expression level of the 15 hypoxia-related genes. Most hypoxia-related genes were expressed more highly in the cluster.A group than in the cluster.B group. We also found that patients in the cluster.A group exhibited higher expression of immune checkpoint-related genes, epithelial-mesenchymal transition-related genes, and immune activation-related genes, as well as elevated immune infiltrates. PCA algorithm indicated that patients in the cluster.A group had higher hypoxia scores than that in in the cluster.B group.Conclusions: In summary, our research elucidated the vital role of hypoxia-related genes in immune infiltrates of OC. Our investigation of hypoxic status may be able to improve the efficacy of immunotherapy for OC.

scholarly journals Comprehensive Analysis of The Significance of Hypoxia-Related Genes in Ovarian Cancer

2021 ◽  
Author(s):  
Wancheng Zhao ◽  
Lili Yin
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Principal Component ◽  
Vital Role ◽  
The Cancer Genome Atlas ◽  
Expression Level ◽  
Consensus Clustering ◽  
Mesenchymal Transition ◽  
Cancer Genome Atlas ◽  
Pca Algorithm

Abstract Background: Hypoxia-related genes have been reported to play important roles in a variety of cancers. However, their roles in ovarian cancer (OC) have remained unknown. Our aim was to explore the significance of hypoxia-related genes in OC patients.Methods: In this study, 15 hypoxia-related genes were screened from The Cancer Genome Atlas (TCGA) database to group the ovarian cancer patients using the consensus clustering method. Principal component analysis (PCA) was used to calculate the hypoxia score to quantify the hypoxic status. Results: The OC patients were divided into two hypoxia statuses based on the expression level of the 15 hypoxia-related genes. Most hypoxia-related genes were more highly expressed in the cluster.A group. We also found that patients in the cluster.A group exhibited higher expression level of immune checkpoint-related genes, epithelial-mesenchymal transition-related genes, and immune activation-related genes, as well as elevated immune infiltrates. PCA algorithm indicated that the cluster.A group had higher hypoxia scores.Conclusions: In summary, our research elucidated the vital role of hypoxia-related genes in immune infiltrates of OC. Our investigation of hypoxic status may be able to improve the efficacy of immunotherapy for OC.

scholarly journals HDAC9 Is Preferentially Expressed in Dedifferentiated Hepatocellular Carcinoma Cells and Is Involved in an Anchorage-Independent Growth

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2734
Author(s):  
Keita Kanki ◽  
Ryota Watanabe ◽  
Le Nguyen Thai ◽  
Chun-Hao Zhao ◽  
Kyoko Naito
Keyword(s):  
Hepatocellular Carcinoma ◽  
Histone Deacetylases ◽  
Epithelial Mesenchymal Transition ◽  
Cell Transformation ◽  
The Cancer Genome Atlas ◽  
Hepatic Differentiation ◽  
Differentiation Markers ◽  
Mesenchymal Transition ◽  
Cancer Genome Atlas ◽  
Hcc Cells

Aberrant activation of histone deacetylases (HDACs) is one of the causes of tumor cell transformation in many types of cancer, however, the critical HDAC responsible for the malignant transformation remain unclear. To identify the HDAC related to the dedifferentiation of hepatocellular carcinoma (HCC) cells, we investigated the expression profile of HDACs in differentiated and undifferentiated hepatoma cells. We found that HDAC9, a member of the class II HDAC, is preferentially expressed in undifferentiated HCC cells. Analysis of 373 HCC patients in The Cancer Genome Atlas (TCGA) database revealed that the expression of HDAC9 mRNA positively correlated with the markers of mesenchymal phenotype and stemness, and conversely, negatively correlated with hepatic differentiation markers. HDAC9 was transcriptionally upregulated in epithelial–mesenchymal transition (EMT)-induced HCC cells treated with TGF-β. Genetic and pharmacological inhibition of HDAC9 in undifferentiated HCC cells showed decreased sphere-forming activity, which indicates an ability of anchorage-independent cell growth and self-renewal. We also showed that aldehyde dehydrogenase 1A3 (ALDH1A3) was downregulated in HDAC9-suppressing cells, and ALDH inhibitor disulfiram significantly decreased the sphere formation of undifferentiated HCC cells. Together, our data provide useful information for the development of HDAC9-specific inhibitors for the treatment of HCC progression.

scholarly journals Abnormally expressed JunB transactivated by IL-6/STAT3 signaling promotes uveal melanoma aggressiveness via epithelial–mesenchymal transition

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Chaoju Gong ◽  
Jie Shen ◽  
Zejun Fang ◽  
Lei Qiao ◽  
Ruifang Feng ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Transcriptional Level ◽  
Mesenchymal Transition ◽  
Stat3 Signaling ◽  
Epithelial Marker ◽  
Cancer Genome Atlas

Uveal melanoma (UM) is the most common primary intraocular tumor in adults, and it carries a high risk of metastasis and mortality. Various proinflammatory cytokines have been found to be significantly increased in the aqueous humor or vitreous fluid of UM patients; however, the role of these cytokines in UM metastasis remains elusive. In the present study, we found that long-term interleukin (IL)-6 exposure promoted the migration and invasion of UM cells, diminished cell–cell adhesion, and enhanced focal adhesion. Moreover, IL-6 treatment decreased the membranous epithelial marker TJP1 and increased the cytoplasmic mesenchymal marker Vimentin. Further investigation demonstrated that JunB played a critical role in IL-6-induced UM epithelial–mesenchymal transition (EMT). In UM cells, the expression of JunB was significantly up-regulated during the IL-6-driven EMT process. Additionally, JunB induction occurred at the transcriptional level in a manner dependent on phosphorylated STAT3, during which activated STAT3 directly bound to the JunB promoter. Importantly, the knockdown of STAT3 prevented the IL-6-induced EMT phenotype as well as cell migration and invasion, whereas JunB overexpression recovered the attenuated aggressiveness of UM cells. Similarly, with IL-6 stimulation, the stable overexpression of JunB strengthened the migratory and invasive capabilities of UM cells and induced the EMT-promoting factors (Snail, Twist1, matrix metalloproteinase (MMP)-2, MMP-14, and MMP-19). Analysis of The Cancer Genome Atlas (TCGA) database indicated that JunB was positively correlated with IL-6 and STAT3 in UM tissues. The present study proposes an IL-6/STAT3/JunB axis leading to UM aggressiveness by EMT, which illustrates the negative side of inflammatory response in UM metastasis.

scholarly journals New Actors Driving the Epithelial–Mesenchymal Transition in Cancer: The Role of Leptin

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1676
Author(s):  
Monserrat Olea-Flores ◽  
Juan C. Juárez-Cruz ◽  
Miriam D. Zuñiga-Eulogio ◽  
Erika Acosta ◽  
Eduardo García-Rodríguez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Epithelial Cancers ◽  
Patients With Cancer

Leptin is a hormone secreted mainly by adipocytes; physiologically, it participates in the control of appetite and energy expenditure. However, it has also been linked to tumor progression in different epithelial cancers. In this review, we describe the effect of leptin on epithelial–mesenchymal transition (EMT) markers in different study models, including in vitro, in vivo, and patient studies and in various types of cancer, including breast, prostate, lung, and ovarian cancer. The different studies report that leptin promotes the expression of mesenchymal markers and a decrease in epithelial markers, in addition to promoting EMT-related processes such as cell migration and invasion and poor prognosis in patients with cancer. Finally, we report that leptin has the greatest biological relevance in EMT and tumor progression in breast, lung, prostate, esophageal, and ovarian cancer. This relationship could be due to the key role played by the enriched tumor microenvironment in adipose tissue. Together, these findings demonstrate that leptin is a key biomolecule that drives EMT and metastasis in cancer.

Complement Component 3 (C3) Is a Mediator of Epithelial-Mesenchymal Transition (EMT)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1421-1421
Author(s):  
Min Soon Cho ◽  
Qianghua Hu ◽  
Rajesha Rupaimoole ◽  
Anil Sood ◽  
Vahid Afshar-Kharghan
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Tumors ◽  
Mouse Embryos ◽  
Ovarian Cancer Cells ◽  
Mesenchymal Transition ◽  
E Cadherin

Abstract We have shown that complement component 3 (C3) is expressed in malignant ovarian epithelial cells and enhances cell proliferation in vitro and tumor growth in vivo. C3 is secreted by cancer cells into the tumor microenvironment and promotes tumor growth through an autocrine loop. To understand the mechanism of upregulation of C3 expression in malignant epithelial cells, we studied the transcriptional regulation of C3, and found that TWIST1, a major regulator of EMT, binds to the C3 promoter and regulates C3 transcription. Knockdown of the TWIST1 gene reduced C3 mRNA, and TWIST1 overexpression increased C3 mRNA. TWIST1 promotes epithelial-mesenchymal transition (EMT) during normal development and in metastasis of malignant tumors. An important marker of EMT is a reduction in the surface expression of E-cadherin on cells facilitating migration and invasion of these cells. TWIST1 is a transcriptional repressor of E-cadherin; and because TWIST1 increases C3 expression, we investigated whether C3 is also a negative regulator of E-cadherin expression. We overexpressed C3 in ovarian cancer cells by stable transduction of lentivirus carrying C3 cDNA. Overexpression of C3 was associated with 32% reduction in the expression of E-cadherin resulting in enhanced migration ability of cells by 2.3 folds and invasiveness by 1.75 folds, as compared to control cells transduced with control lentivirus. To investigate whether TWIST1-induced reduction in E-cadherin is C3-mediated or not, we studied the effect of TWIST1 overexpression simultaneous with C3 knockdown in ovarian cancer cells. Overexpression of TWIST1 alone resulted in 70% reduction in E-cadherin mRNA and this was completely reversed after simultaneous C3 knockdown in these cells. To investigate the correlation between C3 and TWIST1 in vivo, we studied the co-expression of these two proteins in mouse embryos (physiologic EMT) and in malignant tumors (pathologic EMT). Given the role of EMT in embryogenesis we immunostained mouse embryos at different stages of development, using antibodies against TWIST1 or C3. Transverse section of 9.5-day post-coitum (9.5dpc) mouse embryos showed co-expression of TWIST1 and C3 in otocyst (ot) and hindbrain (hb) of neural crest. In the whole-mounted 11.5dpc mouse embryos, C3 and TWIST1 were co-expressed in limb buds. Given the role of EMT in malignancy, tumors induced in mice after intraperitoneal injection of murine ovarian cancer cells were resected and immunostained for C3 and TWIST1 proteins. TWIST1 and C3 co-localized at tumor edges, where EMT and tumor cells migration occur. Taken together, these data provide evidence that TWIST1 regulates C3 expression, and C3 promotes EMT through E-cadherin. Disclosures No relevant conflicts of interest to declare.

scholarly journals MicroRNA-30 inhibits the growth of human ovarian cancer cells by suppressing RAB32 expression

2022 ◽  
Vol 36 ◽  
pp. 205873842110586
Author(s):  
Yan Zhang ◽  
Min Zhou ◽  
Kun Li
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Transcriptional Level ◽  
Human Ovarian Cancer ◽  
Mesenchymal Transition

Introduction MicroRNAs (miRs) exhibit the potential to act as therapeutic targets for the management of human cancers including ovarian cancer. The role of microRNA-30 (miR-30) via modulation of RAB32 expression has not been studied in ovarian cancer. Consistently, the present study was designed to characterize the molecular role of miR-30/RAB32 axis in human ovarian cancer. Methods Cell viability was determined by MTT assay. Expression analysis was carried out by qRT-PCR. Dual luciferase assay was used to confirm the interaction between miR-30 and RAB32. Scratch-heal and transwell chamber assays were used to monitor the cell migration and invasion. Western blotting and immunofluorescence assays were used to determine the protein expression. Results The results revealed significant ( p < 0.05) downregulation of miR-30 in human ovarian cancer cell lines. Overexpression of miR-30 in ovarian SK-OV-3 and A2780 cancer cells significantly ( p < 0.05) inhibited their proliferation. Besides, ovarian cancer cells overexpressing miR-30 showed significantly ( p < 0.05) lower migration and invasion. The miR-30 upregulation also altered the expression pattern of marker proteins of epithelial–mesenchymal transition in ovarian cancer cells. In silico analysis predicted RAB32 as the molecular target of miR-30 at post-transcriptional level. The silencing of RAB32 mimicked the tumor-suppressive effects of miR-30 overexpression in ovarian cancer cells. Nonetheless, overexpression of RAB32 could prevent the tumor-suppressive effects of miR-30 on SK-OV-3 and A2780 cancer cells. Conclusion Taken together, the results suggest the tumor-suppressive role of miR-30 and point towards the therapeutic utility of miR-30/RAB32 molecular axis in the management of ovarian cancer

scholarly journals ITGA3 Is a Reliable Biomarker and Putative Therapeutic Target for Glioma

2020 ◽  
Author(s):  
Qing Zhang ◽  
Chen Zhu ◽  
Gefei Guan ◽  
Shuai Shen ◽  
Yunhe Han ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Glioma Cells ◽  
The Cancer Genome Atlas ◽  
Integrin Subunit ◽  
Central Nervous System Tumor ◽  
Mesenchymal Transition ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Abstract Background: Glioma is the most prevalent and malignant primary central nervous system tumor in adults. As a member of the integrin alpha chain family of proteins, integrin subunit alpha 3 (ITGA3) has been found to play a critical role in the occurrence and progression of several cancers, including lung, ovarian, and pancreatic cancers. However, the role of ITGA3 in glioma remains unclear.Methods: The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), REMBRANDT, GSE16011, GSE59612, and GSE4290 datasets were used to analyze relevant characteristics of ITGA3 in glioma. R language and GraphPad Prism 7.00 were employed as major tools for statistical analysis and graph manipulation.Results: We identified that ITGA3 expression was upregulated in glioma and related to unfavorable outcomes of glioma patients. Expression of ITGA3 also tended to be enriched in aggressive subtypes of glioma. We demonstrated that expression of ITGA3 was negatively correlated with glioma purity. In gliomas with high ITGA3 expression, the anti-glioma immune response was inhibited. ITGA3 also regulated angiogenesis within the glioma microenvironment and promoted the epithelial–mesenchymal transition (EMT) and autophagy of glioma cells. GSEA analysis revealed that ITGA3 could activate ERK1/2 and PI3K/AKT/mTOR pathways.Conclusion: Our data suggested that ITGA3 promoted the malignant progression of glioma by regulating the immunity of glioma as well as the EMT and autophagy of glioma cells, which could act as a therapeutic target for glioma.

scholarly journals On the Reproducibility of TCGA Ovarian Cancer MicroRNA Profiles

2013 ◽  
Author(s):  
Ying-Wooi Wan ◽  
Claire Mach ◽  
Genevera I. Allen ◽  
Matthew Anderson ◽  
Zhandong Liu
Keyword(s):  
Ovarian Cancer ◽  
Cancer Survival ◽  
Human Cancer ◽  
The Cancer Genome Atlas ◽  
Detection Algorithms ◽  
Level 3 ◽  
Cancer Genome Atlas ◽  
Ovarian Cancer Survival ◽  
Generation Sequencing

Dysregulated microRNA (miRNA) expression is a well-established feature of human cancer. However, the role of specific miRNAs in determining cancer outcomes remains unclear. Using Level 3 expression data from the Cancer Genome Atlas (TCGA), we identified 61 miRNAs that are associated with overall survival in 469 ovarian cancers profiled by microarray (p<0.01). We also identified 12 miRNAs that are associated with survival when miRNAs were profiled in the same specimens using Next Generation Sequencing (miRNA-Seq) (p<0.01). Surprisingly, only 1 miRNA transcript is associated with ovarian cancer survival in both datasets. Our analyses indicate that this discrepancy is due to the fact that miRNA levels reported by the two platforms correlate poorly, even after correcting for potential issues inherent to signal detection algorithms. Further investigation is warranted.

scholarly journals Aging-Related Tumor Microenvironment Changes Could Worsen The Prognosis of GBM Patients

2020 ◽  
Author(s):  
Hongwang Song ◽  
Xiaojun Fu ◽  
Chenxing Wu ◽  
Shouwei Li
Keyword(s):  
Tumor Microenvironment ◽  
Epithelial Mesenchymal Transition ◽  
Close Correlation ◽  
Underlying Mechanism ◽  
The Cancer Genome Atlas ◽  
Future Research ◽  
Mesenchymal Transition ◽  
Cancer Genome Atlas ◽  
Differential Expressed Genes ◽  
Genome Atlas

Abstract Background: Glioblastoma multiforme (GBM) is the most malignant tumor in human brain, with highly heterogeneity among different patients. Age could function as an incidence and prognosis risk factor for many tumors.Method: A series of bioinformatic experiments were conducted to evaluate the differences of incidence, differential expressed genes, enriched pathways with the data from Surveillance, Epidemiology, and End Results (SEER) program, the cancer genome atlas (TCGA) and Chinese glioma genome atlas (CGGA) project.Results: We discovered in our present study that distinct difference of incidence and prognosis of different aged GBM patients. By a series of bioinformatic method, we found that the tumor associated fibroblasts (TAFs) was the most crucial tumor microenvironment (TME) component that led to this phenomenon. Epithelial-mesenchymal transition (EMT) could be the mechanism by which TAFs regulate the progression of GBM. Conclusion: We have proposed a close correlation between age and GBM incidence and prognosis, and propose the underlying mechanism behind this correlation by mining different databases, which laid the foundation for future research.

scholarly journals LY75 Suppression in Mesenchymal Epithelial Ovarian Cancer Cells Generates a Stable Hybrid EOC Cellular Phenotype, Associated with Enhanced Tumor Initiation, Spreading and Resistance to Treatment in Orthotopic Xenograft Mouse Model

2020 ◽  
Vol 21 (14) ◽  
pp. 4992
Author(s):  
Sadia Mehdi ◽  
Elizabeth Macdonald ◽  
Kristianne Galpin ◽  
David A. Landry ◽  
Galaxia Rodriguez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Severe Combined Immunodeficiency ◽  
Ovarian Cancer Cells ◽  
M Cells ◽  
Mesenchymal Transition ◽  
Resistance To Treatment

The implications of the epithelial–mesenchymal transition (EMT) mechanisms in the initiation and progression of epithelial ovarian cancer (EOC) remain poorly understood. We have previously shown that suppression of the antigen receptor LY75 directs mesenchymal–epithelial transition (MET) in EOC cell lines with the mesenchymal phenotype, associated with the loss of Wnt/β-catenin signaling activity. In the present study, we used the LY75-mediated modulation of EMT in EOC cells as a model in order to investigate in vivo the specific role of EOC cells, with an epithelial (E), mesenchymal (M) or mixed epithelial plus mesenchymal (E+M) phenotype, in EOC initiation, dissemination and treatment response, following intra-bursal (IB) injections of SKOV3-M (control), SKOV3-E (Ly75KD) and a mixed population of SKOV3-E+M cells, into severe combined immunodeficiency (SCID) mice. We found that the IB-injected SKOV3-E cells displayed considerably higher metastatic potential and resistance to treatment as compared to the SKOV3-M cells, due to the acquisition of a Ly75KD-mediated hybrid phenotype and stemness characteristics. We also confirmed in vivo that the LY75 depletion directs suppression of the Wnt/β-catenin pathway in EOC cells, suggestive of a protective role of this pathway in EOC etiology. Moreover, our data raise concerns regarding the use of LY75-targeted vaccines for dendritic-cell EOC immunotherapy, due to the possible occurrence of undesirable side effects.

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