Identification of CD24 as a potential diagnostic and therapeutic target for malignant pleural mesothelioma

AbstractMalignant pleural mesothelioma (MPM) is an aggressive malignancy of the pleura that is currently incurable due to the lack of an effective early diagnostic method and specific medication. The CDKN2A (p16) and NF2 genes are both frequently mutated in MPM. To understand how these mutations contribute to MPM tumor growth, we generated NF2/p16 double-knockout (DKO) cell clones using human MeT-5A and HOMC-B1 mesothelial cell lines. Cell growth and migration activities were significantly increased in DKO compared with parental cells. cDNA microarray analysis revealed differences in global gene expression profiles between DKO and parental cells. Quantitative PCR and western blot analyses showed upregulation of CD24 concomitant with increased phosphorylation of AKT, p70S6K, and c-Jun in DKO clones. This upregulation was abrogated by exogenous expression of NF2 and p16. CD24 knockdown in DKO cells significantly decreased TGF-β1 expression and increased expression of E-cadherin, an epithelial–mesenchymal transition marker. CD24 was highly expressed in human mesothelioma tissues (28/45 cases, 62%) and associated with the loss of NF2 and p16. Public data analysis revealed a significantly shorter survival time in MPM patients with high CD24 gene expression levels. These results strongly indicate the potential use of CD24 as a prognostic marker as well as a novel diagnostic and therapeutic target for MPM.

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Prognostic significance of epithelial–mesenchymal transition in malignant pleural mesothelioma☆☆☆

European Journal of Cardio-Thoracic Surgery ◽

10.1016/j.ejcts.2009.08.027 ◽

2010 ◽

Vol 37 (3) ◽

pp. 566-572 ◽

Cited By ~ 55

Author(s):

Alexandra Schramm ◽

Isabelle Opitz ◽

Svenja Thies ◽

Burkhardt Seifert ◽

Holger Moch ◽

...

Keyword(s):

Malignant Pleural Mesothelioma ◽

Epithelial Mesenchymal Transition ◽

Prognostic Significance ◽

Pleural Mesothelioma ◽

Mesenchymal Transition

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A case of brain metastasis with pathological transformation of long-surviving malignant pleural mesothelioma: illustrative case

Journal of Neurosurgery: Case Lessons ◽

10.3171/case2099 ◽

2021 ◽

Vol 1 (3) ◽

Author(s):

Ryuichi Noda ◽

Shunsuke Yanagisawa ◽

Masato Inoue ◽

Tetsuo Hara

Keyword(s):

Natural History ◽

Brain Metastasis ◽

Malignant Pleural Mesothelioma ◽

Epithelial Mesenchymal Transition ◽

World Health ◽

Illustrative Case ◽

Pleural Mesothelioma ◽

Mesenchymal Transition ◽

Pathological Result ◽

Number Of Patients

BACKGROUNDMalignant pleural mesothelioma (MPM) is a rare cancer, and in 80% of cases the cause is asbestos exposure. In 1972, the World Health Organization (WHO) declared asbestos is a carcinogenic substance. Since then, every developed country has restricted and banned the product. Because of its high heat resistance, asbestos had been widely used as building material for decades. The WHO estimated that approximately 125 million people are exposed to asbestos, and more than 107,000 die from asbestos-related diseases annually. Because of its long incubation period, the number of patients is estimated to keep increasing in the near future.OBSERVATIONSThe authors report a case of long-surviving MPM with a rushed clinical course after brain metastasis. A 69-year-old woman diagnosed with MPM (epithelial type) 6 years earlier presented with a brain metastasis. The pathological result of the brain metastasis was the sarcomatoid type. This case showed the possibility of subtype transition after long survival.LESSONSThis article aids in understanding the long-term natural history of MPM and the possibility of epithelial-mesenchymal transition. Neurosurgeons have to be aware of its the natural history and the possibility of brain metastasis.

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A COMPARATIVE ANALAYSIS OF INTER-SITE GENE EXPRESSION HETEROGENICITY OF NORMAL HUMAN BUCCAL MUCOSA WITH NORMAL GINGIVAL MUCOSA

10.1101/2021.10.08.463654 ◽

2021 ◽

Author(s):

Rooban Thavarajah ◽

Kannan Ranganathan

Keyword(s):

Gene Expression ◽

Buccal Mucosa ◽

Epithelial Mesenchymal Transition ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Gene Expression Omnibus ◽

Genotypic Difference ◽

Mesenchymal Transition ◽

Normal Human ◽

The Difference

BACKGROUND: Description of heterogeneity of gene expression of various human intraoral sites are not adequate. The aim of this study was to explore the difference of gene expression profiles of whole tissue obtained from apparently normal human gingiva and buccal mucosa (HGM, HBM). MATERIALS AND METHODS: Gene sets fulfilling inclusion and exclusion criteria of HGM and HBM in gene Expression Omnibus(GEO) database were identified, segregated, filtered and analysed using the ExAtlas online web tool using pre-determined cut-off. The differentially expressed genes were studied for epithelial keratinization related, housekeeping(HKG), extracellular matrix related(ECMRG) and epithelial-mesenchymal transition related genes(EMTRGs). RESULTS: In all 40 HBM and 64 HGM formed the study group. In all there were 18012 significantly expressed genes. Of this, 1814 were over-expressed and 1862 under-expressed HBM genes as compared to HGM. One in five of all studied genes significantly differed between HBM and HGM. For the keratinization genes, 1 in 6 differed. One of every 5 HKG-proteomics genes differed between HBM and HGM, while this ratio was 1-in 4 for all ECMRGs and EMTRGs. DISCUSSION: This difference in the gene expression between the HBM and HGM could possibly influence a multitude of biological pathways. This result could explain partly the difference in clinicopathological features of oral lesions occurring in HBM and HGM. The innate genotypic difference between the two intra-oral niches could serve as confounding factor in genotypic studies. Hence studies that compare the HBM and HGM should factor-in these findings while evaluating their results.

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Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas

Acta Endocrinologica ◽

10.1530/eje-17-0702 ◽

2018 ◽

Vol 178 (3) ◽

pp. 295-307 ◽

Cited By ~ 6

Author(s):

Camilla Maria Falch ◽

Arvind Y M Sundaram ◽

Kristin Astrid Øystese ◽

Kjersti Ringvoll Normann ◽

Tove Lekva ◽

...

Keyword(s):

Gene Expression ◽

Tumor Growth ◽

Epithelial Mesenchymal Transition ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Growth Potential ◽

Mesenchymal Transition ◽

Volume Doubling Time ◽

Slow Growing

ObjectiveReliable biomarkers associated with aggressiveness of non-functioning gonadotroph adenomas (GAs) are lacking. As the growth of tumor remnants is highly variable, molecular markers for growth potential prediction are necessary. We hypothesized that fast- and slow-growing GAs present different gene expression profiles and reliable biomarkers for tumor growth potential could be identified, focusing on the specific role of epithelial-mesenchymal transition (EMT).Design and methodsEight GAs selected for RNA sequencing were equally divided into fast- and slow-growing group by the tumor volume doubling time (TVDT) median (27.75 months). Data were analyzed by tophat2, cufflinks and cummeRbund pipeline. 40 genes were selected for RT-qPCR validation in 20 GAs based on significance, fold-change and pathway analyses. The effect of silencingMTDH(metadherin) andEMCN(endomucin) onin vitromigration of human adenoma cells was evaluated.Results350 genes were significantly differentially expressed (282 genes upregulated and 68 downregulated in the fast group,P-adjusted <0.05). Among 40 selected genes, 11 showed associations with TVDT (−0.669<R<−0.46,P < 0.05). These werePCDH18, UNC5D, EMCN, MYO1B, GPM6Aand six EMT-related genes (SPAG9, SKIL, MTDH, HOOK1, CNOT6LandPRKACB).MTDH, but notEMCN, demonstrated involvement in cell migration and association with EMT markers.ConclusionsFast- and slow-growing GAs present different gene expression profiles, and genes related to EMT have higher expression in fast-growing tumors. In addition toMTDH, identified as an important contributor to aggressiveness, the other genes might represent markers for tumor growth potential and possible targets for drug therapy.

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MiR-30a: A Novel Biomarker and Potential Therapeutic Target for Cancer

Journal of Oncology ◽

10.1155/2018/5167829 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 20

Author(s):

Lin-hong Jiang ◽

He-da Zhang ◽

Jin-hai Tang

Keyword(s):

Gene Expression ◽

Therapeutic Target ◽

Epithelial Mesenchymal Transition ◽

Myelogenous Leukemia ◽

Transcriptional Unit ◽

Potential Therapeutic Target ◽

Regulate Gene Expression ◽

Mesenchymal Transition ◽

Proliferation And Metastasis ◽

Complementary Binding

MicroRNAs (miRNAs) are small, highly conserved noncoding RNAs molecules, consisting of 18–25 nucleotides that regulate gene expression by binding to complementary binding sites within the 3′untranslated region (3′UTR) of target mRNAs. MiRNAs have been involved in regulating gene expression and diverse physiological and pathological processes. Several studies have reported that miR-30a, situated on chromosome 6q.13, is produced by an intronic transcriptional unit. Moreover, miR-30a has demonstrated its role in biological processes, including inhibiting proliferation and metastasis in many tumors, autophagy in chronic myelogenous leukemia, and regulating TGF-b1-induced epithelial-mesenchymal transition. However, based on the pathogenetic relationship between miR-30a and cancer in tumorigenesis, we believe that miR-30a may serve as tumor promising biomarker. Moreover, it would offer a therapeutic target for the treatment of cancer.

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KIAA0101 in Malignant Pleural Mesothelioma: a Potential Diagnostic and Prognostic Marker

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207324666210707105634 ◽

2021 ◽

Vol 24 ◽

Author(s):

Ping Lin ◽

Yuean Zhao ◽

Xiaoqian Li ◽

Zongan Liang

Keyword(s):

Gene Expression ◽

Regression Analysis ◽

Malignant Pleural Mesothelioma ◽

Cox Regression ◽

Expression Profiles ◽

Gene Set Enrichment Analysis ◽

High Expression ◽

Pleural Mesothelioma ◽

Hub Genes ◽

Cox Regression Analysis

Background: Currently, there are no reliable diagnostic and prognostic markers for malignant pleural mesothelioma (MPM). The objective of this study was to identify hub genes that could be helpful for diagnosis and prognosis in MPM by using bioinformatics analysis. Materials and Methods: The gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA). Weighted gene co-expression network analysis (WGCNA), LASSO regression analysis, Cox regression analysis, and Gene Set Enrichment Analysis (GSEA) were performed to identify hub genes and their functions. Results: A total of 430 up-regulated and 867 downregulated genes in MPM were identified based on the GSE51024 dataset. According to the WGCNA analysis, differentially expressed genes were classified into 8 modules. Among them, the pink module was most closely associated with MPM. According to genes with GS > 0.8 and MM > 0.8, six genes were selected as candidate hub genes (NUSAP1, TOP2A, PLOD2, BUB1B, UHRF1, KIAA0101) in the pink module. In the LASSO model, three genes (NUSAP1, PLOD2, and KIAA0101) were identified with non-zero regression coefficients and were considered hub genes among the 6 candidates. The hub gene-based LASSO model can accurately distinguish MPM from controls (AUC = 0.98). Moreover, the high expression level of KIAA0101, PLOD2, and NUSAP1 were all associated with poor prognosis compared to the low level in Kaplan–Meier survival analyses. After further multivariate Cox analysis, only KIAA0101 (HR = 1.55, 95% CI = 1.05-2.29) was identified as an independent prognostic factor among these hub genes. Finally, GSEA revealed that high expression of KIAA0101 was closely associated with 10 signaling pathways. Conclusion: Our study identified several hub genes relevant to MPM, including NUSAP1, PLOD2, and KIAA0101. Among these genes, KIAA0101 appears to be a useful diagnostic and prognostic biomarker for MPM, which may provide new clues for MPM diagnosis and therapy.

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Single-cell transcriptomics, scRNA-Seq and C1 CAGE discovered distinct phases of pluripotency during naïve-to-primed conversion in mice

10.1101/2020.09.25.313239 ◽

2020 ◽

Author(s):

Michael Böttcher ◽

Yuhki Tada ◽

Jonathan Moody ◽

Masayo Kondo ◽

Hiroki Ura ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Single Cell ◽

Epithelial Mesenchymal Transition ◽

Expression Profiles ◽

Embryonic Stem ◽

Transition Process ◽

Marker Genes ◽

Sudden Increase ◽

Mesenchymal Transition

AbstractBackgroundTwo types of mammalian pluripotent stem cells (PSC), i.e. naïve and primed possess distinct cellular characteristics. It is largely unknown how these differences are generated during naïve-to-primed transition process. We have established a robust in vitro transition system using a Wnt inhibitor for the first time and analyzed dynamic changes in cellular status via single-cell RNA-sequencing and C1 CAGE analyses.ResultsAnalysis of known marker genes suggested that the cell transition process progresses as expected. However, cluster analyses revealed a sudden increase in expression profile diversities three and four days after induction of the transition. These expression diversities can be reconciled by the presence of two subpopulations with distinct transcription profiles emerging at these time points. One of the subpopulations appears transiently, and surprisingly these cells showed a global downregulation of gene expression. Moreover, initiation of random X chromosome inactivation (XCI) coincides with the appearance of these transient cells. The other subpopulation can be maintained as a stem cell line and possesses expression profiles more similar to those of primed epiblast stem cells (EpiSC) than embryonic stem cells (ESC). However, there are important differences in gene expression related to epithelial-mesenchymal transition (EMT), suggesting that this subpopulation may represent a novel pluripotent state that has an intermediate cellular phenotype between ESC and EpiSC.ConclusionsThese findings should contribute to our understanding of the establishment and maintenance of distinct differentiation statuses of mammalian PSCs and provide new insights into the pluripotency spectrum in general.

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Testing the Gene Expression Classification of the EMT Spectrum

10.1101/452508 ◽

2018 ◽

Author(s):

Dongya Jia ◽

Jason T. George ◽

Satyendra C. Tripathi ◽

Deepali L. Kundnani ◽

Mingyang Lu ◽

...

Keyword(s):

Gene Expression ◽

Gene Expression Data ◽

Regulatory Network ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Expression Profiles ◽

Expression Patterns ◽

M Cells ◽

Expression Data ◽

Mesenchymal Transition

AbstractThe epithelial-mesenchymal transition (EMT) plays a central role in cancer metastasis and drug resistance – two persistent clinical challenges. Epithelial cells can undergo a partial or full EMT, attaining either a hybrid epithelial/mesenchymal (E/M) or mesenchymal phenotype, respectively. Recent studies have emphasized that hybrid E/M cells may be more aggressive than their mesenchymal counterparts. However, mechanisms driving hybrid E/M phenotypes remain largely elusive. Here, to better characterize the hybrid E/M phenotype(s) and tumor aggressiveness, we integrate two computational methods – (a) RACIPE – to identify the robust gene expression patterns emerging from the dynamics of a given gene regulatory network, and (b) EMT scoring metric - to calculate the probability that a given gene expression profile displays a hybrid E/M phenotype. We apply the EMT scoring metric to RACIPE-generated gene expression data generated from a core EMT regulatory network and classify the gene expression profiles into relevant categories (epithelial, hybrid E/M, mesenchymal). This categorization is broadly consistent with hierarchical clustering readouts of RACIPE-generated gene expression data. We show that the EMT scoring metric can be used to distinguish between samples composed of exclusively hybrid E/M cells and those containing mixtures of epithelial and mesenchymal subpopulations using the RACIPE-generated gene expression data.

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