scholarly journals Combined Analysis of RNA Sequence and Microarray Data Reveals a Competing Endogenous RNA Network as Novel Prognostic Markers in Malignant Pleural Mesothelioma

2021 ◽  
Vol 11 ◽  
Author(s):  
Weicheng Duan ◽  
Kang Wang ◽  
Yijie Duan ◽  
Xiuyi Chen ◽  
Xufeng Chu ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Pleural Mesothelioma ◽  
Clinical Prognosis ◽  
Cerna Network ◽  
Aggressive Cancer ◽  
Extracellular Matrix Components ◽  
Competing Endogenous Rnas ◽  
Competing Endogenous Rna Network ◽  
Tumor Pathogenesis ◽  
First Time

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with short survival time. Unbalanced competing endogenous RNAs (ceRNAs) have been shown to participate in the tumor pathogenesis and served as biomarkers for the clinical prognosis. However, the comprehensive analyses of the ceRNA network in the prognosis of MPM are still rarely reported. In this study, we obtained the transcriptome data of the MPM and the normal samples from TCGA, EGA, and GEO databases and identified the differentially expressed (DE) mRNAs, lncRNAs, and miRNAs. The functions of the prognostic genes and the overlapped DEmRNAs were further annotated by the multiple enrichment analyses. Then, the targeting relationships among lncRNA–miRNA and miRNA–mRNA were predicted and calculated, and a prognostic ceRNA regulatory network was established. We included the prognostic 73 mRNAs and 13 miRNAs and 26 lncRNAs into the ceRNA network. Moreover, 33 mRNAs, three miRNAs, and seven lncRNAs were finally associated with prognosis, and a model including seven mRNAs, two lincRNAs, and some clinical factors was finally established and validated by two independent cohorts, where CDK6 and SGMS1-AS1 were significant to be independent prognostic factors. In addition, the identified co-expressed modules associated with the prognosis were overrepresented in the ceRNA network. Multiple enrichment analyses showed the important roles of the extracellular matrix components and cell division dysfunction in the invasion of MPM potentially. In summary, the prognostic ceRNA network of MPM was established and analyzed for the first time and these findings shed light on the function of ceRNAs and revealed the potential prognostic and therapeutic biomarkers of MPM.

scholarly journals Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3932
Author(s):  
Dannel Yeo ◽  
Laura Castelletti ◽  
Nico van Zandwijk ◽  
John E. J. Rasko
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Treatment Options ◽  
Survival Rates ◽  
Treatment Strategies ◽  
Pleural Mesothelioma ◽  
Normal Tissues ◽  
Drug Conjugates ◽  
Aggressive Cancer ◽  
Immunotherapy Target ◽  
Bull's Eye

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options and poor prognosis. MPM originates from the mesothelial lining of the pleura. Mesothelin (MSLN) is a glycoprotein expressed at low levels in normal tissues and at high levels in MPM. Many other solid cancers overexpress MSLN, and this is associated with worse survival rates. However, this association has not been found in MPM, and the exact biological role of MSLN in MPM requires further exploration. Here, we discuss the current research on the diagnostic and prognostic value of MSLN in MPM patients. Furthermore, MSLN has become an attractive immunotherapy target in MPM, where better treatment strategies are urgently needed. Several MSLN-targeted monoclonal antibodies, antibody–drug conjugates, immunotoxins, cancer vaccines, and cellular therapies have been tested in the clinical setting. The biological rationale underpinning MSLN-targeted immunotherapies and their potential to improve MPM patient outcomes are reviewed.

scholarly journals Identification of Redox-Sensitive Transcription Factors as Markers of Malignant Pleural Mesothelioma

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1138
Author(s):  
Martina Schiavello ◽  
Elena Gazzano ◽  
Loredana Bergandi ◽  
Francesca Silvagno ◽  
Roberta Libener ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
Malignant Pleural Mesothelioma ◽  
Antioxidant Defense ◽  
Asbestos Exposure ◽  
Predictive Biomarkers ◽  
Antioxidant Systems ◽  
Pleural Mesothelioma ◽  
Related Factor ◽  
Aggressive Cancer

Although asbestos has been banned in most countries around the world, malignant pleural mesothelioma (MPM) is a current problem. MPM is an aggressive tumor with a poor prognosis, so it is crucial to identify new markers in the preventive field. Asbestos exposure induces oxidative stress and its carcinogenesis has been linked to a strong oxidative damage, event counteracted by antioxidant systems at the pulmonary level. The present study has been focused on some redox-sensitive transcription factors that regulate cellular antioxidant defense and are overexpressed in many tumors, such as Nrf2 (Nuclear factor erythroid 2-related factor 2), Ref-1 (Redox effector factor 1), and FOXM1 (Forkhead box protein M1). The research was performed in human mesothelial and MPM cells. Our results have clearly demonstrated an overexpression of Nrf2, Ref-1, and FOXM1 in mesothelioma towards mesothelium, and a consequent activation of downstream genes controlled by these factors, which in turn regulates antioxidant defense. This event is mediated by oxidative free radicals produced when mesothelial cells are exposed to asbestos fibers. We observed an increased expression of Nrf2, Ref-1, and FOXM1 towards untreated cells, confirming asbestos as the mediator of oxidative stress evoked at the mesothelium level. These factors can therefore be considered predictive biomarkers of MPM and potential pharmacological targets in the treatment of this aggressive cancer.

Biomarkers for malignant pleural mesothelioma: a meta-analysis

2019 ◽  
Vol 40 (11) ◽  
pp. 1320-1331 ◽  
Author(s):  
Christina N Gillezeau ◽  
Maaike van Gerwen ◽  
Julio Ramos ◽  
Bian Liu ◽  
Raja Flores ◽  
...  
Keyword(s):  
Lung Disease ◽  
Malignant Pleural Mesothelioma ◽  
Meta Analysis ◽  
Pleural Mesothelioma ◽  
Control Groups ◽  
Aggressive Cancer ◽  
Comparison Groups ◽  
The Mean ◽  
Mean Differences ◽  
Healthy Participants

Abstract Malignant pleural mesothelioma (MPM) is a rare but aggressive cancer, and early detection is associated with better survival. Mesothelin, fibulin-3 and osteopontin have been suggested as screening biomarkers. The study conducted a meta-analysis of the mean differences of mesothelin, osteopontin and fibulin-3 in blood and pleural samples. PubMed searches were conducted for studies that measured levels of mesothelin, osteopontin and fibulin-3 in participants with MPM compared with malignancy, benign lung disease or healthy participants. Thirty-two studies with mesothelin levels, 12 studies with osteopontin levels and 9 studies with fibulin-3 levels were included in the meta-analysis. Statistically significant mean differences were seen between MPM patients and all other comparison groups for mesothelin blood and pleural levels. Statistically significant differences in blood osteopontin levels were seen between participants with benign lung disease and healthy participants compared with participants with MPM, but not when comparing participants with cancer with MPM participants. There were not enough studies that reported osteopontin levels in pleural fluid to complete a meta-analysis. Statistically significant differences were seen in both blood and pleural levels of fibulin-3 in MPM patients compared with all other groups. On the basis of these results, mesothelin and fibulin-3 levels appear to be significantly lower in all control groups compared with those with MPM, making them good candidates for screening biomarkers. Osteopontin may be a useful biomarker for screening healthy individuals or those with benign lung disease but would not be useful for screening patients with malignancies.

scholarly journals Patient-derived malignant pleural mesothelioma cell cultures: a tool to advance biomarker-driven treatments

Thorax ◽  
2020 ◽  
Vol 75 (11) ◽  
pp. 1004-1008 ◽  
Author(s):  
Nikolaos I Kanellakis ◽  
Rachelle Asciak ◽  
Megat Abd Hamid ◽  
Xuan Yao ◽  
Mark McCole ◽  
...  
Keyword(s):  
Cell Cultures ◽  
Malignant Pleural Mesothelioma ◽  
Poor Prognosis ◽  
Ex Vivo ◽  
Cytotoxic T Cells ◽  
Pleural Mesothelioma ◽  
Ex Vivo Model ◽  
High Throughput Drug Screening ◽  
Aggressive Cancer ◽  
Malignant Pleural Mesothelioma Cell

Malignant pleural mesothelioma (MPM) is an aggressive cancer, associated with poor prognosis. We assessed the feasibility of patient-derived cell cultures to serve as an ex vivo model of MPM. Patient-derived MPM cell cultures (n=16) exhibited stemness features and reflected intratumour and interpatient heterogeneity. A subset of the cells were subjected to high-throughput drug screening and coculture assays with cancer-specific cytotoxic T cells and showed diverse responses. Some of the biphasic MPM cells were capable of processing and presenting the neoantigen SSX-2 endogenously. In conclusion, patient-derived MPM cell cultures are a promising and faithful ex vivo model of MPM.

scholarly journals Identification of a lncRNA-Related Competing Endogenous RNA Network in Recurrent Implantation Failure

2021 ◽  
Author(s):  
Kai Huang ◽  
Ying Shi ◽  
Gezi Chen
Keyword(s):  
Underlying Mechanism ◽  
Control Group ◽  
Implantation Failure ◽  
Rna Seq ◽  
Recurrent Implantation Failure ◽  
Cerna Network ◽  
Regulation Network ◽  
Competing Endogenous Rnas ◽  
Competing Endogenous Rna Network

Abstract Background Impaired endometrial receptivity is supposed to be a major element leading to recurrent implantation failure (RIF). Numerous studies have identified that the lncRNAs-miRNAs-mRNAs regulation network functions in the generation of receptive uterus. Long non-coding RNAs could act as competing endogenous RNAs in the pathogenesis of RIF. However, our understanding of the underlying mechanism is still limited. Results Based on the RNA-Seq results, 617 DEmRNAs, 69 DElncRNAs and 107 DEmiRNAs were identified in the RIF group compared with the control group. To investigate the role of lncRNAs in RIF, we constructed a lncRNA related ceRNA network. A total of 3 lncRNAs, 8 miRNAs and 69 genes were identified. Above all, our study obtained 120 lncRNAs-miRNAs-mRNAs relationships in the ceRNA network. Among three hub lncRNAs, PART1 and PWRN1 were upregulated whereas PGM5P3-AS1 was downregulated in RIF endometrium. Meanwhile, three down-regulated miRNAs (hsa-miR-1207-5p, hsa-miR-134-5p, hsa-miR-1225-5p) and five up-regulated miRNAs (hsa-miR-30c-5p, hsa-miR-30b-5p, hsa-miR-145-5p, hsa-miR-21-5p, hsa-miR-196b-5p) were shown. Conclusions We constructed a lncRNA-related ceRNA network and identified three hub lncRNAs in recurrent implantation failure. The results may provide further understanding in the pathogenesis of RIF as well as potential diagnostic and therapeutic targets.

Effect of the load versus capacity unbalance on the sensitivity of malignant pleural mesothelioma cells to proteasome inhibitors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e18522-e18522
Author(s):  
Genny Jocolle' ◽  
Gianmauro Numico ◽  
Fulvia Cerutti ◽  
Oliva Laura ◽  
Simone Cenci ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Specific Activity ◽  
Load Capacity ◽  
Flow Cytometric Analysis ◽  
Proteasome Inhibitors ◽  
Pleural Mesothelioma ◽  
Ubiquitinated Proteins ◽  
Enhanced Sensitivity ◽  
Aggressive Cancer ◽  
Apoptotic Effect

e18522 Background: Malignant Pleural Mesothelioma (MPM) is an aggressive cancer that originates from the mesothelium of the pleural cavities. Due to its resistance to all chemotherapies available, news therapies against MPM are urgently needed. Bortezomib is a potent Proteasome Inhibitors (PI) that induces apoptosis in different cancers and it was recently approved for treatment of Multiple Myeloma (MM). Since in MM an unbalance between a reduced proteasomal activity (capacity) and an increased proteins degradation (load) was shown to determine apoptotic sensitivity to PI, we challenged this paradigm also in MPM. Methods: Four different MPM (MM98, REN, MMB, MSTO) and a normal (TERT) pleural lines were treated with increasing doses (from 1 to 1000 nM) of Bortezomib and after 24h apoptosis was assessed by flow cytometric analysis of AnnexinV and propidium iodide positive cells. Levels of polyubiquitinated proteins were evaluated by immunofluorescence microscopy and western blotting with the specific monoclonal Ab Fk2 (BIOMOL International). The three main proteasome activities were measured in continuoin cellular extracts at 37°C with a Carry Eclipse spectrofluorometer (Varian, Palo Alto) by means of specific fluorogenic substrates (Suc-LLVY-amc, Bz-VGR-amc, Suc-YVAD-amc). Results: The sensitivity towards Bortezomib greatly differs between the 5 pleural lines analyzed. Specifically the EC50value was higher for the TERT line (130 nM) while for MPM lines ranged between 17 nM (MM98) and 71 nM (MSTO). Importantly, for all the 5 lines analyzed enhanced sensitivity to Bortezomib perfectly correlates with increased levels of ubiquitinated proteins and reduced proteasome specific activity. Conclusions: Our results prove that MPM lines are significantly more sensitive towards the pro-apoptotic effect of Bortezomib than normal pleural cells. Moreover, as in MM, also in MPM PI-sensitivity stems from an unbalance of the load/capacity ratio. Our data, therefore, establish a rationale for the use of Bortezomib (and new second generation PI) in MPM and indicate that combinatorial therapies with other drugs active on the proteostasis network (like HSP inhibitors) might be highly effective against this cancer.

scholarly journals Use of preclinical models for malignant pleural mesothelioma

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-216602
Author(s):  
Marie Shamseddin ◽  
Joanna Obacz ◽  
Mathew J Garnett ◽  
Robert Campbell Rintoul ◽  
Hayley Elizabeth Francies ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Three Dimensional ◽  
Pleural Mesothelioma ◽  
Microfluidic Chips ◽  
Preclinical Models ◽  
In Vivo Models ◽  
Aggressive Cancer ◽  
New Treatments

Malignant pleural mesothelioma (MPM) is an aggressive cancer most commonly caused by prior exposure to asbestos. Median survival is 12–18 months, since surgery is ineffective and chemotherapy offers minimal benefit. Preclinical models that faithfully recapitulate the genomic and histopathological features of cancer are critical for the development of new treatments. The most commonly used models of MPM are two-dimensional cell lines established from primary tumours or pleural fluid. While these have provided some important insights into MPM biology, these cell models have significant limitations. In order to address some of these limitations, spheroids and microfluidic chips have more recently been used to investigate the role of the three-dimensional environment in MPM. Efforts have also been made to develop animal models of MPM, including asbestos-induced murine tumour models, MPM-prone genetically modified mice and patient-derived xenografts. Here, we discuss the available in vitro and in vivo models of MPM and highlight their strengths and limitations. We discuss how newer technologies, such as the tumour-derived organoids, might allow us to address the limitations of existing models and aid in the identification of effective treatments for this challenging-to-treat disease.

scholarly journals Influence of AQP1 on cell adhesion, migration, and tumor sphere formation in malignant pleural mesothelioma is substratum- and histological-type dependent

2016 ◽  
Vol 310 (6) ◽  
pp. L489-L495 ◽  
Author(s):  
Rajesh M. Jagirdar ◽  
Eleni Apostolidou ◽  
Paschalis Adam Molyvdas ◽  
Konstantinos I. Gourgoulianis ◽  
Chrissi Hatzoglou ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Malignant Pleural Mesothelioma ◽  
Cell Types ◽  
Mercury Chloride ◽  
Pleural Mesothelioma ◽  
Tumor Sphere ◽  
Aggressive Cancer ◽  
The Media ◽  
Sphere Formation

Malignant pleural mesothelioma (MPM) is an aggressive cancer. MPM cells express aquaporin-1 (AQP1) that in other cancers has been shown to participate in the tumor metastasis processes. However, in MPM patients AQP1 overexpression is an independent prognostic factor favoring survival. In this study we aimed at evaluating the role of AQP1 in cell adhesion, migration, and tumor sphere formation in nonmalignant mesothelial cells (MeT-5A) and in epithelioid (M14K) and sarcomatoid (ZL34) MPM cell lines. We used fibronectin (FN) or homologous cell-derived extracellular martrix (ECM) substratum to investigate the role of AQP1 in these experimental phenotypes, inhibiting AQP1 by 10−5 M mercury chloride (MC). Deposited ECM during cell culture exhibited significant concentration differences among cell types. ZL34 cell adhesion was significantly higher than MeT-5A or M14K cells on FN and ECM. MeT-5A and M14K cell adhesion on FN was sensitive to AQP1 inhibition, whereas AQP1 inhibition on ECM was limited to M14K cells. Wound healing in ZL34 cells was significantly higher than MeT-5A and M14K cells on FN and ECM. AQP1 inhibition significantly lowered cell migration in ZL34 cells on FN and ECM. Sphere formation was not dependent on FN or ECM in the media. AQP1 inhibition in FN media reduced sphere formation in M14K cells, whereas, in ECM, all three cell types were sensitive to AQP1 inhibition.

scholarly journals Polyphenol Extract from Evening Primrose (Oenothera paradoxa) Inhibits Invasion Properties of Human Malignant Pleural Mesothelioma Cells

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1574
Author(s):  
Malgorzata Chmielewska-Kassassir ◽  
Katarzyna Sobierajska ◽  
Wojciech M. Ciszewski ◽  
Malgorzata Bukowiecka-Matusiak ◽  
Dorota Szczesna ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Original Data ◽  
Pleural Mesothelioma ◽  
Dependent Manner ◽  
Evening Primrose ◽  
Prognostic Features ◽  
Isopropanol Extract ◽  
Cycle Arrest ◽  
M Phase ◽  
First Time

Extracts from the defatted evening primrose (Oenothera paradoxa Hudziok) seeds are the source of a range of stable polyphenolic compounds, including ellagic acid, gallic acid, and catechin. Our studies evaluate, for the first time, the influence of evening primrose isopropanol extract (EPE) on malignant pleural mesothelioma (MPM) cells. MPM is rarely diagnosed, its high aggressiveness and frequently noted chemoresistance limit its treatment schemes and it is characterized by low prognostic features. Here, we demonstrate that EPE inhibited MPM growth in a dose-dependent manner in cells with increased invasion properties. Moreover, EPE treatment resulted in cell cycle arrest in the G2/M phase and increased apoptosis in invasive MPM cell lines. Additionally, EPE strongly limited invasion and MMP-7 secretion in MPM cancer cells. Our original data provide evidence about the potential anti-invasive effects of EPE in MPM therapy treatment.

scholarly journals Identification of a lncRNA-related Competing Endogenous RNA Network in Recurrent Implantation Failure

2021 ◽  
Author(s):  
Kai Huang ◽  
Ying Shi ◽  
Gezi Chen
Keyword(s):  
Underlying Mechanism ◽  
Control Group ◽  
Implantation Failure ◽  
Rna Seq ◽  
Recurrent Implantation Failure ◽  
Cerna Network ◽  
Regulation Network ◽  
Competing Endogenous Rnas ◽  
Competing Endogenous Rna Network

Abstract Background: Impaired endometrial receptivity is supposed to be a major element leading to recurrent implantation failure (RIF). Numerous studies have identified that the lncRNAs-miRNAs-mRNAs regulation network functions in the generation of receptive uterus. Long non-coding RNAs could act as competing endogenous RNAs in the pathogenesis of RIF. However, our understanding of the underlying mechanism is still limited. Results: Based on the RNA-Seq results, 617 DEmRNAs, 69 DElncRNAs and 107 DEmiRNAs were identified in the RIF group compared with the control group. To investigate the role of lncRNAs in RIF, we constructed a lncRNA related ceRNA network. A total of 3 lncRNAs, 8 miRNAs and 69 genes were identified. Above all, our study obtained 120 lncRNAs-miRNAs-mRNAs relationships in the ceRNA network. Among three hub lncRNAs, PART1 and PWRN1 were upregulated whereas PGM5P3-AS1 was downregulated in RIF endometrium. Meanwhile, three down-regulated miRNAs (hsa-miR-1207-5p, hsa-miR-134-5p, hsa-miR-1225-5p) and five up-regulated miRNAs (hsa-miR-30c-5p, hsa-miR-30b-5p, hsa-miR-145-5p, hsa-miR-21-5p, hsa-miR-196b-5p) were shown. Conclusions: We constructed a lncRNA-related ceRNA network and identified three hub lncRNAs in recurrent implantation failure. The results may provide further understanding in the pathogenesis of RIF as well as potential diagnostic and therapeutic targets.

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