International Journal of Molecular Medicine

Our medical research library holds 13 studies published in International Journal of Molecular Medicine (1999–2021). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 13 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: D.A. Spandidos
• Published: 1998 to the present, Greece
• Language: English
• ISSN: 1107-3756 (print), 1791-244X (electronic)
• Its record in the NLM Catalog

2020s

• Overexpression of microRNA‑486 affects the proliferation and chemosensitivity of mesothelioma cell lines by targeting PIM1. S. Pinelli, R. Alinovi, D. Poli, et al. 2021;47(6). PubMed · Publisher · Free full text

  Abstract

  Dysregulated levels of microRNAs (miRNAs or miRs), involved in oncogenic pathways, have been proposed to contribute to the aggressiveness of malignant pleural mesothelioma (MPM). Previous studies have highlighted the downregulation of miRNA miR‑486‑5p in patients with mesothelioma and the introduction of miRNA mimics to restore their reduced or absent functionality in cancer cells is considered an important therapeutic strategy. The aim of the present study was to evaluate the mechanisms through which miRNAs may influence the functions, proliferation and sensitivity to cisplatin of MPM cells. In the present study, a miR‑486‑5p mimic was transfected into the H2052 and H28 MPM cell lines, and cell viability, proliferation, apoptosis and mitochondrial membrane potential were monitored. miR‑486‑5p overexpression led to a clear impairment of cell proliferation, targeting CDK4 and attenuating cell cycle progression. In addition, transfection with miR‑486‑5p mimic negatively regulated the release of inflammatory factors and the expression of Provirus integration site for Moloney murine leukaemia virus 1 (PIM1). The sensitivity of the cells to cisplatin was enhanced by enhancing the apoptotic effects of the drug and impairing mitochondrial function. On the whole, the present study demonstrates that miR‑486‑5p may play an important role in MPM treatment by targeting multiple pathways involved in tumour development and progression. These activities may be mostly related to the downregulation of PIM1, a crucial regulator of cell survival and proliferation. Furthermore, these results provide support for the combined use of miR‑486‑5p with chemotherapy as a therapeutic strategy for MPM.

2010s

• Pathway deviation-based biomarker and multi-effect target identification in asbestos-related squamous cell carcinoma of the lung. J. Du, L. Zhang. 2017;39(3):579-586. PubMed · Publisher · Free full text

  Abstract

  Asbestos-related lung carcinoma is one of the most devastating occupational cancers, and effective techniques for early diagnosis are still lacking. In the present study, a systematic approach was applied to detect a potential biomarker for asbestos-related lung cancer (ARLC); in particular asbestos-related squamous cell carcinoma (ARLC-SCC). Microarray data (GSE23822) were retrieved from the Gene Expression Omnibus database, including 26 ARLC-SCCs and 30 non-asbestos-related squamous cell lung carcinomas (NARLC-SCCs). Differentially expressed genes (DEGs) were identified by the limma package, and then a protein-protein interaction (PPI) network was constructed according to the BioGRID and HPRD databases. A novel scoring approach integrating an expression deviation score and network degree of the gene was then proposed to weight the DEGs. Subsequently, the important genes were uploaded to DAVID for pathway enrichment analysis. Pathway correlation analysis was carried out using Spearman's rank correlation coefficient of the pathscore. In total, 1,333 DEGs, 391 upregulated and 942 downregulated, were obtained between the ARLC-SCCs and NARLC-SCCs. A total of 524 important genes for ARLC-SCC were significantly enriched in 22 KEGG pathways. Correlation analysis of these pathways showed that the pathway of SNARE interactions in vesicular transport was significantly correlated with 12 other pathways. Additionally, obvious correlations were found between multiple pathways by sharing cross-talk genes (EGFR, PRKX, PDGFB, PIK3R3, SLK, IGF1, CDC42 and PRKCA). On the whole, our data demonstrate that 8 cross-talk genes were found to bridge multiple ARLC-SCC-specific pathways, which may be used as candidate biomarkers and potential multi-effect targets. As these genes are involved in multiple pathways, it is possible that drugs targeting these genes may thus be able to influence multiple pathways simultaneously.

• Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor. S.G. Gray, A.M. Baird, F. O'Kelly, et al. 2012;30(6):1505-11. PubMed · Publisher

  Abstract

  Gemcitabine is indicated in combination with cisplatin as first-line therapy for solid tumours including non-small cell lung cancer (NSCLC), bladder cancer and mesothelioma. Gemcitabine is an analogue of pyrimidine cytosine and functions as an anti-metabolite. Structurally, however, gemcitabine has similarities to 5-aza-2-deoxycytidine (decitabine/Dacogen®), a DNA methyltransferase inhibitor (DNMTi). NSCLC, mesothelioma and prostate cancer cell lines were treated with decitabine and gemcitabine. Reactivation of epigenetically silenced genes was examined by RT-PCR/qPCR. DNA methyltransferase activity in nuclear extracts and recombinant proteins was measured using a DNA methyl-transferase assay, and alterations in DNA methylation status were examined using methylation-specific PCR (MS-PCR) and pyrosequencing. We observe a reactivation of several epigenetically silenced genes including GSTP1, IGFBP3 and RASSF1A. Gemcitabine functionally inhibited DNA methyltransferase activity in both nuclear extracts and recombinant proteins. Gemcitabine dramatically destabilised DNMT1 protein. However, DNA CpG methylation was for the most part unaffected by gemcitabine. In conclusion, gemcitabine both inhibits and destabilises DNA methyltransferases and reactivates epigenetically silenced genes having activity equivalent to decitabine at concentrations significantly lower than those achieved in the treatment of patients with solid tumours. This property may contribute to the anticancer activity of gemcitabine.

• Interleukin gene polymorphisms in pneumoconiosis. S. Helmig, M. Grossmann, J. Wübbeling, et al. 2012;30(2):401-8. PubMed · Publisher

  Abstract

  Inhaled asbestos fibres are known to cause inflammation processes with the result of lung or pleural fibrosis and malignancies. Interleukins (IL), such as IL-1β, IL-6 and IL-10, have various functions in the regulation of the inflammatory response and in proliferative processes after inhalation of silica dust and can, therefore, influence the pathogenesis of asbestos-induced fibrosis and carcinogenesis. Polymorphisms within these genes may be associated with susceptibility to silica and asbestos-induced lung diseases. Thus, IL-1β, IL-6 and IL-10 polymorphisms were examined to determine an association with asbestos or silica-induced fibrosis or malignancies. Association studies were performed in 1180 individuals, using control subjects (n=177), fibrosis patients (n=605), lung cancer (LC) patients (n=364) and malignant mesothelioma (MM) patients (n=34). IL-1β (C-511T; C+3954T), IL-6 (G-174C) as well as IL-10 (G-1082A) polymorphisms were investigated. Compared to a healthy (control) group, a higher risk was seen for malignant mesothelioma patients in all investigated polymorphisms. The IL-6 -174C allele showed a tendency towards a higher risk for fibrosis or asbestos-induced lung cancer (ORasbestosis, 1.338; 95% CI, 0.71-2.53; ORsilicosis, 1.226; 95% CI, 0.54-2.81; ORfibrosis other aetiology, 1.313; 95% CI, 0.58-2.98 and ORLC asbestos, 2.112; 95% CI, 0.75-5.92). The IL-10 -1082A carrier seemed to be at higher risk for silicosis (ORsilicosis, 2.064; 95% CI, 0.78-5.49) but not for asbestosis. In summary, this study did not reveal sufficient evidence for a significant association of the investigated interleukin polymorphisms with asbestos or silica-induced diseases in the population studied.

• Role of transcription factor Sp1 in the quercetin-mediated inhibitory effect on human malignant pleural mesothelioma. J.I. Chae, J.H. Cho, K.A. Lee, et al. 2012;30(4):835-41. PubMed · Publisher

  Abstract

  Quercetin (Qu) is found in plants, including red onions and in the skins of red apples, and induces the apoptosis of certain malignant cells. However, no report has been issued on the apoptotic effect of Qu on human malignant pleural mesothelioma. In the present study, it was found that MSTO-211H mesothelioma cell viability was reduced and apoptotic cell death was increased by Qu (20-80 µM), which was found to have an IC₅₀ of 58 µM. In addition, Qu increased the sub-G₁ cell population, and was found to interact with specificity protein 1 (Sp1) and significantly suppressed its expression at the protein and mRNA levels. Furthermore, Qu modulated the levels of Sp1 regulatory genes, such as cyclin D1, myeloid cell leukemia (Mcl)-1 and survivin in MSTO-211H cells. Apoptotic signaling cascades were activated by the cleavage of Bid, caspase-3 and PARP, and by the downregulation of Bcl-xL and the upregulation of Bax in MSTO-211H cells. Our results strongly suggest that Sp1 be considered as a novel molecular target of Qu in human malignant pleural mesothelioma.

• The flavonoid resveratrol suppresses growth of human malignant pleural mesothelioma cells through direct inhibition of specificity protein 1. K.A. Lee, Y.J. Lee, J.O. Ban, et al. 2012;30(1):21-7. PubMed · Publisher

  Abstract

  Resveratrol (Res), from the skin of red grapes, induces apoptosis in some malignant cells, but there are no reports on the apoptotic effect of Res on human malignant pleural mesothelioma. We found that Res interacts with specificity protein 1 (Sp1). The IC50 for Res was 17 µM in MSTO-211H cells. Cell viability was decreased and apoptotic cell death was increased by Res (0-60 µM). Res increased the Sub-G1 population in MSTO-211H cells and significantly suppressed Sp1 protein levels, but not Sp1 mRNA levels. Res modulated the expression of Sp1 regulatory proteins including p21, p27, cyclin D1, Mcl-1 and survivin in mesothelioma cells. After treatment with Res, apoptosis signaling cascades were activated by the activation of Bid, Bim, caspase-3 and PARP, upregulation of Bax and downregulation of Bcl-xL. Res (20 mg/kg daily for 4 weeks) effectively suppressed tumor growth in vivo in BALB/c athymic (nu+/nu+) mice injected with MSTO-211H cells, an effect that was mediated by inhibition of Sp1 expression and induction of apoptotic cell death. Our results strongly suggest that Sp1 is a novel molecular target of Res in human malignant pleural mesothelioma.

• Exon deletion in the MSLN gene encoding MPF/mesothelin precursor protein during Laurasiatherian mammal evolution. D.S. Kim, Y. Hahn. 2011;27(2):289-93. PubMed · Publisher

  Abstract

  Mesothelin is a cell surface glycoprotein that is present in normal mesothelial cells and is highly expressed in several human cancers, including mesotheliomas and ovarian, pancreatic, and lung cancers. The human mesothelin gene (MSLN) encodes a precursor protein, which is processed into 2 mature polypeptides: the N-terminal soluble megakaryocyte-potentiating factor (MPF) and the C-terminal membrane-bound mesothelin which functions as a cell adhesion molecule. In this study, we report the identification and sequence comparison of the MSLN genes in various mammalian species. We found that multiple exon deletion occurred in the Laurasiatherian MSLN genes including 6 exons in the cow, pig, horse, cat, dog, and panda genes and 8 exons in the hedgehog gene. The genomic deletion did not change the open reading frame of the resulting Laurasiatherian MSLN genes, producing internally deleted precursor proteins. The modified precursor was still able to produce the intact cell surface mesothelin protein but would not confer the MPF activity. Genomic sequence comparison showed that a breakage and rejoining event of ancestral introns 2 and 8 was responsible for the deletion. The present findings support that exon deletion is one of the molecular mechanisms underlying gene evolution in mammalian genomes.

• Decreased Cyp2E1 mRNA expression in human leucocytes in patients with fibrotic and inflammatory lung diseases. S. Helmig, J. Döhrel, J. Schneider. 2010;26(1):143-9. PubMed · Publisher

  Abstract

  Cytochrome P450 2E1 (CYP2E1), a phase I enzyme, is involved in the activation of a broad spectrum of pro-carcinogens. The importance of this enzyme for pharmacology is derived from its unique substrate spectrum. Large inter-individual differences in the toxicity of its substrates are known. We investigated the quantitative Cyp2E1 mRNA expression in a cohort of patients with fibrotic and inflammatory lung diseases (n=137) and healthy controls (n=221) considering tobacco-smoke, exposure to asbestos, silica, organic dust or chemical irritating particles in relation to the C1053T (RsaI) polymorphism of Cyp2E1. For quantitative comparison of Cyp2E1 mRNA levels real-time PCR was performed using a LightCycler System. Calculations of expression were made with the 2(-DeltaDeltaCT) method. Detection of the C1053T (RsaI) polymorphism of the Cyp2E1 gene was performed by rapid capillary PCR with melting curve analysis. Fibrotic (0.016+/-0.002; n=52; p=0.000) and inflammatory (0.013+/-0.002; n=16, p=0.000) lung disease patients showed a significantly reduced Cyp2E1 mRNA expression compared to healthy controls (0.026+/-0.002; n=206). Exposure to asbestos (0.019+/-0.003; n=40; p=0.016), organic dust (0.016+/-0.003; n=39; p=0.000) and irritative chemicals (0.016+/-0.002; n=22; p=0.000) revealed a highly significant reduced Cyp2E1 expression. Cyp2E1 mRNA expression of occupational disease (OD) patients suffering from lung or pleural asbestosis OD-No. 4103 (0.018+/-0,003; n=31; p=0.024), allergic obstructive airway diseases OD-No. 4301 (0.013+/-0.002; n=23; p=0.000), exogenic allergic alveolitis OD-No. 4201 (0.009+/-0.002; n=6; p=0.000) and obstructive airway diseases caused by irritative chemicals OD-No. 4302 (0.013+/-0.001; n=11; p=0.000) was highly significantly reduced. In conclusion, we demonstrated a significantly decreased mRNA expression in patients with fibrotic and inflammatory lung diseases compared to healthy controls.

• Suppression of cell death by the secretory form of N-terminal ERC/mesothelin. T. Wang, K. Kajino, M. Abe, et al. 2010;26(2):185-91. PubMed · Publisher

  Abstract

  ERC/mesothelin is highly expressed in malignant mesothelioma, pancreatic cancer, and ovarian cancer. It is cleaved to a 30 kDa N-terminal secretory form (N-ERC) and a 40 kDa C-terminal membranous form (C-ERC). Several functions have been reported for full-length ERC (full-ERC) and C-ERC/mesothelin, such as in cell adhesion and invasion, stimulation of cell proliferation, and the suppression of cell death. However, there have been no studies to date on the function of secretory N-ERC, despite the fact that it is abundantly secreted into the sera of mesothelioma patients. In this study, we investigated whether N-ERC could function as a secretory factor to stimulate tumor progression. Full-, N, or C-ERC was overexpressed in the human hepatocellular carcinoma cell line Huh7 that lacks endogenous expression of ERC/mesothelin. Changes in the rates of cell proliferation and cell death were determined, and the state of signal transducers was examined using various endpoints: total cell counts, trypan blue exclusion rate, BrdU incorporation rate, TUNEL assay, and the phosphorylation of ERK1/2 and Stat3. In cells overexpressing N-ERC, phosphorylation of ERK1/2 was enhanced and the rate of cell death decreased, leading to the increase of cell number. The culture medium containing the secretory N-ERC also had the activity to increase the number of cells. Our data suggested that one of the full-ERC functions reported previously was mediated by the secretory N-ERC.

2000s

• Karyotype analysis of tumorigenic human bronchial epithelial cells transformed by chrysolite asbestos using chemically induced premature chromosome condensation technique. M. Suzuki, C.Q. Piao, Y.L. Zhao, et al. 2001;8(1):43-7. PubMed · Publisher

  Abstract

  We examined karyotypic changes of tumorigenic human bronchial epithelial cell lines transformed by asbestos fibers. Using Calyculin A mediated premature chromosome condensation (PCC) assay and Giemsa-trypsin banding, we showed that the common changes of all tumorigenic cell lines were the loss of one or two copies of chromosome 5, the monosomy of chromosome 19 and the increased trisomy of chromosome 8. The results indicate that the karyotypic change of chromosome 5, 8 and 19 could play an important role in asbestos-induced tumorigenic conversion of human bronchial epithelial cells from an immortalized to tumorigenic state.

• Adenovirus-mediated wild-type p53 overexpression reverts tumourigenicity of human mesothelioma cells. M. Giuliano, A. Catalano, L. Strizzi, et al. 2000;5(6):591-6. PubMed · Publisher

  Abstract

  Pleural malignant mesothelioma (MM) shows poor survival, regardless of tumour stage at diagnosis. MM is unresponsive to present treatment regimens and new protocols are desperately needed. The localised nature, the potential accessibility, and the relative lack of distant metastases make MM a particularly attractive candidate for somatic gene therapy. A common target for cancer gene therapy is the tumour suppressor protein p53. p53 does not seem to be mutated or deleted in MM, but it can be inactivated by binding to other proteins, like mdm2 and SV40 large T antigen. We tested the effects of a replication-deficient adenoviral vector carrying wild-type p53 cDNA in human MM cells. Our results show that >95% of MM cells were efficiently infected with 25 multiplicity of infection (MOI) of vector. Wild-type p53 was effectively expressed resulting in >80% inhibition of proliferation in MM cells. AdCMV.p53 infection induced apoptosis while controls did not show any evident morphological alterations. Ex vivo p53 gene transfer experiments inhibited tumourigenesis in nude mice. In vivo, direct intratumour injection of AdCMV.p53 arrested tumour growth and prolonged survival of treated mice. These results indicate that p53-gene therapy should be strongly exploited for clinical trials in MM patients.

1990s

• Man-made mineral fibers induce apoptosis of human peripheral blood mononuclear cells similarly to chrysotile B. Z. Ma, T. Otsuki, A. Tomokuni, et al. 1999;4(6):633-7. PubMed · Publisher

  Abstract

  The aim of this study was to investigate whether man-made mineral fibers (MMMF) induce apoptosis of human peripheral blood mononuclear cells (PBMC), as we recently demonstrated for chrysotile B. In vitro cultivation of PBMC with various MMMF as well as chrysotile B clearly produced apoptotic cells. The alteration of the expression for apoptosis related genes at the mRNA level during in vitro cultures of PBMC with various MMMF revealed upregulation of Flice and Apaf-1 genes and down regulation of TNF receptor 1 and Bid genes. These results indicate that MMMF induce apoptosis of PBMC in a similar manner to chrysotile B. However, the process may be mediated not only by the Fas-related apoptotic pathway but also a mitochondrial pathway. Thus, one should be aware that respiratory and immunological abnormalities may occur in workers who are exposed to MMMFs.

• Migration of mesothelioma cells correlates with histotype-specific synthesis of extracellular matrix. S. Scarpa, A. Giuffrida, M. Fazi, et al. 1999;4(1):67-71. PubMed · Publisher

  Abstract

  Three human pleural malignant mesothelioma cell cultures (MM) of epithelioid (E1), fibrous (F1) and byphasic (B1) histotype were studied in their synthesis of the extracellular matrix (ECM) components laminin (LM), fibronectin (FN), type IV collagen (cIV), and in their chemotactic and haptotactic migration towards the ECM produced proteins. MM-B1 showed the highest FN synthesis and release; MM-E1 produced the highest quantity of basement membrane constituents LM and cIV; MM-F1 weakly produced and released FN, LM and cIV. MM-B1 had the highest chemotactic and haptotactic motility, MM-F1 migrated toward the lowest concentration of LM while had reduced chemotactic activity toward FN and cIV; MM-E1 had the lowest migratory activity toward each ECM substrate. We demonstrated that three MM of different histotype are characterized by different ECM production and that these differences determine a variable ability of each MM to spread and migrate towards ECM substrates.

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