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Objective(s): Growing evidence supports that isothiocyanates exert a wide range of bioactivities amongst of which is their capacity to interact with the epigenetic machinery in various cancers including melanoma. Our aim was to characterise the effect of sulforaphane and iberin on histone acetylation and methylation as a potential anti-melanoma strategy. Methods: We have utilised an in vitro model of malignant melanoma [consisting of human (A375, Hs294T, VMM1) and murine (B16F-10) melanoma cell lines as well as a non-melanoma (A431) and a non-tumorigenic immortalised keratinocyte (HaCaT) cell line] exposed to sulforaphane or iberin. Cell viability was evaluated by the Alamar blue assay whilst total histone deacetylases and acetyltransferases activities were determined by the Epigenase HDAC Activity/Inhibition and EpiQuik HAT Activity/Inhibition assay kits, respectively. The expression levels of specific histone deacetylases and acetyltransferases together with those of lysine acetylation and methylation marks were obtained by western immunoblotting. Results: Overall, both sulforaphane and iberin were able to (1) reduce cell viability, (2) decrease total histone deacetylase activity and (3) modulate the expression levels of various histone deacetylases as well as acetyl and methyl transferases thus modulating the acetylation and methylation status of specific lysine residues on histones 3 and 4 in malignant melanoma cells. Conclusions: Our findings highlight novel insights as to how sulforaphane and iberin differentially regulate the epigenetic response in ways compatible with their anticancer action in malignant melanoma. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

Background: Taurine (Tau) ameliorates cancer pathogenesis. Researchers have focused on the functional properties of bromamine T (BAT), a stable active bromine molecule. Both N-bromotaurine (TauNHBr) and BAT exert potent anti-inflammatory properties, but the landscape remains obscure concerning the anti-cancer effect of BAT. Methods: We used Crystal Violet, colony formation, flow cytometry and Western blot experiments to evaluate the effect of BAT and Tau on the apoptosis and autophagy of cancer cells. Xenograft experiments were used to determine the in vivo cytotoxicity of either agent. Results: We demonstrated that both BAT and Tau inhibited the growth of human colon, breast, cervical and skin cancer cell lines. Among them, BAT exerted the greatest cytotoxic effect on both RKO and MDA-MB-468 cells. In particular, BAT increased the phosphorylation of c-Jun N-terminal kinases (JNK12 ), p38 mitogen-activated protein kinase (MAPK), and extracellular-signal-regulated kinases (ERK12 ), thereby inducing mitochondrial apoptosis and autophagy in RKO cells. In contrast, Tau exerted its cytotoxic effect by upregulating JNK12 forms, thus triggering mitochondrial apoptosis in RKO cells. Accordingly, colon cancer growth was impaired in vivo. Conclusions: BAT and Tau exerted their anti-tumor properties through the induction of (i) mitochondrial apoptosis, (ii) the MAPK family, and iii) autophagy, providing novel anti-cancer therapeutic modalities. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

The coronavirus disease-2019 (coVid-19) pandemic, caused by the new coronavirus SarS-coV-2, has spread around the globe with unprecedented consequences for the health of millions of people. While the pandemic is still in progress, with new incidents being reported every day, the resilience of the global society is constantly being challenged. under these circumstances, the future seems uncertain. SarS-coV-2 coronavirus has spread panic among civilians and insecurity at all socio-political and economic levels, dramatically disrupting everyday life, global economy, international travel and trade. The disease has also been linked to the onset of depression in many individuals due to the extreme restriction measures that have been taken for the prevention of the rapid spreading of coVid-19. First, the socio-economic, political and psychological implications of the coVid-19 pandemic were explored. Substantial evidence is provided for the consequences of the pandemic on all aspects of everyday life, while at the same time we unravel the role and the pursuits of national regimes during this unforeseen situation. The second goal of this review is related to the scientific aspect of the pandemic. Hence, we explain why SarS-coV-2 is not a so-called ‘invisible enemy’, and also attempt to give insight regarding the origin of the virus, in an effort to reject the conspiracy theories that have arisen during the pandemic. Finally, rational strategies were investigated for successful vaccine development. We are optimistic that this review will complement the knowledge of specialized scientists and inform non‑specialized readers on basic scientific questions, and also on the social and economic implications of the coVid-19 pandemic. © 2020 Spandidos Publications. All rights reserved.

Objective(s): Isothiocyanates (ITCs) are biologically active plant secondary metabolites capable of mediating various biological effects including modulation of the epigenome. Our aim was to characterize the effect of allyl isothiocyanate (AITC) on lysine acetylation and methylation marks as a potential epigenetic-induced anti-melanoma strategy. Methods: Our malignant melanoma model consisted of (1) human (A375) and murine (B16-F10) malignant melanoma as well as of human; (2) brain (VMM1) and lymph node (Hs 294T) metastatic melanoma; (3) non-melanoma epidermoid carcinoma (A431) and (4) immortalized keratinocyte (HaCaT) cells subjected to AITC. Cell viability, histone deacetylases (HDACs) and acetyltransferases (HATs) activities were evaluated by the Alamar blue, Epigenase HDAC Activity/Inhibition and EpiQuik HAT Activity/Inhibition assay kits, respectively, while their expression levels together with those of lysine acetylation and methylation marks by western immunoblotting. Finally, apoptotic gene expression was assessed by an RT-PCR-based gene expression profiling methodology. Results: AITC reduces cell viability, decreases HDACs and HATs activities and causes changes in protein expression levels of various HDACs, HATs, and histone methyl transferases (HMTs) all of which have a profound effect on specific lysine acetylation and methylation marks. Moreover, AITC regulates the expression of a number of genes participating in various apoptotic cascades thus indicating its involvement in apoptotic induction. Conclusions: AITC exerts a potent epigenetic effect suggesting its potential involvement as a promising epigenetic-induced bioactive for the treatment of malignant melanoma. © 2019, The Author(s).

Many studies have shown evidence in support of the beneficial effects of hytochemicals in preventing chronic diseases, including cancer. Among such phytochemicals, sulphur containing compounds (e.g., isothiocyanates (ITCs)) have raised scientific interest by exerting unique chemo-preventive properties against cancer pathogenesis. ITCs are the major biologically active compounds capable of mediating the anticancer effect of cruciferous vegetables. Recently, many studies have shown that a higher intake of cruciferous vegetables is associated with reduced risk of developing various forms of cancers primarily due to a plurality of effects, including (i) metabolic activation and detoxification, (ii) inflammation, (iii) angiogenesis, (iv) metastasis and (v) regulation of the epigenetic machinery. In the context of human malignant melanoma, a number of studies suggest that ITCs can cause cell cycle growth arrest and also induce apoptosis in human malignant melanoma cells. On such basis, ITCs could serve as promising chemo-therapeutic agents that could be used in the clinical setting to potentiate the efficacy of existing therapies. © 2019 by the authors.

Cytokines are pivotal mediators of the immune response, and their coordinated expression protects host tissue from excessive damage and oxidant stress. Nevertheless, the development of lung pathology, including asthma, chronic obstructive pulmonary disease, and ozone-induced lung injury, is associated with oxidant stress; as evidence, there is a significant increase in levels of the modified guanine base 7,8-dihydro-8-oxoguanine (8-oxoG) in the genome. 8-OxoG is primarily recognized by 8-oxoguanine glycosylase 1 (OGG1), which catalyzes the first step in the DNA base excision repair pathway. However, oxidant stress in the cell transiently halts enzymatic activity of substrate-bound OGG1. The stalled OGG1 facilitates DNA binding of transactivators, including NF-κB, to their cognate sites to enable expression of cytokines and chemokines, with ensuing recruitments of inflammatory cells. Hence, defective OGG1 will modulate the coordination between innate and adaptive immunity through excessive oxidant stress and cytokine dysregulation. Both oxidant stress and cytokine dysregulation constitute key elements of oncogenesis by KRAS, which is mechanistically coupled to OGG1. Thus, analysis of the mechanism by which OGG1 modulates gene expression helps discern between beneficial and detrimental effects of oxidant stress, exposes a missing functional link as a marker, and yields a novel target for lung cancer. © 2018 Elsevier Inc.

Natural products are characterized by extreme structural diversity and thus they offer a unique source for the identification of novel anti-tumor agents. Herein, we report that the herbal substance acteoside being isolated by advanced phytochemical methods from Lippia citriodora leaves showed enhanced cytotoxicity against metastatic tumor cells; acted in synergy with various cytotoxic agents and it sensitized chemoresistant cancer cells. Acteoside was not toxic in physiological cellular contexts, while it increased oxidative load, affected the activity of proteostatic modules and suppressed matrix metalloproteinases in tumor cell lines. Intraperitoneal or oral (via drinking water) administration of acteoside in a melanoma mouse model upregulated antioxidant responses in the tumors; yet, only intraperitoneal delivery suppressed tumor growth and induced anti-tumor-reactive immune responses. Mass-spectrometry identification/quantitation analyses revealed that intraperitoneal delivery of acteoside resulted in significantly higher, vs. oral administration, concentration of the compound in the plasma and tumors of treated mice, suggesting that its in vivo anti-tumor effect depends on the route of administration and the achieved concentration in the tumor. Finally, molecular modeling studies and enzymatic activity assays showed that acteoside inhibits protein kinase C. Conclusively, acteoside holds promise as a chemical scaffold for the development of novel anti-tumor agents. © 2018 The Authors

The elucidation of the genetic basis of cancer is the result of the research conducted since the beginning of the previous century, which peaked during the decades of 1960s and 1970s. It has been achieved through two different but convergent routes: the first includes the study of oncogenic viruses in rodents and birds and the second includes the use of chemical carcinogens in cells or in animal model systems (mice). Within this framework, the identification of genes that present mutations, alterations in expression levels, and epigenetic modifications has been facilitated through the development of animal carcinogenesis models. One of these models is the well-characterized mouse multistage skin cancer system discussed in this review. In addition, recent evidence shows the great significance that cancer stem cells seem to have in the emergence and progression of carcinogenesis. Finally, herein we discuss the critical role that miRNAs have emerged to play in cancer progression. miRNAs emerged as molecules with an impact on most cancer-related cellular processes, involving cell proliferation, cell death (apoptosis), angiogenesis, migration/motility,and rearrangement of the cytoskeleton. Their discovery has given rise to studies with a focus on miRNAs as key players in crucial oncogenesis-related processes and thus as potential targets in cancer therapeutics. © 2017 by Begell House, Inc.

The transcription factor p73 is homologous to the well-known tumor-suppressor p53. The p73-regulated networks are of significant clinical interest, because they may substitute for impaired p53-regulated networks which are commonly perturbed in cancer. Herein, we aimed to characterize a p73-regulated network that mediates cell migration and restores anti-oncogenic responses in p53-mutant cancer cells. In this study, we demonstrate that p73 regulates a network underlying cell migration, which consists of MIR34A/MIR3158/vimentin/β-catenin/lef1. The p73 isoforms transactivate the miRNA components (MIR34A/MIR3158) of this network, which in turn, downregulate their EMT-related mRNA co-targets (vimentin/β-catenin/lef1) to decrease cell-migration. Modulation of this network, by increasing the level of the novel p73-dependent target MIR3158, was found to induce anti-oncogenic/anti-invasive responses in p53-mutant cancer cells. Taken together, a p73-regulated, MIR3158-containing, network restores anti-invasive phenotypes in p53-mutant cancer cells; this property could be exploited towards the development of anticancer therapeutics. © 2016 Elsevier Ireland Ltd

Drug delivery systems that target subcellular organelles and, in particular, mitochondria are considered to have great potential in treating disorders that are associated with mitochondrial dysfunction, including cancer or neurodegenerative diseases. To this end, a novel hyperbranched mitochondriotropic nanocarrier was developed for the efficient co-delivery of two different (both in chemical and pharmacological terms) bioactive compounds. The carrier is based on hyperbranched poly(ethyleneimine) functionalized with triphenylphosphonium groups that forms ~100 nm diameter nanoparticles in aqueous media and can encapsulate doxorubicin (DOX), a well-known anti-cancer drug, and chloroquine (CQ), a known chemosensitizer with arising potential in anticancer medication. The anticancer activity of this system against two aggressive DOX-resistant human prostate adenocarcinoma cell lines and in in vivo animal studies was assessed. The co-administration of encapsulated DOX and CQ leads to improved cell proliferation inhibition at extremely low DOX concentrations (0.25 μM). In vivo experiments against DU145 human prostate cancer cells grafted on immunodeficient mice resulted in tumor growth arrest during the three-week administration period and no pervasive side effects. The findings put forward the potential of such targeted low dose combination treatments as a therapeutic scheme with minimal adverse effects. © 2017 by the authors. Licensee MDPI, Basel, Switzerland.

Homeobox (HOX) genes are a superfamily of highly conserved genes with essential functions in many aspects of mammalian development. Their expression is tightly regulated throughout the duration of definitive hematopoiesis, so the pathogenetic mechanism that leads to leukemia suggests that malignant transformation is directly intertwined with the deregulation of HOX gene expression. Even though HOX gene involvement has been reviewed extensively in adult leukemias, childhood leukemias have received much less attention and mainly in the context of leukemias harboring MLL (mixed-lineage leukemia) gene translocations. In recent years, scientific evidence has highlighted HOX gene involvement in the development of other subtypes of childhood leukemias and added HOX gene family members that were previously unrelated to the pathogenesis of childhood leukemia. This has significant implications when considering both the risk stratification of pediatric patients and potential targets for successful therapy. Through the identification of HOX target genes, their resulting interactions, and the cognate signaling pathways, we hope to gain a better understanding of the molecular mechanism(s) underlying the ectopic activation of these genes in childhood leukemias and subsequently to reveal new molecular targets for successful therapy in cases of poor prognosis or resistant disease. © 2017 by Begell House, Inc.

MicroRNAs are small, non-coding RNAs which regulate post-transcriptionally hundreds of target mRNAs. Given that their expression is deregulated in several cancer types, they represent potential diagnostic, prognostic, and predictive biomarkers, as well as next-generation therapeutic targets. Nevertheless, the involvement of miRNAs in non-melanoma skin cancer, a cancer type with increasing prevalence, is not extensively studied, and their comprehensive characterization as regard to the initiation, promotion, and progression stages is missing. To this end, we exploited a well-established multistage mouse skin carcinogenesis model in order to identify miRNAs consistently implicated in different stages of skin carcinogenesis. The cell lines comprising this model were subjected to miRNA expression profiling using microarrays, followed by bioinformatics analysis and validation with Q-PCR, as well as treatment with miRNA modulators. We showed that among all deregulated miRNAs in our system, only a functionally coherent group consisting of the miR-200 family members and miR-205-5p displays a pattern of progressive co-downregulation from the early toward the most aggressive stages of carcinogenesis. Their overlapping, co-regulated putative targets are potentially inter-associated and, of these, the EMT-related Rap1a is overexpressed toward aggressive stages. Ectopic expression of miR-205-5p in spindle cancer cells reduces Rap1a, mitigates cell invasiveness, decreases proliferation, and delays tumor onset. We conclude that deregulation of this miRNA group is primarily associated with aggressive phenotypes of skin cancer cells. Restoration of the miR-205-5p member of this group in spindle cells reduces the expression of critical, co-regulated targets that favor cancer progression, thus reversing the EMT characteristics. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Glucocorticoids (GCs) are frequently used in anticancer combination regimens; however, their continuous use adds selective pressure on cancer cells to develop GC-resistance via impairment of the glucocorticoid receptor (GR), therefore creating a need for GC-alternatives. Based on the drug repurposing approach and the commonalities between inflammation and neoplasia, drugs that are either in late-stage clinical trials and/or already marketed for GC-refractory inflammatory diseases could be evaluated as GC-substitutes in the context of cancer. Advantageously, unlike new molecular entities currently being de novo developed to restore GC-responsiveness of cancer cells, such drugs have documented safety and efficacy profile, which overall simplifies their introduction in clinical cancer trials. In this study, we estimated the potential of a well-established, multistage, cell line-based, mouse skin carcinogenesis model to be exploited as an initial screening tool for unveiling covert GC-substitutes. First, we categorized the cell lines of this model to GC-sensitive and GC-resistant, in correlation with their corresponding GR status, localization, and functionality. We found that GC-resistance starts in papilloma stages, due to a dysfunctional GR, which is overexpressed, DNA binding-competent, but transactivation-incompetent in papilloma, squamous, and spindle stages of the model. Then, aided by this tool, we evaluated the ability of N-bromotaurine, a naturally occurring, small-molecule, nonsteroid anti-inflammatory drug which is under consideration for use interchangeably/in replacement to GCs in skin inflammations, to restore antiproliferative response of GC-resistant cancer cells. Unlike GCs, N-bromotaurine inhibited cell-cycle progression in GC-resistant cancer cells and efficiently synergized with cisplatin, thus indicating a potential to be exploited instead of GCs against cancer. © 2016 Elsevier Inc.

Schizophrenia (SZ) and cancer (Ca) have a broad spectrum of clinical phenotypes and a complex biological background, implicating a large number of genetic and epigenetic factors. SZ is a chronic neurodevelopmental disorder signified by an increase in the expression of apoptotic molecular signals, whereas Ca is conversely characterized by an increase in appropriate molecular signaling that stimulates uncontrolled cell proliferation. The rather low risk of developing Ca in patients suffering from SZ is a hypothesis that is still under debate. Recent evidence has indicated that microRNAs (miRNAs or miRs), a large group of small non-coding oligonoucleotides, may play a significant role in the development of Ca and major psychiatric disorders, such as SZ, bipolar disorder, autism spectrum disorders, suicidality and depression, through their interference with the expression of multiple genes. For instance, the possible role of let-7, miR-98 and miR-183 as biomarkers for Ca and SZ was investigated in our previous research studies. Therefore, further investigations on the expression profiles of these regulatory, small RNA molecules and the molecular pathways through which they exert their control may provide a plausible explanation as to whether there is a correlation between psychiatric disorders and low risk of developing C.a.

Ethnopharmacological relevance Cornus mas L. (cornelian cherry) fruits have been used for centuries as traditional cuisine and folk medicine in various countries of Europe and Asia. In folk medicines, the fruits and other parts of the plant have been used for prevention and treatment of a wide range of diseases such as diabetes, diarrhea, gastrointestinal disorders, fevers, rheumatic pain, skin and urinary tract infections, kidney and liver diseases, sunstroke, among others. This review provides a systematic and constructive overview of ethnomedicinal uses, chemical constituents and pharmacological activities of this plant as well as future research need for its commercial utilization as nutraceutical food supplement and medicine. Materials and methods This review is based on available literature on ethnomedicinal uses, phytochemical, pharmacological, toxicity and clinical studies on Cornus mas L. (cornelian cherry) fruits and other organs that was collected from electronic (SciFinder, PubMed, Science Direct and ACS among others) and library searches of books and journals. Results Versatile ethnomedicinal uses of the plant in different European and Asian countries have been reported. Phytochemical investigations on different parts of this plant have resulted in the identification of 101 compounds, among which anthocyanins, flavonoids and iridoids are the predominant groups. The crude extracts of fruits and other parts of the plant and their pure isolates exhibit a broad spectrum of pharmacological activities such as anti-microbial, anti-diabetic, anti-atherosclerotic, cyto-, hepato-, neuro- and renalprotective, antiplatelet and antiglaucomic activities. Anthocyanins, flavonoids, iridoids and vitamin C are the major bioactive constituents of the fruits. Fruits are non-toxic and safe food on acute toxicity studies in rat and human models. Clinical trials in diabetic type2 and hyperlipidemic patients showed significant trends of amelioration in sugar level, insulin secretion in diabetic patients and amelioration of lipid profile, apolipoprotein status and vascular inflammation in hyperlipidemic patients. Conclusion Based on our review, Cornus mas L. (cornelian cherry) fruits and leaves can be used mainly in the treatment of diabetes, obesity, atherosclerosis, skin diseases, gastrointestinal and rheumatic problems. Some indications from ethnomedicines have been validated by pharmacological activities of the fruits and its extracts/pure isolates. The reported data reveal that the fruits are a potential source for treatment of diabetes, obesity, hyperlipidemia and gastrointestinal disorders. Unfortunately, the pharmacological studies in these areas are still insufficient to substantiate these preventive effects in confirmatory trials on the mass-scale clinical settings. Future studies on mechanisms of action, bioavailability, pharmacokinetics and adverse effects of the extracts and their bioactive constituents as well as their effective doses and long term toxic effects in humans are needed for commercial applications of these extracts/isolates in modern medicines. The available literature showed that most of the activities of the extracts are due to their constituents, anthocyanins, flavonoids and other phenolics, iridoids and vitamins for their antioxidant and other properties. © 2016 Elsevier Ireland Ltd

Recent evidence supports a role of microRNAs in cancer and psychiatric disorders such as schizophrenia and bipolar disorder, through their regulatory role on the expression of multiple genes. The rather rare co-morbidity of cancer and schizophrenia is an old hypothesis which needs further research on microRNAs as molecules that might exert their oncosuppressive or oncogenic activity in the context of their role in psychiatric disorders. The expression pattern of a variety of different microRNAs was investigated in patients (N = 6) suffering from schizophrenia termed control, patients with a solid tumor (N = 10) and patients with both schizophrenia and tumor (N = 8). miRNA profiling was performed on whole blood samples using the miRCURY LNA microRNA Array technology (6th & 7th generation). A subset of 3 microRNAs showed a statistically significant differential expression between the control and the study groups. Specifically, significant down-regulation of the let-7p-5p, miR-98-5p and of miR-183-5p in the study groups (tumor alone and tumorand schizophrenia) was observed (p

Ptch1 is a key regulator of embryonic development, acting through the sonic hedgehog (SHH) signaling pathway. Ptch1 is best known as a tumor suppressor, as germline or somatic mutations in Ptch1 lead to the formation of skin basal cell carcinomas. Here we show that Ptch1 also acts as a lineage-dependent oncogene, as overexpression of Ptch1 in adult skin in K14Ptch FVB transgenic mice synergizes with chemically induced Hras mutations to promote squamous carcinoma development. These effects were not because of aberrant activation of SHH signaling by the K14Ptch FVB transgene, as developmental defects in the highest expressing transgenic lines were consistent with the inhibition of this pathway. Carcinomas from K14Ptch FVB transgenic mice had only a small number of nonproliferative Ptch1 transgene-positive cells, suggesting that the Ptch1 transgene is not required for tumor maintenance, but may have a critical role in cell-fate determination at the initiation stage. © 2013 The Society for Investigative Dermatology.

The DNA damage response (DDR) pathway and ARF function as barriers to cancer development. Although commonly regarded as operating independently of each other, some studies proposed that ARF is positively regulated by the DDR. Contrary to either scenario, we found that in human oncogene-transformed and cancer cells, ATM suppressed ARF protein levels and activity in a transcription-independent manner. Mechanistically, ATM activated protein phosphatase 1, which antagonized Nek2-dependent phosphorylation of nucleophosmin (NPM), thereby liberating ARF from NPM and rendering it susceptible to degradation by the ULF E3-ubiquitin ligase. In human clinical samples, loss of ATM expression correlated with increased ARF levels and in xenograft and tissue culture models, inhibition of ATM stimulated the tumour-suppressive effects of ARF. These results provide insights into the functional interplay between the DDR and ARF anti-cancer barriers, with implications for tumorigenesis and treatment of advanced tumours. © 2013 Macmillan Publishers Limited. All rights reserved.

Previous studies have suggested that schizophrenia is associ ated with a reduced risk of cancer. Genes that are involved in cell cycle regulation seem to have additional functions in post-mitotic neurons involved in neuronal migration and synaptic plasticity. MicroRNAs (miRNAs) play a dominant role in the regulation of gene expression in the central nervous system (CNS). Due to their involvement in a large number of CNS pathways, miRNAs pose as appealing molecules for further investigation, with potential diagnostic, prognostic and therapeutic value. In the present study, we investigated the potential association between cancer and schizophrenia in 2 patient sample groups. We analyzed a large number of miRNAs in a control group of 6 schizophrenic patients and a study group of 8 schizophrenic patients with a solid tumor. A comparison between the control and study groups showed that only miR-183 was differentially expressed. Specifically, a significant downregulation of miR-183 in the samples of the study group was observed. Although a larger sample size is required to validate this result for the general patient population, our findings provide a first indication that miR-183 may play a role in regulating the expression of other genes with onco-suppressor activity. Our results are in agreement with the theory that patients with schizophrenia may have a tumor suppressor gene or enhanced neuronal apoptotic activities. Further studies are required in order to shed light on the role of miRNAs and particularly, on the suppressive role of miR-183 in the neurobiological pathways involved in schizophrenia.

Inflammation is a double-edged sword presenting a dual effect on cancer development, from one hand promoting tumor initiation and progression and from the other hand protecting against cancer through immunosurveillance mechanisms. Cytokines are crucial components of inflammation, participating in the interaction between the cells of tumor microenvironment. A comprehensive study of the role of cytokines in the context of the inflammation-tumorigenesis interplay helps us to shed light in the pathogenesis of cancer. In this paper we focus on the role of cytokines in the development of genomic instability, an evolving hallmark of cancer. © 2012 Ioannis L. Aivaliotis et al.

To investigate the expression of RhoA, RhoB, RhoC, Rac1 and Cdc42 kinases in urothelial cell carcinoma (UCC) of the urinary bladder and determine the expression profile of 107 Rho-associated genes, including GTPases, GDIs, GAPs and GEFs.Rho expression was investigated using microarrays, qPCR and Western blotting in 77 UCC specimens with paired normal urothelium. Computational analysis was also performed on Gene Expression Omnibus datasets. Further microarray analysis was carried out for the expression profiling of the Rho-associated genes.RhoB mRNA and protein levels were significantly lower in UCC, suggesting a tumour-suppressor role. On the contrary, mRNA of RhoC and protein levels of RhoA, RhoC and Cdc42, respectively, were significantly higher in UCC vs. normal tissue. High Cdc42 mRNA levels correlated with worse overall survival (p=0.027), whereas high RhoB mRNA levels correlated both with better overall (p=0.0258) and cancer-specific (p=0.0272) survival. Computational analysis verified the expression profile of Rho kinases among superficial UCCs, muscle-invasive UCCs and normal tissues.The majority of the Rho-related genes showed over-expression in UCC vs. normal tissue. Alterations in RhoA, RhoB, RhoC, Rac1 and Cdc42 expression play a significant role in the genesis and progression of UCC of the urinary bladder.

Background/Aims: The brain-derived neurotrophic factor (BDNF) levels in serum and the central nervous system are altered in patients with schizophrenia, suggesting that changes in the expression of BDNF might contribute to the disease pathophysiology. Long duration of untreated psychosis (DUP) has been associated with poorer prognosis in patients with schizophrenia. Such a relationship of untreated psychosis to outcome may indicate a neurodegenerative process and may have important implications for understanding the pathophysiology of schizophrenia. Methods: In this study, we investigated the association between serum BDNF levels and DUP in a sample of drug-naïve patients in their first episode of schizophrenia (FEP). We investigated serum BDNF levels in a sample of 37 drug-naïve FEP patients and 21 matched healthy subjects. Results: The serum BDNF level in the sample of FEP was significantly reduced compared to the healthy subjects (18.87 ± 8.23 vs. 29.2 ± 7.73 ng/ml, t = 4.76, d.f. = 57, p = 0.01). A negative correlation was found between serum BDNF levels and DUP in the group of patients (r = -0.346, p = 0.036). Conclusions: Our findings indicate that low serum BDNF levels at the onset of schizophrenia were associated with a long DUP and this could reflect an acute neurodegenerative reaction during the untreated phase of psychosis. © 2010 S. Karger AG.

Osteosarcoma is the most common primary bone cancer. Mutations of the RB gene represent the most frequent molecular defect in this malignancy. A major consequence of this alteration is that the activity of the key cell cycle regulator E2F1 is unleashed from the inhibitory effects of pRb. Studies in animal models and in human cancers have shown that deregulated E2F1 overexpression possesses either "oncogenic" or " oncosuppressor" properties, depending on the cellular context. To address this issue in osteosarcomas, we examined the status of E2F1 relative to cell proliferation and apoptosis in a clinical setting of human primary osteosarcomas and in E2F1-inducible osteosarcoma cell line models that are wild-type and deficient for p53. Collectively, our data demonstrated that high E2F1 levels exerted a growth-suppressing effect that relied on the integrity of the DNA damage response network. Surprisingly, induction of p73, an established E2F1 target, was also DNA damage response-dependent. Furthermore, a global proteome analysis associated with bioinformatics revealed novel E2F1-regulated genes and potential E2F1-driven signaling networks that could provide useful targets in challenging this aggressive neoplasm by innovative therapies. Copyright © American Society for Investigative Pathology.

Sex steroids, through their receptors, have potent effects on the signal pathways involved in osteogenic or myogenic differentiation. However, a considerable segment of those signal pathways has a prominent role in epithelial neoplastic transformation. The capability to intervene locally has focused on specific ligands for the receptors. Nevertheless, many signals are mapped to interactions of steroid receptor motifs with heterologous regulatory proteins. Some of those proteins interact with the glucocorticoid receptor and other factors essential to cell fate. Interactions of steroid receptor domain motifs with heterologous proteins affect specific target pathways; consequently, manipulation of specified protein modules complexed with steroid receptors may be a next major step for enhancing molecular targeted therapeutics. In the future, intervention at specific sections of receptor primary sequence may prove therapeutically more efficient in targeting pathways of choice than ligand selectivity can be. © 2009 Wiley Periodicals, Inc.

Journal URL: http://cancerres.aacrjournals.org/

Journal URL: http://www.iiar-anticancer.org/main.php?id=2 p53 is an oncosuppressor protein, which acts via transcriptional and non-transcriptional mechanisms. The transcriptional function of p53 is mediated by specific responsive elements. In the present study we found active responsive elements, specific for the p53 within the 5'flanking region and within the first intron of the gene encoding for the CD59 membrane inhibitor of reactive lysis, and within the first intron of the gene encoding for the CD58 membrane protein (LFA-3). The results suggest that p53 may enhance the transcription of both CD59 and CD58 and imply a novel role for p53 as a direct regulator of the immune response.

Activating Transcription Factor-2 is a sequence-specific DNA-binding protein that belongs to the bZIP family of proteins and plays diverse roles in the mammalian cells. In response to stress stimuli, it activates a variety of gene targets including cyclin A, cyclin D and c-jun, which are involved in oncogenesis in various tissue types. ATF-2 expression has been correlated with maintenance of a cancer cell phenotype. However, other studies demonstrate an antiproliferative or apoptotic role for ATF-2. In this review, we summarize the signaling pathways that activate ATF-2, as well as its downstream targets. We examine the role of ATF-2 in carcinogenesis with respect to other bZIP proteins, using data from studies in human cancer cell lines, human tumours and mouse models, and we propose a potential model for its function in carcinogenesis, as well as a theoretical basis for its utility in anticancer drug design. © 2008 Wiley Periodicals, Inc.

Objective: To investigate the relative expression and the DNA-binding status of estrogen receptors α and β in fibroids and normal myometrial tissue to explore the molecular basis of altered estrogen responsiveness of leiomyomas. Design: Biopsy samples from uterine fibroids and adjacent normal myometrial tissue at the follicular phase of the menstrual cycle. Setting: Aretaieio University Hospital and the National Hellenic Research Foundation, Athens, Greece. Patient(s): Thirty-five patients who underwent hysterectomy or myomectomy because of myoma symptoms. Intervention(s): None. Main Outcome Measure(s): Deoxyribonucleic acid-binding status of estrogen receptors α and β. Result(s): The level of messenger RNA expression of estrogen receptor α and β and the level of estrogen receptor as a whole are increased on average to a similar extent in leiomyomas compared with normal myometrium. Occasionally, however, estrogen receptor α is disproportionately increased in leiomyomas, and this appears to increase the amount of estrogen receptor α that binds to the estrogen-responsive element of estrogen target genes as homodimer rather than as heterodimer with estrogen receptor β. Conclusion(s): The estrogen receptor α-to-estrogen receptor β expression ratio rather than the individual expression levels determines the fraction of DNA-binding homodimers of estrogen receptor α and possibly the growth potential of myomas. © 2008 American Society for Reproductive Medicine.

The accurate execution of DNA replication requires a strict control of the replication licensing factors hCdt1 and hCdc6. The role of these key replication molecules in carcinogenesis has not been clarified. To examine how early during cancer development deregulation of these factors occurs, we investigated their status in epithelial lesions covering progressive stages of hyperplasia, dysplasia, and full malignancy, mostly from the same patients. Abnormal accumulation of both proteins occurred early from the stage of dysplasia. A frequent cause of unregulated hCdc6 and hCdt1 expression was gene amplification, suggesting that these components can play a role per se in cancer development. Overexpression of hCdt1 and hCdc6 promoted rereplication and generated a DNA damage response, which activated the antitumor barriers of senescence and apoptosis. Generating an inducible hCdt1 cellular system, we observed that continuous stimulus by deregulated hCdt1 led to abrogation of the antitumor barriers and resulted in the selection of clones with more aggressive properties. In addition, stable expression of hCdc6 and hCdt1 in premalignant papilloma cells led to transformation of the cells that produced tumors upon injection into nude mice depicting the oncogenic potential of their deregulation. ©2007 American Association for Cancer Research.

We have isolated from the plant Onobrychis ebenoides three novel arylobenzofurans with binding affinity for the estrogen receptor. In this study, we evaluated these arylobenzofurans, namely ebenfuran I, ebenfuran II and ebenfuran III for their potential selective estrogen receptor modulator (SERM)-like properties. We examined their ability, (1) to induce the insulin growth factor binding protein-3 (IGFBP-3) in MCF-7 breast cancer cells, (2) to stimulate differentiation and mineralization of osteoblastic cell culture by histochemical staining for alkaline phosphatase, Alizarin Red-S staining and calcium levels in the supernatants and (3) to inhibit cell proliferation of cervical adenocarcinoma (Hela) cells by use of the MTT assay. An estrogen receptor mediated effect was investigated by carrying out chloramphenicol acetyl transferase (CAT) assay on transient MCF-7 transfectants. Estradiol and the "pure" antiestrogen ICI 182780 were included to serve as control samples of the estrogenic and antiestrogenic effect respectively. Our data reveal that ebenfuran II is a highly potent SERM, exhibiting antiestrogenic activity in breast cancer cells via the estrogen receptor, estrogenic effect on osteoblasts and no stimulatory effect on cervix adenocarcinoma cells. In conclusion, our study is the first to demonstrate that plant derived arylobenzofurans show a SERM profile and may be considered for the prevention and treatment of diseases such as breast cancer, cervical cancer and osteoporosis. © 2004 Elsevier Inc. All rights reserved.

Activating transcription factor (ATF)-2 is a member of the ATF/cyclic AMP-responsive element binding protein family of transcription factors. It has been shown, in vitro, to possess growth factor-independent proliferation and transformation capacity. The information concerning the involvement of ATF-2 in carcinogenesis is rather limited. In a previous report, we showed a progressive increase in the levels of various activator protein (AP)-1 components, including phosphorylated ATF-2, in a series of mouse skin cell lines that represented developmental stages of the mouse skin carcinogenesis system. In the present study, we examined in detail the role of ATF-2 in the development of mouse skin spindle cells A5 and CarB, which correspond to the late and most aggressive stage of the mouse skin carcinogenesis model. To address this issue, we overexpressed a dominant negative form of ATF-2 in the A5 and CarB cell lines and examined their behavior in vitro and in vivo at the molecular and cellular level. The stable transfectants expressed decreased levels of phosphorylated ATF-2 and c-Jun. Subsequently, we observed that dominant negative ATF-2 affected the composition and reduced the activity of AP-1. The above biochemical changes were followed, both in vitro and in vivo in BALB/c severe combined inummodeficient mice, by suppression of the aggressive characteristics of the A5 and CarB mouse skin spindle cells. We attributed this behavior to the significant down-regulation of cyclin D1, cyclin A, and ATF-3, known AP-1 targets implicated in cell cycle control and promotion. In conclusion, our findings underscore a key regulatory role of ATF-2 in tumor growth and progression of mouse skin tumors.

Intercellular adhesion molecule-1 (ICAM-1) is a crucial receptor in the cell-cell interaction, a process central to the reaction to all forms of injury. Its expression is upregulated in response to a variety of inflammatory/immune mediators, including cellular stresses. The NF-κB signalling pathway is known to be important for activation of ICAM-1 transcription. Here we demonstrate that ICAM-1 induction represents a new cellular response to p53 activation and that NF-κB inhibition does not prevent the effect of p53 on ICAM-1 expression after DNA damage. Induction of ICAM-1 is abolished after treatment with the specific p53 inhibitor pifithrin-α and is abrogated in p53-deficient cell lines. Furthermore, we map two functional p53-responsive elements to the introns of the ICAM-1 gene, and show that they confer inducibility to p53 in a fashion similar to other p53 target genes. These results support an NF-κB-independent role for p53 in ICAM-1 regulation that may link p53 to ICAM-1 function in various physiological and pathological settings.

Intron 1 of the human I-I-l ns gene possesses a polymorphism consisting of repetitions of the GGGCCT consensus. Three alleles have been reported at this locus. We confirmed that two, pi and PZ, display four and two repeats, respectively, with their internal sequence structure similar to that previously described. The third, P3, previously assigned as a three-unit repetition allele according to its electrophoretic mobility and with no other information regarding its internal structure, was also found. Sequence analysis of the P3 allele revealed that it consists of three perfect repeats of the GGGCCT consensus. This polymorphism is present only in human c-H-ras gene, although single hexanucleotide repeats are found scattered within intron 1 of this gene in rodents. Analysis of this locus in matched tumor/distant normal samples from. (i) 38 patients with nonsmall-cell lung carcinoma (NSCLC), and (ii) 35 patients with sporadic invasive breast carcinoma, revealed: (1) 6.6% and 19% loss of heterozygosity (LOH) respectively, and (2) 10.5% and 2.9% hexanucleotide instability (III) respectively, detected by the presence of shifted in length alleles. Shifted alleles exhibited altered internal sequence structure in comparison to normal ones, suggesting complex mutational events. The same pattern of alterations was also detected in tissues adjacent to lung adenocarcinomas and dysplasias adjacent to squamous cell carcinomas (7.7% LOH, 5.9% III), implying that abnormalities at this locus may be early events in lung carcinogenesis. The frequency of alterations (LOH vs. HI) was significantly different among NSCLC and breast cancer (P=.005), probably due to the different tumor biology of each system. Finally, altered mRNA expression of H-ras gene was detected in all cases with HI, but this finding was also observed in samples without I-II. In view of reports showing that elements in intron 1 of H-ras gene potentially influence its transcriptional regulation, from our results we cannot exclude that the hexanucleotide locus could be an element with possible involvement in expressional regulation of this gene. (C) 2001 Elsevier Science Tnc. All rights reserved.

Background: Recent in vitro studies provide evidence that the cell cycle molecules pRb, p53 and MDM2 form a tightly regulated protein network. In this study, Mle examined the relationship of this protein network in a series of non-small cell lung carcinomas (NSCLCs), with the kinetic parameters, including proliferative activity or proliferation index (PI) and apoptotic index (AI), and ploidy status of the tumors. Material and Methods: A total of 87 NSCLCs were examined using immunohistochemical and molecular methods in order to estimate the status of the pRb-p53-MDM2 network. The kinetic parameters and the ploidy status of the tumors were assessed by in situ assays. The possible associations between alterations of the network, kinetic parameters and ploidy status of the carcinomas were assessed with a series of statistical methods. Results: Aberrant expression of pRb (Ab) and overexpression of p53 (P) and MDM2 (P) proteins were observed in 39%, 57%, and 68% of the carcinomas, respectively. The comprehensive analysis revealed that concurrent alterations in all three cell cycle regulatory molecules were the most frequent pattern, pRb(Ab)/p53(P)/MDM2(P); this “full abnormal” phenotype represented approximately 27% of the cases. This immunoprofile obtained the highest PI/AI value; whereas, the “normal” phenotype was the lowest one (p = 0.004). Furthermore, the pattern pRb(Ab)/p53(P)/MDM2(P) acquired the highest PI (p < 0.001) and lowest AI (p < 0.001) scores. Interestingly, the groups of carcinomas with impaired expression of one or two molecules attained PI/Al ratio values clustered in a narrow range placed in the middle of the scores exhibited by the “normal” and “full abnormal” phenotypes. These tumors had significantly lower AI, but similar PI values, compared with those noticed in the normal pattern. Ln addition, it was observed that the pRb(Ab)/p53(P)/ MDM2(P) phenotype was also significantly associated with aneuploidy (p = 0.002) and a tendency was observed when the expression of two components was altered (p = 0.055). Conclusions: Our findings suggest that simultaneous deregulation of all members of the pRb-p53-MDM2 network confers an additive effect on tumor growth. The apoptotic pathway seems to be more susceptible to its defects than the cell proliferation machinery. The findings of the ploidy analysis, which are in parallel with those regarding the proliferative activity and the apoptotic rate study, further support the concept that these molecules constitute a tightly regulated network participating in cell cycle control and chromosomal stability.

The present study represents a continuation of previous works in which we observed that lung carcinomas co-expressing MDM2 protein and p53 mutants (mt p53) exhibited more aggressive behaviour. In the above studies, we suggested a ‘gain of function’ mechanism of mt p53 proteins based on the fact that the MDM2 gene possesses a p53-responsive element (MDM2-p53RE). In this study, to prove our hypothesis, we selected 12 cases from a series of 51 bronchogenic carcinomas. In these 12 cases, we examined the ability of the expressed mt p53 to bind the MDM2-p53RE and correlated the findings with MDM2 expression. Furthermore, we constructed four of these p53 mutants and studied their transactivation properties by co-transfecting them with a reporter plasmid carrying MDM2-p53RE in the p53 null non-small-cell lung carcinoma cell line (NSCLC) H1299. We observed mutant p53 protein DNA-binding activity, which depended on the nature and the position of the amino acid substitution. The fact that the cases with DNA-binding activity were accompanied with MDM2 protein isoforms’ overexpression is indicative of a ‘gain of function’ phenotype. This hypothesis was enforced by the findings of the transfection experiments, which revealed that certain p53 mutants enhanced the expression of the luciferase reporter gene either directly or indirectly via a dominant positive effect on the wild-type p53. In conclusion, this work is one first attempt to examine if the deregulation of the p53/MDM2 autoregulatory feedback loop is due to novel properties of certain p53 mutants in the specific environment of a subset of bronchogenic carcinomas.

Forty-one bronchogenic carcinomas were investigated for expression of MDM2 protein isoforms and their relationship to p53 protein levels and p53 gene alterations using molecular and immunohistochemical techniques. The findings were correlated with the pathological features of the carcinomas. MDM2 protein was overexpressed in 26 cases (63 per cent). Western blot analysis with two monoclonal antibodies, 1B10 and IF2, revealed three MDM2 protein isoforms, p90, p57 and p76/74. p90 and p57 are capable of interacting with p53 protein, while p76/74 is not. Various patterns of MDM2 isoforms were seen. Although no correlation between the patterns and pathological features was observed, lymph node metastases were more frequent in the cases with MDM2 overexpression (P < 0.005). In 3 out of 17 specimens of normal lung tissue examined, there was a low level of expression of p90. Molecular analysis revealed that MDM2 overexpression was a consequence of increased transcription rather than MDM2 gene amplification. p53 protein was overexpressed in 21 cases (51 per cent) and p53 gene alterations (mutations + allelic deletions) were detected in 23 patients (56 per cent). A high degree of concordance (76 per cent) between p53 mutations and p53 staining was noticed (P < 10-5). p53 gene alterations were significantly associated with lymph node disease (P < 0.01). MDM2 and p53 proteins were simultaneously detected in 21 cases (51 per cent), of which 17 (42 per cent) showed p53 and MDM2 overexpression. The latter group was positively correlated with p53 mutations (P < 0.05). A strong correlation between MDM2/p53 co-expression and lymph node metastases was observed (P < 0.001). The findings suggest that MDM2 overexpression is a common event in bronchogenic carcinoma. The selective expression of some MDM2 isoforms in neoplastic tissue and not in the surrounding normal areas underscores the pathological role of the various MDM2 products. Finally, the coexistence of MDM2 protein(s) and p53 aberrations (mutations and/or overexpression) in a subset of lung carcinomas may be indicative of a 'gain of function' phenotype, with more aggressive characteristics.