The apoptotic machinery as a biological complex system: analysis of its omics and evolution, identification of candidate genes for fourteen major types of cancer, and experimental validation in CML and neuroblastoma

Pietro, Cinzia Di; Ragusa, Marco; Barbagallo, Davide; Duro, Laura R.; Guglielmino, Maria Rosa; Majorana, Alessandra; Angelica, Rosario; Scalia, Marina; Statello, Luisa; Salito, Loredana; Tomasello, Luisa; Pernagallo, Salvatore; Valenti, Salvo; D’Agostino, Vito; Triberio, Patrizio; Tandurella, Igor; Palumbo, Giuseppe A.; Cava, Piera La; Cafiso, Viviana; Bertuccio, Taschia; Santagati, Maria; G, Li Destri; Lanzafame, Salvatore; Raimondo, Francesco Di; Stefani, Stefania; Mishra, Bud; Purrello, Michele

doi:10.1186/1755-8794-2-20

Cited by 22 publications

(24 citation statements)

References 100 publications

(105 reference statements)

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“…In killifish, caspase-8 (CASP8) expression showed population-dependent upregulation (Fig.4R) upon hypo-osmotic challenge. CASP8 is a key regulator of the apoptotic cascade, is centrally located within the network of apoptotic machinery components (Di Pietro et al, 2009), and increased expression is associated with enhanced sensitivity to apoptosis (Jiang et al, 2008). Cyclin-dependent kinase 1 (CDK1) upregulation was correlated with CASP8 expression (Fig.4R).…”

Section: Apoptosismentioning

confidence: 98%

Salinity- and population-dependent genome regulatory response during osmotic acclimation in the killifish (Fundulus heteroclitus) gill

Whitehead

Roach

Zhang

et al. 2012

Journal of Experimental Biology

128

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SUMMARYThe killifish Fundulus heteroclitus is abundant in osmotically dynamic estuaries and it can quickly adjust to extremes in environmental salinity. We performed a comparative osmotic challenge experiment to track the transcriptomic and physiological responses to two salinities throughout a time course of acclimation, and to explore the genome regulatory mechanisms that enable extreme osmotic acclimation. One southern and one northern coastal population, known to differ in their tolerance to hypo-osmotic exposure, were used as our comparative model. Both populations could maintain osmotic homeostasis when transferred from 32 to 0.4p.p.t., but diverged in their compensatory abilities when challenged down to 0.1p.p.t., in parallel with divergent transformation of gill morphology. Genes involved in cell volume regulation, nucleosome maintenance, ion transport, energetics, mitochondrion function, transcriptional regulation and apoptosis showed population-and salinity-dependent patterns of expression during acclimation. Network analysis confirmed the role of cytokine and kinase signaling pathways in coordinating the genome regulatory response to osmotic challenge, and also posited the importance of signaling coordinated through the transcription factor HNF-4. These genome responses support hypotheses of which regulatory mechanisms are particularly relevant for enabling extreme physiological flexibility. Supplementary material available online at

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Section: Apoptosismentioning

confidence: 98%

Salinity- and population-dependent genome regulatory response during osmotic acclimation in the killifish (Fundulus heteroclitus) gill

Whitehead

Roach

Zhang

et al. 2012

Journal of Experimental Biology

128

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“…It has been noticed that the levels of mRNAs and the encoded proteins are often not overlapping. This could have a number of causes, such as posttranscriptional regulation (13). In this context, miRNAs could have a critical role in controlling the complex signaling activated by cues internal and external to the organism, including antitumoral therapeutic strategies (28).…”

Section: Discussionmentioning

confidence: 99%

“…Expression data in Results section are shown as natural logarithm (ln) of relative quantity (RQ) of miRNAs, normalized with respect to snRNA U6 from a calibrator sample (the time-matched untreated controls). To identify differentially expressed miRNAs, we applied a paired t test (or t test between subject in the comparison between cell lines) among DCt by using the following parameters: assumption of equal variance; a (overall threshold P value) ¼ 0.01; the P value was based on permutation; the significance was determined by the adjusted Bonferroni correction (13). We considered as up-or downregulated those genes that have a natural logarithm of expression fold change of at least 1 or greater and À1 or less, respectively.…”

Section: Expression Data Analysismentioning

confidence: 99%

Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Ragusa¹,

Majorana²,

Statello³

et al. 2010

Molecular Cancer Therapeutics

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The relationship between therapeutic response and modifications of microRNA (miRNA) transcriptome in colorectal cancer (CRC) remains unknown. We investigated this issue by profiling the expression of 667 miRNAs in 2 human CRC cell lines, one sensitive and the other resistant to cetuximab (Caco-2 and HCT-116, respectively), through TaqMan real-time PCR. Caco-2 and HCT-116 expressed different sets of miRNAs after treatment. Specifically, 21 and 22 miRNAs were differentially expressed in Caco-2 or HCT-116, respectively (t test, P < 0.01). By testing the expression of differentially expressed miRNAs in CRC patients, we found that miR-146b-3p and miR-486-5p are more abundant in K-ras-mutated samples with respect to wild-type ones (Wilcoxon test, P < 0.05). Sixty-seven percent of differentially expressed miRNAs were involved in cancer, including CRC, whereas 19 miRNA targets had been previously reported to be involved in the cetuximab pathway and CRC. We identified 25 transcription factors putatively controlling these miRNAs, 11 of which have been already reported to be involved in CRC. On the basis of these data, we suggest that the downregulation of let-7b and let-7e (targeting K-ras) and the upregulation of miR-17* (a CRC marker) could be considered as candidate molecular markers of cetuximab resistance. Global network functional analysis (based on miRNA targets) showed a significant overrepresentation of cancer-related biological processes and networks centered on critical nodes involved in epidermal growth factor receptor internalization and ubiquitin-mediated degradation. The identification of miRNAs, whose expression is linked to the efficacy of therapy, should allow the ability to predict the response of patients to treatment and possibly lead to a better understanding of the molecular mechanisms of drug response.

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“…Di Pietro et al 30 conducted an extensive study on Genomics, Transcriptomics, Table 10 where column number 1 lists the 13 different cancer types, column numbers 2-7 list the change in the levels of mRNA of proteins which are present in our model (extracted from Figure 7A in their paper) and the last column gives our simulation results. In this table 0 denotes no level change, and + and -denote up and downregulation (black, red and green regions, respectively, in their Figure 7A).…”

Section: Comparison Of Theoretical Results With Experimentsmentioning

confidence: 99%

“…We have also compared the experimental methods of Kim et al 29 with the theoretical predictions of our modified model. We also compared the predictions of our model with the experimental results compiled by di Pietro et al 30 from several databases. It should be emphasized that our focus in this study is on malfunction in apoptosis and resistance to treatments for it and not the much more complicated problem, chemotherapy resistance to cancer.…”

Section: Introductionmentioning

confidence: 95%

Analysis of a mathematical model of apoptosis: individual differences and malfunction in programmed cell death

Bagci

Şen

Çamurdan

2013

J Clin Monit Comput

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Apoptosis is an important area of research because of its role in keeping a mature multicellular organism's number of cells constant hence, ensuring that the organism does not have cell accumulation that may transform into cancer with additional hallmarks.Firstly, we have carried out sensitivity analysis on an existing mitochondria-dependent mathematical apoptosis model to find out which parameters have a role in causing monostable cell survival i.e., malfunction in apoptosis. We have then generated three healthy cell models by changing these sensitive parameters while preserving bistability i.e., healthy functioning. For each healthy cell, we varied the proapoptotic production rates, which were found to be among the most sensitive parameters, to yield cells that have malfunctioning apoptosis. We simulated caspase-3 activation, by numerically integrating the governing ordinary differential equations of a mitochondria-dependent apoptosis model, in a hypothetical malfunctioning cell which is treated by four potential

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The apoptotic machinery as a biological complex system: analysis of its omics and evolution, identification of candidate genes for fourteen major types of cancer, and experimental validation in CML and neuroblastoma

Cited by 22 publications

References 100 publications

Salinity- and population-dependent genome regulatory response during osmotic acclimation in the killifish (Fundulus heteroclitus) gill

Salinity- and population-dependent genome regulatory response during osmotic acclimation in the killifish (Fundulus heteroclitus) gill

Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Analysis of a mathematical model of apoptosis: individual differences and malfunction in programmed cell death

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