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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.

Di Pietro C, Ragusa M, Barbagallo D, Duro LR, Guglielmino MR, Majorana A, Angelica R, Scalia M, Statello L, Salito L, Tomasello L, Pernagallo S, Valenti S, D'Agostino V, Triberio P, Tandurella I, Palumbo GA, La Cava P, Cafiso V, Bertuccio T, Santagati M, Li Destri G, Lanzafame S, Di Raimondo F, Stefani S, Mishra B, Purrello M - BMC Med Genomics (2009)

Bottom Line: This project exploited the methodology commonly used in Computational Biology (i.e., mining of many omics databases of the web) as well as the High Throughput biomolecular analytical techniques.The comparison of the fourteen mutated AM networks (both protein- as MIR-based) has allowed us to pinpoint the hubs with a general and critical role in tumour development and, conversely, in cell physiology: in particular, we found that some of these had already been used as targets for pharmacological anticancer therapy.This approach could pave the way for future studies and applications in molecular and clinical Medicine with important perspectives both for Oncology as for Regenerative Medicine.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dipartimento di Scienze BioMediche, Sezione di Biologia Generale, Biologia Cellulare, Genetica Molecolare G Sichel, Unità di Biologia Genomica e dei Sistemi Complessi, Genetica, Bioinformatica, Università di Catania, 95123 Catania, Italy. dipietro@unict.it

ABSTRACT

Background: Apoptosis is a critical biological phenomenon, executed under the guidance of the Apoptotic Machinery (AM), which allows the physiologic elimination of terminally differentiated, senescent or diseased cells. Because of its relevance to BioMedicine, we have sought to obtain a detailed characterization of AM Omics in Homo sapiens, namely its Genomics and Evolution, Transcriptomics, Proteomics, Interactomics, Oncogenomics, and Pharmacogenomics.

Methods: This project exploited the methodology commonly used in Computational Biology (i.e., mining of many omics databases of the web) as well as the High Throughput biomolecular analytical techniques.

Results: In Homo sapiens AM is comprised of 342 protein-encoding genes (possessing either anti- or pro-apoptotic activity, or a regulatory function) and 110 MIR-encoding genes targeting them: some have a critical role within the system (core AM nodes), others perform tissue-, pathway-, or disease-specific functions (peripheral AM nodes). By overlapping the cancer type-specific AM mutation map in the fourteen most frequent cancers in western societies (breast, colon, kidney, leukaemia, liver, lung, neuroblastoma, ovary, pancreas, prostate, skin, stomach, thyroid, and uterus) to their transcriptome, proteome and interactome in the same tumour type, we have identified the most prominent AM molecular alterations within each class. The comparison of the fourteen mutated AM networks (both protein- as MIR-based) has allowed us to pinpoint the hubs with a general and critical role in tumour development and, conversely, in cell physiology: in particular, we found that some of these had already been used as targets for pharmacological anticancer therapy. For a better understanding of the relationship between AM molecular alterations and pharmacological induction of apoptosis in cancer, we examined the expression of AM genes in K562 and SH-SY5Y after anticancer treatment.

Conclusion: We believe that our data on the Apoptotic Machinery will lead to the identification of new cancer genes and to the discovery of new biomarkers, which could then be used to profile cancers for diagnostic purposes and to pinpoint new targets for pharmacological therapy. This approach could pave the way for future studies and applications in molecular and clinical Medicine with important perspectives both for Oncology as for Regenerative Medicine.

No MeSH data available.


Related in: MedlinePlus

Correlation between drug targeting and betweenness of nodes. yFiles Circular Layout of AM network that emphasizes the nodes with high betweenness. The nodes with high betweenness are localized on the left half of the circle (blue colour and highest density of the edges). These proteins are characterized by their propensity to be drug targets, as shown with the major size of nodes.
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Figure 15: Correlation between drug targeting and betweenness of nodes. yFiles Circular Layout of AM network that emphasizes the nodes with high betweenness. The nodes with high betweenness are localized on the left half of the circle (blue colour and highest density of the edges). These proteins are characterized by their propensity to be drug targets, as shown with the major size of nodes.

Mentions: By plotting the available data related to drugs targeted at the AM network, we found that most of AM proteins targeted by drugs were characterized by high connectivity; particularly, there was a highly significant association between the betweenness of these proteins and their being targets of drugs (p < = 0.004072, Wilcoxon Signed-Rank Test) (Figure 15).


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.

Di Pietro C, Ragusa M, Barbagallo D, Duro LR, Guglielmino MR, Majorana A, Angelica R, Scalia M, Statello L, Salito L, Tomasello L, Pernagallo S, Valenti S, D'Agostino V, Triberio P, Tandurella I, Palumbo GA, La Cava P, Cafiso V, Bertuccio T, Santagati M, Li Destri G, Lanzafame S, Di Raimondo F, Stefani S, Mishra B, Purrello M - BMC Med Genomics (2009)

Correlation between drug targeting and betweenness of nodes. yFiles Circular Layout of AM network that emphasizes the nodes with high betweenness. The nodes with high betweenness are localized on the left half of the circle (blue colour and highest density of the edges). These proteins are characterized by their propensity to be drug targets, as shown with the major size of nodes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2683874&req=5

Figure 15: Correlation between drug targeting and betweenness of nodes. yFiles Circular Layout of AM network that emphasizes the nodes with high betweenness. The nodes with high betweenness are localized on the left half of the circle (blue colour and highest density of the edges). These proteins are characterized by their propensity to be drug targets, as shown with the major size of nodes.
Mentions: By plotting the available data related to drugs targeted at the AM network, we found that most of AM proteins targeted by drugs were characterized by high connectivity; particularly, there was a highly significant association between the betweenness of these proteins and their being targets of drugs (p < = 0.004072, Wilcoxon Signed-Rank Test) (Figure 15).

Bottom Line: This project exploited the methodology commonly used in Computational Biology (i.e., mining of many omics databases of the web) as well as the High Throughput biomolecular analytical techniques.The comparison of the fourteen mutated AM networks (both protein- as MIR-based) has allowed us to pinpoint the hubs with a general and critical role in tumour development and, conversely, in cell physiology: in particular, we found that some of these had already been used as targets for pharmacological anticancer therapy.This approach could pave the way for future studies and applications in molecular and clinical Medicine with important perspectives both for Oncology as for Regenerative Medicine.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dipartimento di Scienze BioMediche, Sezione di Biologia Generale, Biologia Cellulare, Genetica Molecolare G Sichel, Unità di Biologia Genomica e dei Sistemi Complessi, Genetica, Bioinformatica, Università di Catania, 95123 Catania, Italy. dipietro@unict.it

ABSTRACT

Background: Apoptosis is a critical biological phenomenon, executed under the guidance of the Apoptotic Machinery (AM), which allows the physiologic elimination of terminally differentiated, senescent or diseased cells. Because of its relevance to BioMedicine, we have sought to obtain a detailed characterization of AM Omics in Homo sapiens, namely its Genomics and Evolution, Transcriptomics, Proteomics, Interactomics, Oncogenomics, and Pharmacogenomics.

Methods: This project exploited the methodology commonly used in Computational Biology (i.e., mining of many omics databases of the web) as well as the High Throughput biomolecular analytical techniques.

Results: In Homo sapiens AM is comprised of 342 protein-encoding genes (possessing either anti- or pro-apoptotic activity, or a regulatory function) and 110 MIR-encoding genes targeting them: some have a critical role within the system (core AM nodes), others perform tissue-, pathway-, or disease-specific functions (peripheral AM nodes). By overlapping the cancer type-specific AM mutation map in the fourteen most frequent cancers in western societies (breast, colon, kidney, leukaemia, liver, lung, neuroblastoma, ovary, pancreas, prostate, skin, stomach, thyroid, and uterus) to their transcriptome, proteome and interactome in the same tumour type, we have identified the most prominent AM molecular alterations within each class. The comparison of the fourteen mutated AM networks (both protein- as MIR-based) has allowed us to pinpoint the hubs with a general and critical role in tumour development and, conversely, in cell physiology: in particular, we found that some of these had already been used as targets for pharmacological anticancer therapy. For a better understanding of the relationship between AM molecular alterations and pharmacological induction of apoptosis in cancer, we examined the expression of AM genes in K562 and SH-SY5Y after anticancer treatment.

Conclusion: We believe that our data on the Apoptotic Machinery will lead to the identification of new cancer genes and to the discovery of new biomarkers, which could then be used to profile cancers for diagnostic purposes and to pinpoint new targets for pharmacological therapy. This approach could pave the way for future studies and applications in molecular and clinical Medicine with important perspectives both for Oncology as for Regenerative Medicine.

No MeSH data available.


Related in: MedlinePlus