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Open Access Highly Accessed Research article

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

Cinzia Di Pietro1, Marco Ragusa1, Davide Barbagallo1, Laura R Duro1, Maria R Guglielmino1, Alessandra Majorana1, Rosario Angelica1, Marina Scalia1, Luisa Statello1, Loredana Salito1, Luisa Tomasello1, Salvo Pernagallo1, Salvo Valenti1, Vito D'Agostino1, Patrizio Triberio1, Igor Tandurella1, Giuseppe A Palumbo2, Piera La Cava2, Viviana Cafiso3, Taschia Bertuccio3, Maria Santagati3, Giovanni Li Destri4, Salvatore Lanzafame5, Francesco Di Raimondo2, Stefania Stefani3, Bud Mishra6 and Michele Purrello1*

Author Affiliations

1 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

2 Dipartimento di Scienze BioMediche, Sezione di Ematologia, Università di Catania, 95125 Catania, Italy

3 Dipartimento di Scienze Ginecologiche e Microbiologiche, Università di Catania, 95125 Catania, Italy

4 Dipartimento di Scienze Chirurgiche, Università di Catania, 95125 Catania, Italy

5 Dipartimento di Anatomia, Patologia Diagnostica, Medicina Legale, Igiene e Sanità Pubblica, Università di Catania, 95125 Catania, Italy

6 Courant Institute of Mathematical Sciences, New York University, New York, NY 10012, USA

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BMC Medical Genomics 2009, 2:20  doi:10.1186/1755-8794-2-20

Published: 30 April 2009

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.