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 Pietro^{* 1} , Marco Ragusa^{* 1} , 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

¹Dipartimento 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

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

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

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

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

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

author email corresponding author email* Contributed equally

BMC Medical Genomics 2009, 2:20doi: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.