Molecular pathways undergoing dramatic transcriptomic changes during tumor development in the human colon

BMC Cancer

Nicola Ancona⁴  Giancarlo Marra⁶  Angelo Andriulli³  Federico Buffoli¹  Teresa Staiano¹  Orazio Palumbo²  Massimo Carella²  Anna Panza³  Ada Piepoli³  Endre Laczko⁵  Elisa Cattaneo⁶  Vania Cosma Liuzzi⁴  Rosalia Maglietta⁴ 

[1]Endoscopy and Gastroenterology Unit, Hospital of Cremona, Cremona, Italy

[2]Servizio di Genetica Medica IRCCS “Casa Sollievo della Sofferenza” Ospedale, Viale Cappuccini, 71013, San Giovanni Rotondo, (FG), Italy

[3]Divisione di Gastroenterologia IRCCS “Casa Sollievo della Sofferenza” Ospedale, Viale Cappuccini, 71013, San Giovanni Rotondo, (FG), Italy

[4]Istituto di Studi sui Sistemi Intelligenti per l'Automazione - C.N.R., Via Amendola 122/D-I, 70126 Bari, Italy

[5]Functional Genomics Center, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland

[6]Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland

关键词: Random set method;    Cell cycle pathways;    Molecular pathways;    Transcriptomics;    Colorectal cancer;    Colorectal adenoma;   

Others  :  1080006
DOI  :  10.1186/1471-2407-12-608

 received in 2012-06-09, accepted in 2012-12-13,  发布年份 2012

【 摘 要 】

Background

The malignant transformation of precancerous colorectal lesions involves progressive alterations at both the molecular and morphologic levels, the latter consisting of increases in size and in the degree of cellular atypia. Analyzing preinvasive tumors of different sizes can therefore shed light on the sequence of these alterations.

Methods

We used a molecular pathway-based approach to analyze transcriptomic profiles of 59 colorectal tumors representing early and late preinvasive stages and the invasive stage of tumorigenesis. Random set analysis was used to identify biological pathways enriched for genes differentially regulated in tumors (compared with 59 samples of normal mucosa).

Results

Of the 880 canonical pathways we investigated, 112 displayed significant tumor-related upregulation or downregulation at one or more stages of tumorigenesis. This allowed us to distinguish between pathways whose dysregulation is probably necessary throughout tumorigenesis and those whose involvement specifically drives progression from one stage to the next. We were also able to pinpoint specific changes within each gene set that seem to play key roles at each transition. The early preinvasive stage was characterized by cell-cycle checkpoint activation triggered by DNA replication stress and dramatic downregulation of basic transmembrane signaling processes that maintain epithelial/stromal homeostasis in the normal mucosa. In late preinvasive lesions, there was also downregulation of signal transduction pathways (e.g., those mediated by G proteins and nuclear hormone receptors) involved in cell differentiation and upregulation of pathways governing nuclear envelope dynamics and the G2>M transition in the cell cycle. The main features of the invasive stage were activation of the G1>S transition in the cell cycle, upregulated expression of tumor-promoting microenvironmental factors, and profound dysregulation of metabolic pathways (e.g., increased aerobic glycolysis, downregulation of pathways that metabolize drugs and xenobiotics).

Conclusions

Our analysis revealed specific pathways whose dysregulation might play a role in each transition of the transformation process. This is the first study in which such an approach has been used to gain further insights into colorectal tumorigenesis. Therefore, these data provide a launchpad for further exploration of the molecular characterization of colorectal tumorigenesis using systems biology approaches.

【 授权许可】

   
2012 Maglietta et al.; licensee BioMed Central Ltd.

【 图 表 】

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