Hepatocellular carcinoma computational models identify key protein-complexes associated to tumor progression

Maxime Folschette (1, 2, 3, 4) , Vincent Legagneux (1) , Arnaud Poret (4) , Carito Guziolowski (4, 5) , Nathalie Théret (1, 2)

1 Irset - Institut de recherche en santé, environnement et travail
2 Dyliss - Dynamics, Logics and Inference for biological Systems and Sequences
3 IFB-CORE - Institut Français de Bioinformatique - UMS CNRS 3601
4 LS2N - Laboratoire des Sciences du Numérique de Nantes
5 ECN - École Centrale de Nantes

Motivation: Integrating genome-wide gene expression patient profiles with regulatory knowledge is a challenging task because of the inherent heterogeneity, noise and incompleteness of biological data. From the computational side, several solvers for logic programs are able to perform extremely well in decision problems for combinatorial search domains. The challenge then is how to process the biological knowledge in order to feed these solvers to win insights in a biological study. It requires formalizing the biological knowledge to give a precise interpretation of this information; currently, very few pathway databases offer this. The presented work proposes a workflow to generate novel computational predictions related to the state of expression or activity of biological molecules in the context of hepatocellular carcinoma (HCC) progression. Results: Our working base is a graph of 3,383 nodes and 13,771 edges extracted from the KEGG database, in which we integrate 209 differentially expressed genes between low and high aggressive HCC across 294 patients. Our computational model predicts the shifts of expression of 146 initially non-observed biological components. Our predictions were validated at 88% using a larger experimental dataset and cross-validation techniques. In particular, we focus on the protein-complexes predictions and show for the first time that NFKB1/BCL-3 complexes are activated in aggressive HCC. In spite of the large dimension of the reconstructed models, our analyses over the computational predictions discover a well constrained region where KEGG regulatory knowledge constrains gene expression of several biomolecules. These regions can offer interesting windows to perturb experimentally such complex systems.

Domaines: Bio-informatique [q-bio.QM]; Modélisation et simulation; Réseaux moléculaires [q-bio.MN]; Cancer

Maxime Folschette, Vincent Legagneux, Arnaud Poret, Carito Guziolowski, Nathalie Théret. Hepatocellular carcinoma computational models identify key protein-complexes associated to tumor progression. 2019. ⟨hal-02095930v2⟩