Abstract
Network biology has become a key tool in unravelling the mechanisms of complex diseases. Detecting dys-regulated subnetworks from molecular networks is a task that needs efficient computational methods. In this work, we constructed an integrated network using gene interaction data as well as protein–protein interaction data of differentially expressed genes derived from the microarray gene expression data. We considered the level of differential expression as well as the topological weight of proteins in interaction network to quantify dys-regulation. Then, a nature-inspired Smell Detection Agent (SDA) optimisation algorithm is designed with multiple agents traversing through various paths in the network. Finally, the algorithm provides a maximum weighted module as the optimum dys-regulated subnetwork. The analysis is performed for samples of triple-negative breast cancer as well as colorectal cancer. Biological significance analysis of module genes is also done to validate the results. The breast cancer subnetwork is found to contain (i) valid biomarkers including PIK3CA, PTEN, BRCA1, AR and EGFR; (ii) validated drug targets TOP2A, CDK4, HDAC1, IL6, BRCA1, HSP90AA1 and AR; (iii) synergistic drug targets EGFR and BIRC5. Moreover, based on the weight values assigned to nodes in the subnetwork, PLK1, CTNNB1, IGF1, AURKA, PCNA, HSPA4 and GAPDH are proposed as drug targets for further studies. For colorectal cancer module, the analysis revealed the occurrence of approved drug targets TYMS, TOP1, BRAF and EGFR. Considering the higher weight values, HSP90AA1, CCNB1, AKT1 and CXCL8 are proposed as drug targets for experimentation. The derived subnetworks possess cancer-related pathways as well. The SDA-derived breast cancer subnetwork is compared with that of tools such as MCODE and Minimum Spanning Tree, and observed a higher enrichment (75%) of significant elements. Thus, the proposed nature-inspired algorithm is a novel approach to derive the optimum dys-regulated subnetwork from huge molecular network.
Highlights
Communities are significant components that are found in networks, such as social networks and biological networks
To evaluate the significance of genes/proteins in the obtained module, we have considered a few techniques in literature, and the findings in comparison are given in 16 genes found within this module, extracted by Cytoscape, 11 genes were overlapped with genes found by our approach
We have proposed an optimisation framework to elucidate the dys-regulated subnetwork from a weighted network curated out of differentially expressed genes and the corresponding proteins
Summary
Communities are significant components that are found in networks, such as social networks and biological networks. Its constituent elements are highly interconnected to perform the intended function. The structural, as well as functional, aspects of biological systems are well represented as biological networks comprising of different biomolecular elements. These networks can encode knowledge about local molecular interaction as well as some higher-level cellular communication. Studies show that changes to the network properties are very much linked to the phenotypes, such as tumors and mendelian disorders [1]. Network data in the form of interactome, functional regulatory networks and gene co-expression networks, along with other public repositories, helped biologists to gain a deep understanding of variations in cellular processes.
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