Abstract
Cancer metastasis is a disease of extreme clinical relevance, as it is responsible for more than 90% of cancer-associated mortality. The molecular mechanism and critical regulators involved in this complex multi-stage process of metastasis is poorly deciphered in soft tissue sarcomas (STS), a heterogeneous group of rare tumors with high metastatic potential. Therefore, we aimed at identifying miRNA and transcription factor (TF) regulatory networks and paths in STS metastasis. We integrated mRNA and miRNA expression profiles with curated regulations (TF→gene, TF→miRNA, miRNA→gene) from different databases and constructed a potentially active regulatory sub-network in STS metastasis. From functional and topological analysis, we found nine novel regulators of Notch signaling sub-network which are conjectured to play critical role in metastasis of STS. This illustrated that the sub-network is promising for identification of critical regulators. Further analysis deploying our developed tool ‘RiNAcyc’ and computing coverage ratio of known STS associated genes and miRNAs identified a 15 node active path. This potential path highlights the crucial role of BMP2, hsa-miR-24, AP2 and MYC as the up-stream regulators of the path and hsa-miR-215 and TYMS as potential indicator of chemotherapeutic benefit in STS metastasis.
Highlights
Chibon and his colleagues identified a set of 67 genes termed as complexity index in sarcomas (CINSARC) which are predicted to be involved in mitosis and chromosome integrity and can predict metastatic outcomes in STS4
Functional analysis of the differentially expressed (DE) genes and miRNAs using Metacore TM resulted in 47 genes and 11 miRNAs to be involved in metastasis of cancers
Only 21 genes and 2 miRNAs mapped to the transcription factor (TF)-miRNA regulatory network as seed nodes
Summary
Unraveling novel TF-miRNA regulatory crosstalk in metastasis of Soft Tissue Sarcoma. Devyani Samantarrai, Mousumi Sahu, Jyoti Roy, Bedanta Ballav Mohanty, Garima Singh, Chandra Bhushan & Bibekanand Mallick. We amalgamated expression profiles of different STSs, curated data on various regulatory interactions (TFRgene, TFRmiRNA, miRNARgene) from different databases to identify potentially active sub-network (PASN) from a larger bio-molecular network which might be active during metastasis of STS Integrating these with known STS related genes and miRNAs to improve prediction accuracy followed by network topology and functional studies, we were able to find potentially significant STS metastasis specific paths, hubs and regulators from the network. In addition to finding acylic paths, we generated a sub-network from the components of a core pathway, the Notch signaling pathway and identified novel regulatory components which might participate in STS metastasis-specific Notch signaling This signaling is more alluring for investigation as this highly conserved pathway is reported to be involved in developmental processes, proliferation, apoptosis and play critical role in modulating other oncogenic signaling besides its role in sarcoma invasion and metastasis[16,17,18]. This miRNA-TF regulatory network generation and path analysis, first of its kind in STS will provide a framework for further understanding and targeting crucial step in STS progression to harness these for therapeutics
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