Non-coding RNAs in fluid shear stress-driven and reactive oxygen species-mediated colon cancer metastasis

Background: Colon adenocarcinoma (COAD) is the third most common cancer in the world. Fluid shear stress (FSS) and intracellular reactive oxygen species (ROS) levels are known to mediate COAD metastasis. The present work was performed to explore the role of regulatory non-coding RNA molecules associated with FSS and ROS in COAD metastasis. Methods: The interactions between the mRNAs associated with FSS and ROS, the corresponding miRNAs, lncRNAs and circRNAs in COAD metastasis were used to generate the mRNA-miRNA-lncRNA-circRNA network. The expression levels of the RNAs in the network were also considered besides the identification of RNA hubs and modules. Further, functional enrichment and survival analysis of the significant miRNAs together with the OncoPrint as well as survival analysis of the selected mRNAs were performed. Subsequently, their functional role was also corroborated with existing literature. Results: Ten significant miRNA hubs were identified, out of which hsa-miR-17-5p and hsa-miR-20a-5p were found to interact with a lncRNA, CCAT2 and hsa-miR-335 was found to interact with four circRNAs. 60% of the FSS and ROS associated mRNAs and 90% of the top ten miRNA-enriched pathways that emerged from the functional analysis were reported to be involved in COAD metastasis. 15 significant miRNAs were identified in ten different modules suggesting their importance in FSS and ROS mediated COAD metastasis. Finally, ten miRNAs and three mRNAs associated with FSS and/or ROS were identified as significant overall survival markers; 33 mRNAs were also identified as metastasis-free survival markers whereas 15 mRNAs showed >10% gene alterations in TCGA-COAD data and hence emerged as significant molecular markers in the process. Conclusion: We hypothesize that the biologically significant RNAs identified in this integrated analysis may provide valuable insights to understand the molecular mechanism of the FSS driven and ROS mediated COAD metastasis and to design efficient treatment strategies.