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An integrated approach to understand fluid shear stress-driven and reactive oxygen species-mediated metastasis of colon adenocarcinoma through mRNA-miRNA-lncRNA-circRNA networks

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Abstract

Development of colon adenocarcinoma (COAD) metastasis involves several mediators including fluid shear stress (FSS), intracellular ROS levels, and non-coding RNAs. In our present study, we identified and investigated the role of regulatory non-coding RNA molecules specifically involved in COAD metastasis and their association with FSS and ROS. Interactions between the mRNAs associated with FSS and ROS, the corresponding microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in COAD metastasis were used to generate the mRNA-miRNA-lncRNA-circRNA network. Experimental validation of the identified RNA hubs using quantitative real-time PCR demonstrated a direct effect of the FSS on their expression levels in cancer cells. FSS resulted in the downregulation of HMGA1 and RAN, as well as the upregulation of HSP90AA1, PMAIP1 and BIRC5. Application of shear stress also led to downregulation of hsa-miR-26b-5p and hsa-miR-34a-5p levels in HCT116 cells. Further, functional enrichment and survival analysis of the significant miRNAs, as well as the OncoPrint and the survival analyses of the selected mRNAs were performed. Subsequently, their functional role was also corroborated with existing literature. Ten significant miRNA hubs were identified, out of which hsa-miR-17-5p and hsa-miR-20a-5p were found to interact with lncRNA (CCAT2) while hsa-miR-335 was found to interact with four circRNAs. Fifteen significant miRNAs were identified in 10 different modules suggesting their importance in FSS and ROS-mediated COAD metastasis. Finally, 10 miRNAs and 3 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 may serve as promising therapeutic biomarkers in the COAD metastasis.

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Abbreviations

COAD:

Colon adenocarcinoma

GO:

Gene Ontology

FSS:

Fluid shear stress

ROS:

Reactive oxygen species

HCMDB:

Human cancer metastasis database

GEPIA:

Gene expression profiling interactive analysis

DE:

Differentially expressed

dbDEMC:

Database of differentially expressed microRNAs

TCGA:

The Cancer Genome Atlas

miRNA:

MicroRNA

lncRNA:

Long coding RNA

circRNA:

Circular RNA

miEAA:

MicroRNA Enrichment Analysis and Annotation

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Acknowledgements

The authors would like to thank Dr. Swagatika Sahoo, Department of Chemical Engineering, IIT Madras, India and Dr. Karthik Raman, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, IIT Madras, India for providing invaluable inputs to fine-tune and strengthen the analysis. We would also like to thank Priyanshu Sharma and Anand Kumar Patel, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, IIT Madras, India for providing useful suggestions in the analysis of real-time PCR results.

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Authors and Affiliations

  1. Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, IIT Madras, Chennai, 600036, India

    Siluveru KrishnaPriya, Sonal Omer, Satarupa Banerjee, Devarajan Karunagaran & G. K. Suraishkumar

  2. School of Bioscience and Technology, Vellore Institute of Technology, Vellore, India

    Satarupa Banerjee

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  1. Siluveru KrishnaPriya
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  2. Sonal Omer
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  3. Satarupa Banerjee
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Contributions

SK and SB conceptualized the work, processed the data and performed the network analysis. SK and SO performed the real-time PCR experiments and analyzed the data. DK and GK oversaw the work and provided directions to improve it. All the authors worked on the manuscript together.

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Correspondence to Satarupa Banerjee.

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Communicated by Martine Collart.

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438_2022_1924_MOESM1_ESM.docx

Supplementary file1 Supplementary Fig. 1a: Top 5 most significant Reactome pathways enriched with common miRNA interacting partners of FSS, ROS and HCMDB-COAD (p-value ≤ 0.05). Supplementary Fig. 1b: Top 5 most significant Gene Ontology terms enriched with common miRNA interacting partners of FSS, ROS and HCMDB-COAD (p-value ≤ 0.05). Supplementary Fig. 2a: ROS mRNA-mRNA-miRNA network. Supplementary Fig. 2b: FSS mRNA-mRNA-miRNA network. Supplementary Fig. 2c: HCMDB-COAD mRNA-mRNA-miRNA network. Supplementary Fig. 2d: Merged FRM mRNA-mRNA-miRNA network. Supplementary Fig. 3a: Degree based top 20 RNA hubs of ROS mRNA-mRNA-miRNA network. Supplementary Fig. 3b: Degree based top 20 RNA hubs of FSS mRNA-mRNA-miRNA network. Supplementary Fig. 3c: Degree based top 20 RNA hubs of HCMDB-COAD mRNA-mRNA-miRNA network. Supplementary Fig. 4: InteractiVenn diagram representing mRNA from degree-based top 20 hubs of individual FSS, ROS, HCMDB-COAD, merged FRM mRNA-mRNA-miRNA networks and the DE genes in COAD (GEPIA-TCGA-COAD). Supplementary Fig. 5: FRM COAD mRNA-miRNA-lncRNA-circRNA network. Supplementary Fig. 6: FRM COAD DE mRNA-DE miRNA-DE lncRNA-DE circRNA expression network. Supplementary Fig. 7: Module analysis using FRM mRNA-mRNA-miRNA network as the input: Extraction of modules showing direct association of identified miRNAs with either ROS and HCMDB-COAD or FSS and HCMDB-COAD. Supplementary Fig. 8: OncoPrint analysis of nine significant mRNAs associated with FSS, ROS, and HCMDB-COAD obtained using MSKCC metastasis data. (DOCX 2458 KB)

438_2022_1924_MOESM2_ESM.xlsx

Supplementary file2 Supplementary Table 1: Common and unique genes obtained from the InteractiVenn diagram representing genes associated with FSS, ROS, HCMDB-COAD and the DE genes in COAD (GEPIA-TCGA-COAD). Supplementary Table 2: Role of FSS- and ROS-associated genes in COAD metastasis based on a literature survey. Supplementary Table 3: List of 134 DE miRNAs (DE-miRs) – common among [DE miR COAD-FSS] and [DE miR COAD-ROS] and [DE miR COAD-HCMDB COAD]. Supplementary Table 4: Common miRNA-enriched pathways and their role in COAD metastasis based on a literature survey. Supplementary Table 5: List of miRNAs directly associated with FSS and ROS based on miEAA result data. Supplementary Table 6: Degree-based top 20 RNA hubs of ROS mRNA-mRNA-miRNA network. Supplementary Table 7: Degree-based top 20 RNA hubs of FSS mRNA-mRNA-miRNA network. Supplementary Table 8: Degree-based top 20 RNA hubs of HCMDB-COAD mRNA-mRNA-miRNA network. Supplementary Table 9: Degree-based top 20 RNA hubs of merged FRM mRNA-mRNA-miRNA network. Supplementary Table 10: Common mRNAs among top 20 degree-based hubs of individual FSS, ROS, HCMDB-COAD, FRM mRNA-mRNA-miRNA networks and the DE genes in COAD (GEPIA-TCGA-COAD). Supplementary Table 11: Degree-based top 20 RNA hubs of FRM COAD mRNA-miRNA- lncRNA-circRNA network. Supplementary Table 12: Degree-based top 20 RNA hubs of FRM COAD DE mRNA-DE miRNA-DE lncRNA-DE circRNA network. Supplementary Table 13: Variation of metastasis-free survival status of COAD patients with the expression levels of significant mRNAs associated with FSS and ROS. Supplementary Table 14: Variation of survival status of COAD patients with the expression levels of significant miRNAs and mRNAs associated with FSS and ROS using TCGA data. Supplementary Table 15: List of primers used in reverse transcription (RT) and quantitative real-time PCR (qRT-PCR) (XLSX 119 KB)

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KrishnaPriya, S., Omer, S., Banerjee, S. et al. An integrated approach to understand fluid shear stress-driven and reactive oxygen species-mediated metastasis of colon adenocarcinoma through mRNA-miRNA-lncRNA-circRNA networks. Mol Genet Genomics 297, 1353–1370 (2022). https://doi.org/10.1007/s00438-022-01924-z

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