Metastasis is the process through which tumor cells spread from their primary site to other human body organs. The mechanism of metastasis is still a significant challenge in cancer management because more than 90% of cancer-associated fatalities occur due to metastasis of cancer. In this work, we present a novel idea of utilizing shear stress experienced by metastasizing cancer cells as an elegant means to deactivate the cancer cells. By making the cancer cells more susceptible to shear stresses that they usually experience during metastasis, this strategy aims to disrupt the metastatic process and inhibit the spread of cancer. The proposed approach involves microRNAs and reactive oxygen species as molecular mediators.

Computational analysis was performed to understand the interactions between messenger RNAs associated with reactive oxygen species and shear stress and the involvement of various non-coding RNAs in colon adenocarcinoma metastasis. Survival analysis and functional enrichment of the important microRNAs, survival analyses, and the OncoPrint of the significant messenger RNAs were investigated. Consequently, the physiological role of the RNAs was validated using published data. Ten noteworthy microRNA hubs were recognized; long-coding RNA CCAT2 was observed to connect with hsa-miR-20a-5p and hsa-miR-17-5p, and four circular RNAs were identified to be linked with hsa-miR-335. Ten modules, which included fifteen important microRNAs, were recognized, demonstrating their importance in the metastasis of COAD mediated by ROS and FSS. Subsequently, notable markers for overall survival (three messenger RNAs and ten microRNAs related to ROS and/or FSS), markers for metastasis-free survival (33 messenger RNAs), and 15 messenger RNAs with >10% gene modifications in TCGA COAD data were identified a may serve as promising therapeutic biomarkers in COAD metastasis.

The HCT116 colon cancer cells were exposed to a defined shear rate induced by a fabricated cone-and-plate device, and the resultant molecular changes were evaluated. The shear rate influenced the cells’ growth characteristics and enhanced the intracellular reactive oxygen species (superoxide and hydroxyl) levels. HCT116 cell growth was observed at specific shear rates of 0 and 0.63 s-1 but not at higher rates. Specific levels of hsa-miR-34a-5p and hsa-miR-335-5p showed downregulation and upregulation, respectively, under shear stress. The levels of these two shear-sensitive miRNAs and hsa-miR-26b-5p negatively correlated with specific intracellular hydroxyl radical levels. Reactive oxygen species-associated messenger RNAs, such as PMAIP1, and other mRNAs, such as HMGA1, RAN, RACGAP1, CD44, BIRC5, EZH2, and FASN, showed differential expression under shear stress.

Thus, targeting these shear-sensitive and reactive oxygen species-modulated microRNAs and possibly some messenger RNAs could be a potential approach to managing colon cancer metastasis.
Publications:

KrishnaPriya, S., Omer, S., Banerjee, S.*, Karunagaran, D., & Suraishkumar, G. K.* (2022). An integrated approach to understand fluid shear stress-driven and reactive oxygen species-mediated metastasis of colon adenocarcinoma through mRNA-miRNA-lncRNA-circRNA networks. Molecular Genetics and Genomics, 297(5), 1353–1370. https://doi.org/10.1007/s00438-022-01924-z
KrishnaPriya S., Pallavi S Nair, Prerna Bhalla, Karunagaran D., & Suraishkumar G. K.* (2023) Shear Stress and MicroRNAs: Toward Better Metastatic Cancer Management. Biotechnology Progress journal; e3396. https://doi.org/10.1002/btpr.3396