Abstract
Background: The mechanisms underlying low intensity ultrasound (LIUS) mediated suppression of inflammation and tumorigenesis remain poorly determined.Methods: We used microarray datasets from NCBI GEO Dataset databases and conducted a comprehensive data mining analyses, where we studied the gene expression of 299 cell death regulators that regulate 13 different cell death types (cell death regulatome) in cells treated with LIUS.Results: We made the following findings: (1) LIUS exerts a profound effect on the expression of cell death regulatome in cancer cells and non-cancer cells. Of note, LIUS has the tendency to downregulate the gene expression of cell death regulators in non-cancer cells. Most of the cell death regulator genes downregulated by LIUS in non-cancer cells are responsible for mediating inflammatory signaling pathways; (2) LIUS activates different cell death transcription factors in cancer and non-cancer cells. Transcription factors TP-53 and SRF- were induced by LIUS exposure in cancer cells and non-cancer cells, respectively; (3) As two well-accepted mechanisms of LIUS, mild hyperthermia and oscillatory shear stress induce changes in the expression of cell death regulators, therefore, may be responsible for inducing LIUS mediated changes in gene expression patterns of cell death regulators in cells; (4) LIUS exposure may change the redox status of the cells. LIUS may induce more of antioxidant effects in non-cancer cells compared to cancer cells; and (5) The genes modulated by LIUS in cancer cells have distinct chromatin long range interaction (CLRI) patterns to that of non-cancer cells.Conclusions: Our analysis suggests novel molecular mechanisms that may be utilized by LIUS to induce tumor suppression and inflammation inhibition. Our findings may lead to development of new treatment protocols for cancers and chronic inflammation.
Highlights
Ultrasound, alone or combined with contrast agent microbubbles, have numerous applications ranging from being a well-established diagnostic tool [1, 2] to a method of drug delivery [3]
The 31 cell death regulators that were downregulated by low intensity ultrasound (LIUS) treatment seem to attenuate several pro-inflammatory pathways including neuroinflammation signaling pathway, inflammasome pathway, NF-κB signaling, TREM1 signaling, role of pattern recognition receptors in recognition of bacteria and viruses, role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis, HMGB1 signaling, Toll-like receptor signaling, altered T cell and B cell signaling in rheumatoid arthritis, communication between innate and adaptive immune cells, hepatic fibrosis/hepatic stellate cell activation, type I diabetes mellitus signaling, and role of osteoblasts, osteoclasts and chondrocytes in rheumatoid arthritis (Figure 1). This data suggests that LIUS treatment may significantly impact the inflammatory status of non-cancer cells. These results suggest that first, LIUS exerts a profound effect on cell the gene expression of the cell death regulatome in cancer cells and non-cancer cells; second, LIUS treatment has the tendency to reduce the expression of cell death regulators than activating them in non-cancer cells; third, in non-cancer cells, the death regulators that are downregulated by LIUS attenuate several inflammatory signaling pathways
Most of the cell death regulator genes downregulated by LIUS in non-cancer cells are responsible for mediating inflammatory signaling pathways; [2] LIUS inhibits the expression of several inflammatory cell death regulators potentially via TP53, and serum response factor (SRF), mediated pathways in cancer cells and non-cancer cells, respectively; [3] Thermal effects and osmotic shear stress associated with LIUS may play a role in altering the cell death regulator expression patterns; [4] LIUS has the tendency to induce antioxidant effects in noncancer cells; and [5] The genes that were modulated in cancer cells by LIUS have unique chromatin long range interaction (CLRI) patterns, different from that of non-cancer cells
Summary
Ultrasound, alone or combined with contrast agent microbubbles, have numerous applications ranging from being a well-established diagnostic tool [1, 2] to a method of drug delivery [3]. The application of microbubbles and ultrasound to deliver nanoparticle carriers for drug and gene delivery is a research area that has expanded greatly in recent years. Ultrasound therapy now is widely used in clinical practice, and clinical/translational research in the treatment of various human malignancies and pathologies including breast cancer, leukemia, lymphoma, melanoma, pancreatic neuroendocrine tumors [8], hepatic cancer, nasopharyngeal cancers, glioma, ovarian cancer, colon cancer, gastric cancer [9], sarcoma [10,11,12], stroke [13], prostatic hyperplasia, renal masses [14], treatment of abdominal subcutaneous adipose tissue [15], bone repair [16], osteoarthritis [17], and carpal tunnel syndrome [18]. The mechanisms underlying low intensity ultrasound (LIUS) mediated suppression of inflammation and tumorigenesis remain poorly determined
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