A Database Mining Approach To Identify The Mechanism Of Low Intensity Ultrasound Therapy In Cancer And Non-Cancer Diseases

Background:LIUS is a form of ultrasound that delivered intensity lower than 3 W/cm2,and it is widely used in clinical practice and clinical/translational research for promoting bone-fracture healing,accelerating soft-tissue regeneration,inhibiting inflammatory responses and suppressing cancer.LIUS was reported to induce apoptosis,autophagy or necrosis in cancer cells including nasopharyngeal cancer cells,laryngeal cancer cells,hepatocellular cancer cells,leukemia cells,lymphoma cells,and osteosarcoma cells.In contrast,LIUS was reported to promote cell proliferation,affect cell differentiation in various non-cancer cells for bone-fracture healing,accelerating soft-tissue regeneration.However,it remains unclear how LIUS can distinguish cancer cells from non-cancer cells and induce differential biological responses.Further,molecular and cellular mechanisms underlying LIUS therapy in cancer and non-cancer diseases are not understood.Objective:In the study,the possible molecular and cellular mechanisms that LIUS therapy in cancer and non-cancer diseases will be investigated by comparing the expressions of cell death regulator genes,ROS generating enzyme,antioxidant enzymes and chromosome conformation regulators.Methods:1)we determined the gene expression of 299 cell death regulators that regulate13 different cell death types of LIUS treatment in lymphoma U937 cells,MC3T3-E1 pre-osteoblast cells and bone marrow cells.The differentially expressed genes were identified and uploaded into IPA for analyzing the molecular and cellular pathways;2)we determined the expression of 22 oxidant stress genes that including ROS generating enzymes and antioxidant enzymes of LIUS treatment in lymphoma U937 cells,MC3T3-E1 pre-osteoblast cells and bone marrow cells;3)we determined the gene expression of 299 cell death regulators that regulate13 different cell death types of mild hyperthermia and Oscillatory shear stress treatment in lymphoma U937 cells,fibroblast OUMS-36 cells and human lymphatic endothelial cells.The differentially expressed genes were identified and uploaded into IPA for analyzing the molecular and cellular pathways;and 4)We extracted the data related to interact gene and interaction sites interacting with LIUS regulated-cell death genes from 4D Genome database,then calculated the distances between the interaction sites and LIUS-modulated gene promoters.Results:1)LIUS exerts a profound effect on the expression of cell death regulators in cancer cells and non-cancer cells.Of note,LIUS has the tendency to downregulate 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 treatment in cancer cells promote ROS generation by promoting the gene expression of NOX1,NOX3 and NOS2.LIUS has the tendency to induce antioxidant effects in non-cancer cells by attenuating the gene expression of NOS2 and NOS3,which promote ROS generation,while promoting the expression of antioxidant genes GPX3 and GPX7;3)Thermal effects and non-thermal effects associated with LIUS may promote cell death regulator gene expression changes in cancer cells and non-cancer cells.Non-thermal effects of LIUS such as OSS may mainly be responsible for inducing biological effects observed in non-cancer cells;and 4)The genes modulated by LIUS in cancer cells have distinct chromatin long range interaction patterns to that of non-cancer cells.Conclusions:1)LIUS exerts cancer suppressing effects by promoting apoptosis,autophagy and immune regulatory signaling pathways,which results in cancer cells death.However,it shows tissue repair by inhibiting inflammation-related signaling pathways,which reduces non-cancer cells proptosis.2)LIUS exerts cancer suppressing effects by inducing ROS generation,which result in cancer cells death.However,it shows tissue repair by reduced oxidative stress in non-cancer diseases.3)Thermal effect may play an indispensable role for the LIUS induced modulation of cell death regulators.Non-thermal effects of LIUS may be responsible for inducing biological effects observed in non-cancer cells.4)LIUS may modulate chromatin long range interactions to regulate gene expression in cancer cells and non-cancer cells.