Low-intensity ultrasound enhances the chemosensitivity of hepatocellular carcinoma cells to cisplatin via altering the miR-34a/c-Met axis

Recently, the use of low-intensity ultrasound (LIUS) combined with chemotherapeutic agents is widely used in clinical practice, mainly for the treatment of cancer; however, the mechanisms as to how LIUS enhances the antitumor effects of these agents are not fully understood. The aim of the present study was to explore the synergistic antitumor effects and mechanisms of cisplatin (DDP) combined with LIUS (LIUS-DDP) in hepatocellular carcinoma (HCC). We reported that LIUS effectively enhanced Huh7 and HCCLM3 cell sensitivity to a low concentration of DDP. Reverse transcription-quantitative polymerase chain reaction analysis revealed that LIUS could increase the expression of microRNA-34a (miR-34a) in HCC cells following DDP treatment. In addition, LIUS-DDP significantly increased intracellular reactive oxygen species (ROS) levels in vitro, and the upregulation of miR-34a induced by LIUS-DDP was reversed by the ROS scavenger N-acetylcysteine, suggesting that LIUS upregulates the expression of miR-34a via production of ROS. In addition, knockdown of miR-34a in HCC cells significantly suppressed the synergistic effects of LIUS-DDP treatment. Conversely, overexpression of miR-34a enhanced these synergistic effects. The results of a dual-luciferase assay indicated that c-Met, a well-known oncogene, was a target of miR-34a. We also determined that LIUS-DDP treatment inhibited the expression of c-Met, possibly due to increased ROS production, which upregulated miR-34a expression. Furthermore, overexpression of c-Met reversed the synergistic effects of LIUS-DDP treatment. Our findings suggest that LIUS could enhance the chemosensitivity of HCC cells to DDP by altering the miR-34a/c-Met axis. Therefore, DDP combined with LIUS may be a potential therapeutic application for the clinical treatment of patients with HCC.