Ropivacaine combined with sorafenib attenuates hepatocellular carcinoma cell proliferation and metastasis by inhibiting the miR‐224/HOXD10 axis

Abstract

AbstractObjectiveThe development of drug resistance in hepatocellular carcinoma (HCC) cells limits the effectiveness of sorafenib (Sor). However, the regulatory mechanisms underlying the effects of the combination Sor and ropivacaine (Rop) on HCC cells remain unclear.MethodsmiR‐224 and HOXD10 mRNA expression in HCC cells was analyzed using qRT‐PCR. CCK‐8, Transwell assays and tumor formation experiments in nude mice were used to assess HCC cell proliferation, migration, and invasion. Migration of HCC cells was also analyzed using a cell scratch assay. Hematoxylin and eosin staining was used to detect tumor area.ResultsmiR‐224 expression profoundly increased in HepG2 and Huh7 cells. Treatment with Rop and/or Sor blocked miR‐244 expression, especially the combination treatment. Transfection of miR‐224 mimic increased HCC cell proliferation and tumor size in nude mice, and migration and invasion in vitro in the presence of Rop and Sor compared to the negative control mimic. Dual‐luciferase reporter assays showed that HOXD10 was targeted by miR‐224. HOXD10 protein expression and was markedly reduced in HepG2 and Huh7 cells. Rop and/or Sor treatment increased HOXD10 protein expression, particularly the combination treatment. miR‐224 negatively regulated HOXD10 expression in HCC cells treated with Rop and Sor. Transfection‐mediated silencing of HOXD10 increased HCC cell proliferation, migration, and invasion in the presence of Rop and Sor compared with negative control transfection.ConclusionThe combination of Rop and Sor attenuates HCC cell proliferation and metastasis via the miR‐224/HOXD10 axis.