Objective:: Oxaliplatin (OXA) is commonly used in combination therapy for patients with advanced hepatocellular carcinoma. While the emergence of acquired resistance dramatically reduces its efficacy. It was previously found that the sensitivity of drug-resistant hepatocellular carcinoma cells to OXA could be enhanced by a synthesized ethyl derivative (patented) of epigallocatechin-3-gallate, and also initially found that the reversal mechanism might be related to the miR-338-3p/HIF-1α/ TWIST pathway. In this study, the function of the miR-338- 3p/HIF-1α / TWIST pathway was investigated in OXA-resistant hepatocellular carcinoma cells, particularly its involvement in reversing chemoresistance mediated by EMT. Methods:: The cell viability, migration, invasion, and epithelial-mesenchymal transition markers of SMMC-7721 and SMMC-7721/OXA cells were measured using the MTT assay, wound healing assay, transwell assay, western blot, and qRT-PCR. The effects of miR-338-3p overexpression were evaluated by transfecting cells with miR-338-3p mimic or negative control mimic. Results and Discussion: The SMMC-7721/OXA cells exhibited an epithelial-mesenchymal transition phenotype, characterized by increased migration and invasion, reduced E-cadherin, and elevated vimentin expression. The miR-338-3p expression was dramatically downregulated in SMMC-7721/OXA cells. Overexpression of miR-338-3p enhanced OXA sensitivity, with the IC50 value of OXA decreasing from 51.23 μM to 19.26 μM, reversed the epithelialmesenchymal transition phenotype, and reduced the expression of hypoxia-inducible factor-1α and twist family bHLH transcription factor 1, key regulators of epithelial-mesenchymal transition. The results indicated that the miR-338-3p regulates epithelial-mesenchymal transition and chemoresistance in OXA-resistant hepatocellular carcinoma cells by targeting hypoxiainducible factor-1α and subsequently down-regulating twist family bHLH transcription factor 1. Conclusion:: This study implies that the resistance of SMMC-7721/OXA cells to OXA is likely related to the acquisition of the EMT phenotype. The up-regulating miR-338-3p could be a new treatment method for over-coming OXA resistance in hepatocellular carcinoma.
Huang et al. (Mon,) studied this question.