Tumor necrosis factor-related apoptotic induction ligand can induce cell apoptosis in various tumor cells. However, many cancer cells are resistant to tumor necrosis factor-related apoptotic induction ligand. Therefore, overcoming the tumor necrosis factor-related apoptotic induction ligand resistance makes it possible for tumor necrosis factor-related apoptotic induction ligand-based anti-cancer therapies. In this study, we took mesenchymal epithelial transition factor as the research target to study its role in tumor necrosis factor-related apoptotic induction ligand-resistant hepatocellular carcinoma. Mesenchymal epithelial transition factor gene has been proved to be an effective predictor of recurrence after hepatocellular carcinoma resection. The expression of mesenchymal epithelial transition factor and cyclin B1 were measured in tumor necrosis factor-related apoptotic induction ligand-resistant and non-resistant hepatocellular carcinoma tissues. Cyclin B1-knockdown and cyclin B1-overexpression hepatocellular carcinoma cells were treated with tumor necrosis factor-related apoptotic induction ligand; mesenchymal epithelial transition factor knockout, mesenchymal epithelial transition factor re-introduction and cyclin B1 restored in hepatocellular carcinoma cells treated with tumor necrosis factor-related apoptotic induction ligand were established. And MTT, bromodeoxyuridine, flow cytometry and western blotting were performed to evaluate the effect of mesenchymal epithelial transition factor and cyclin B1 on hepatocellular carcinoma cells treated with tumor necrosis factor-related apoptotic induction ligand. In addition, subcutaneous tumor transplantation in nude mice was conducted to access the effect of mesenchymal epithelial transition factor and cyclin B1 on tumor formation in vivo. In conclusion, cyclin B1 enhanced the cell growth and inhibited apoptosis in tumor necrosis factor-related apoptotic induction ligand-resistant hepatocellular carcinoma cells. And mesenchymal epithelial transition factor promoted the cell growth and apoptosis in tumor necrosis factor-related apoptotic induction ligand-resistant hepatocellular carcinoma cells by regulating cyclin B1. Therefore, mesenchymal epithelial transition factor regulates the cyclin B1 to regulate tumor necrosis factor-related apoptotic induction ligand resistance in hepatocellular carcinoma cells. Our results suggest a novel molecular mechanism for regulating tumor necrosis factor-related apoptotic induction ligand resistance, which might be helpful to select drug targets in the treatment of liver cancer.

肿瘤坏死因子相关的凋亡诱导配体可诱导多种肿瘤细胞凋亡。然而，许多癌细胞对肿瘤坏死因子相关的凋亡诱导配体具有抗性。因此，克服肿瘤坏死因子相关的凋亡诱导配体耐药性，为肿瘤坏死因子相关的凋亡诱导配体的抗癌治疗提供了可能。本研究以间充质上皮转化因子为研究靶点，研究其在肿瘤坏死因子相关凋亡诱导配体耐药肝细胞癌中的作用。间充质上皮转化因子基因已被证明是肝细胞癌切除术后复发的有效预测因子。在肿瘤坏死因子相关的凋亡诱导配体抗性和非抗性肝细胞癌组织中测量间充质上皮转化因子和细胞周期蛋白 B1 的表达。用肿瘤坏死因子相关的凋亡诱导配体处理细胞周期蛋白B1-knockdown和细胞周期蛋白B1-过表达肝癌细胞；建立了用肿瘤坏死因子相关的凋亡诱导配体处理的肝细胞癌细胞中间充质上皮转化因子敲除、间充质上皮转化因子重新引入和细胞周期蛋白B1恢复。还有 MTT，溴脱氧尿苷，进行流式细胞术和蛋白质印迹以评估间充质上皮转化因子和细胞周期蛋白B1对用肿瘤坏死因子相关的凋亡诱导配体处理的肝细胞癌细胞的影响。此外，还进行了裸鼠皮下肿瘤移植，以了解间充质上皮转化因子和细胞周期蛋白B1对肿瘤形成的影响体内。总之，细胞周期蛋白B1增强了肿瘤坏死因子相关的凋亡诱导配体抗性肝细胞癌细胞的细胞生长并抑制了细胞凋亡。间充质上皮转化因子通过调节细胞周期蛋白B1促进肿瘤坏死因子相关凋亡诱导配体耐药肝细胞癌细胞的生长和凋亡。因此，间充质上皮转化因子通过调节细胞周期蛋白 B1 来调节肝细胞癌细胞中肿瘤坏死因子相关的凋亡诱导配体抗性。我们的研究结果提出了一种调控肿瘤坏死因子相关凋亡诱导配体抗性的新分子机制，这可能有助于选择治疗肝癌的药物靶点。