Ma Wenjia, Cui Yan, Liu Min, Tan Zhigang, Jiang Yugang
Department of Neurosurgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hu'nan Province, China.
Aging (Albany NY). 2019 May 5;11(9):2670-2680. doi: 10.18632/aging.101939.
Overexpression of Tafazzin (TAZ), a mitochondrial protein, is often observed in many cancers. However, the association between aberrant expression of TAZ and drug resistance remains unclear. The aim of this study is to explore the role of TAZ in regulating the TRAIL resistance in glioma. We thus established the TRAIL resistance models on glioma by using the U87 and U251 cell lines (U87/R and U251/R). As the results, obvious overexpression of TAZ was observed in U87/R and U251/R cells. However, knockdown of TAZ increased the sensitivity of U87/R and U251/R cells to TRAIL-induced apoptosis. By contrast, expression of miR-125b was downregulated in U87/R and U251/R cells compared to the parental U87 and U251 cells. Furthermore, decrease of miR-125b was responsible for overexpression of TAZ, because the results of dual-luciferase reporter assays verified that TAZ was targeted by miR-125b. We then showed that enforced expression of miR-125b resensitized the U87/R and U251/R cells to TRAIL-dependent damage of mitochondria and activation of caspase-9 and -3. We demonstrated that overexpression of TAZ caused by downregulation of miR-125b promoted resistance of glioma cells to TRAIL. MiR-125b/TAZ axis may represent a potential strategy to reverse the TRAIL in glioma.
塔法兹蛋白（TAZ）是一种线粒体蛋白，在许多癌症中经常观察到其过表达。然而，TAZ异常表达与耐药性之间的关联仍不清楚。本研究的目的是探讨TAZ在调节胶质瘤对肿瘤坏死因子相关凋亡诱导配体（TRAIL）耐药中的作用。因此，我们使用U87和U251细胞系（U87/R和U251/R）建立了胶质瘤的TRAIL耐药模型。结果显示，在U87/R和U251/R细胞中观察到TAZ明显过表达。然而，敲低TAZ可增加U87/R和U251/R细胞对TRAIL诱导凋亡的敏感性。相比之下，与亲代U87和U251细胞相比，U87/R和U251/R细胞中miR-125b的表达下调。此外，miR-125b的减少是TAZ过表达的原因，因为双荧光素酶报告基因检测结果证实TAZ是miR-125b的靶标。然后我们表明，强制表达miR-125b可使U87/R和U251/R细胞对TRAIL依赖的线粒体损伤以及半胱天冬酶-9和-3的激活重新敏感。我们证明，miR-125b下调导致的TAZ过表达促进了胶质瘤细胞对TRAIL的耐药性。miR-125b/TAZ轴可能是逆转胶质瘤中TRAIL耐药的一种潜在策略。
