hsa-miR-631 resensitizes bortezomib-resistant multiple myeloma cell lines by inhibiting UbcH10
hsa-miR-631 resensitizes bortezomib-resistant multiple myeloma cell lines by inhibiting UbcH10
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hsa-miR-631 通过抑制 UbcH10 使硼替佐米耐药的多发性骨髓瘤细胞系重新敏感
DOI：
10.3892/or.2016.5318
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发表时间：
2017-02-01
期刊：
影响因子：
4.2
通讯作者：
Zhao, Li-Ming
中科院分区：
文献类型：
--
作者：
Xi, Hao;Li, Lu;Zhao, Li-Ming
虽然硼替佐米（BTZ）仍然是多发性骨髓瘤（MM）治疗的一线药物，但BTZ耐药的发展已成为MM患者预后不良的指标。因此，迫切需要制定策略，以恢复MM对BTZ的脆弱性。本研究首次证实UbcH 10在BTZ抗性骨髓瘤细胞系U-266/BTZ、NCI-H929/BTZ和RPMI-8226/BTZ中高度表达，这归因于转录后控制的失活。深入研究显示，在这些细胞中BTZ抗性的发展过程中，hsa-miR-631水平降低，这导致靶基因UbcHlO的表达增加。我们还发现，由于UbcH 10高表达导致MDR 1的遍在蛋白化减少，因此多重耐药蛋白MDR 1与UbcH 10呈正相关。在miR-631过表达后，耐药细胞中BTZ敏感性和BTZ诱导的凋亡均增强。同时，通过miR-631过表达的再敏化被不受细胞内miR-631调节的UbcH 10的外源性表达阻断。总之，miR-631/UbcH 10/MDR 1通路与骨髓瘤细胞BTZ耐药的发生密切相关，miR-631过表达可显著提高耐药骨髓瘤细胞BTZ敏感性。
Although bortezomib (BTZ) remains a first-line agent for multiple myeloma (MM) therapy, the development of BTZ resistance has become an indicator of poor prognosis in MM patients. It is thus urgent to develop strategies to restore the vulnerability of MM to BTZ. This study demonstrated, for the first time, that UbcHlO is highly expressed in BTZ-resistant myeloma cell lines U-266/BTZ, NCI-H929/BTZ and RPMI-8226/BTZ, which is attributed to the inactivation of post-transcriptional control. The in-depth study revealed that during the development of BTZ resistance in these cells, the hsa-miR-631 levels were decreased, which resulted in the increased expression of the target gene UbcHlO. We also found that the multiple drug-resistant protein MDR1 exhibited a positive correlation with UbcH10 due to the reduced ubiquitination of MDR1, which was caused by high UbcH10 expression. Following overexpression of miR-631, both BTZ sensitivity and BTZ-induced apoptosis were enhanced in the resistant cells. Meanwhile, resensitization by miR-631 overexpression was blocked by exogenous expression of UbcH10, which was not regulated by intracellular miR-631. In conclusion, the miR-631/UbcH10/MDR1 pathway is closely associated with the development of BTZ resistance in myeloma cells, and the overexpression of miR-631 can significantly improve BTZ sensitivity in resistant myeloma cells.