Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center of Cancer, Tianjin 300060, People's Republic of China.
Biol Chem. 2019 Mar 26;400(4):545-553. doi: 10.1515/hsz-2018-0292.
Osteosarcoma (OS) patients often exhibit pulmonary metastasis, which results in high patient mortality. Our present study established the doxorubicin (Dox) resistant human OS MG-63 and HOS cells and named them MG-63/Dox and HOS/Dox, respectively. The Dox resistant OS cells had greater invasion ability than that of parental cells. The expression of ZEB1, while not FOXM1, Snail, HIF-1α, or Sp1, was significantly increased in Dox resistant OS cells. Silencing of ZEB1 can attenuate the metastasis and increase Dox sensitivity of MG-63/Dox and HOS/Dox cells. The upregulation of ZEB1 can increase of the expression of interlukin-6 (IL-6). Anti-IL-6 inhibited the invasion and increase the Dox sensitivity of MG-63/Dox and HOS/Dox cells. There was no significant difference of ZEB1 mRNA between Dox resistant and control cells. The upregulation of ZEB1 in Dox resistant OS cells can be attributed to the increase of protein half-life. This was confirmed by results that the inhibitor of proteasomal degradation can increase ZEB1 in Dox resistant OS cells. Over expression of SIAH1 can inhibit the expression of ZEB1 and increase the Dox sensitivity of MG-63/Dox and HOS/Dox cells. Collectively, we confirmed that SIAH1 induced ZEB1 is involved in the Dox resistance of OS cells.
骨肉瘤（OS）患者常发生肺转移，导致患者死亡率高。本研究建立了多柔比星（Dox）耐药的人骨肉瘤 MG-63 和 HOS 细胞，并分别命名为 MG-63/Dox 和 HOS/Dox。耐药 OS 细胞的侵袭能力强于亲本细胞。耐药 OS 细胞中 ZEB1 的表达增加，而 FOXM1、Snail、HIF-1α或 Sp1 的表达不变。沉默 ZEB1 可减弱 MG-63/Dox 和 HOS/Dox 细胞的转移并增加 Dox 敏感性。ZEB1 的上调可增加白细胞介素 6（IL-6）的表达。抗 IL-6 可抑制侵袭并增加 MG-63/Dox 和 HOS/Dox 细胞的 Dox 敏感性。耐药和对照细胞之间 ZEB1 mRNA 无显著差异。Dox 耐药 OS 细胞中 ZEB1 的上调归因于蛋白半衰期的延长。蛋白酶体降解抑制剂的结果证实了这一点，该抑制剂可增加 Dox 耐药 OS 细胞中的 ZEB1。SIAH1 的过表达可抑制 ZEB1 的表达并增加 MG-63/Dox 和 HOS/Dox 细胞的 Dox 敏感性。总之，我们证实 SIAH1 诱导的 ZEB1 参与了 OS 细胞的 Dox 耐药性。
