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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.

SIAH1/ZEB1/IL-6 axis is involved in doxorubicin (Dox) resistance of osteosarcoma cells