Multidrug resistance gene 1 (MDR1), a key factor contributing to drug insensitivity, has been associated with treatment failure and poor prognoses in various cancers, including bladder urothelial carcinoma (UC). Here we show that positive Nkx2.8 expression was associated with better prognosis of UC patients received chemotherapy. Patients with positive Nkx2.8 expression had promising prognosis from adjuvant chemotherapy. Enforced expression of Nkx2.8 promotes drug sensitivity of UC cells. Mechanistic investigations showed that Nkx2.8 negatively regulated expression of MDR1 by binds directly to the MDR1 promoter and transcriptionally represses MDR1 expression. P-gp inhibitor reversed chemosensitivity inhibition by Nkx2.8 scilencing. In clinical UC specimens, expression of Nkx2.8 inversely correlated with P-gp expression, and UC patients with Nkx2.8 positivity and low P-gp expression displayed the best prognosis. Our findings uncovered a new mechanism of chemosensitivity in UC cells and proposing Nkx2.8-MDR1 axis as a novel candidate target for therapeutic intervention of UC.

多药耐药基因 1 (MDR1) 是导致药物不敏感的一个关键因素，与包括膀胱尿路上皮癌 (UC) 在内的各种癌症的治疗失败和预后不良有关。在这里，我们显示阳性 Nkx2.8 表达与接受化疗的 UC 患者的更好预后相关。Nkx2.8 表达阳性的患者辅助化疗预后良好。Nkx2.8 的强制表达促进 UC 细胞的药物敏感性。机制研究表明，Nkx2.8 通过直接结合 MDR1 负向调节 MDR1 的表达启动子并转录抑制 MDR1 表达。P-gp 抑制剂通过 Nkx2.8 沉默逆转化学敏感性抑制。在临床UC标本中，Nkx2.8的表达与P-gp的表达呈负相关，Nkx2.8阳性和低P-gp表达的UC患者预后最好。我们的研究结果揭示了 UC 细胞化学敏感性的新机制，并提出 Nkx2.8-MDR1 轴作为 UC 治疗干预的新候选靶点。