Nkx2.8 promotes chemosensitivity in bladder urothelial carcinoma via transcriptional repression of MDR1.
Nkx2.8 promotes chemosensitivity in bladder urothelial carcinoma via transcriptional repression of MDR1.
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Nkx2.8 通过 MDR1 转录抑制促进膀胱尿路上皮癌的化疗敏感性
DOI：
10.1038/s41419-022-04947-x
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发表时间：
2022-05-24
影响因子：
9
通讯作者：
Yu, Chunping
中科院分区：
文献类型：
--
作者：
Zhou, Zhaohui;Xiong, Longbin;Wu, Zeshen;Jiang, Lijuan;Li, Yonghong;Li, Zhiyong;Peng, Yulu;Ning, Kang;Zou, Xiangpeng;Liu, Zefu;Wang, Jun;Li, Zhen;Zhou, Fangjian;Liu, Zhuowei;Zhang, Zhiling;Yu, Chunping
多药耐药基因1(MDR1)是导致药物不敏感的关键因素，在包括膀胱尿路上皮癌(UC)在内的多种癌症中与治疗失败和预后不良有关。我们的研究表明，Nkx2.8的阳性表达与接受化疗的UC患者的预后良好相关。Nkx2.8表达阳性的患者辅助化疗预后良好。Nkx2.8的表达增强了UC细胞对药物的敏感性。机制研究表明，Nkx2.8通过直接与mdr1启动子结合而负调控mdr1的表达，并在转录水平上抑制mdr1的表达。P-gp抑制剂通过Nkx2.8转录逆转化疗敏感性抑制。在UC临床标本中，Nkx2.8的表达与P-gp的表达呈负相关，Nkx2.8阳性、P-gp低表达的UC患者预后最好。我们的发现揭示了UC细胞化疗敏感性的新机制，并建议Nkx2.8-MDR1轴作为UC治疗干预的新候选靶点。
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.
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影响因子：
16.2
作者：
Feng, Rui-Mei;Zong, Yi-Nan;Xu, Rui-Hua
通讯作者：
Xu, Rui-Hua
影响因子：
158.5
作者：
Grossman, HB;Natale, RB;Crawford, ED
通讯作者：
Crawford, ED
影响因子：
2.9
作者：
TSAO, DHH;GRUSCHUS, JM;FERRETTI, JA
通讯作者：
FERRETTI, JA
影响因子：
45.3
作者：
von der Maase, H;Hansen, SW;Conte, PF
通讯作者：
Conte, PF
肿瘤抑制基因 Nkx2.8 通过上调 FOXO3a 和抑制 MEK/ERK 信号通路来抑制膀胱癌增殖
影响因子：
4.7
作者：
Yu, Chunping;Zhang, Zhiling;Song, Libing
通讯作者：
Song, Libing