GALNT1-Mediated Glycosylation and Activation of Sonic Hedgehog Signaling Maintains the Self-Renewal and Tumor-Initiating Capacity of Bladder Cancer Stem Cells
GALNT1-Mediated Glycosylation and Activation of Sonic Hedgehog Signaling Maintains the Self-Renewal and Tumor-Initiating Capacity of Bladder Cancer Stem Cells
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GALNT1 介导的 Sonic Hedgehog 信号的糖基化和激活维持膀胱癌干细胞的自我更新和肿瘤启动能力
DOI：
10.1158/0008-5472.can-15-2309
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发表时间：
2016-03-01
期刊：
影响因子：
11.2
通讯作者：
Fan, Zusen
中科院分区：
文献类型：
--
作者：
Li, Chong;Du, Ying;Fan, Zusen
膀胱癌干细胞(BCSC)的存在是膀胱癌发生和复发的基础。Sonic Hedgehog(SHH)信号与促进肿瘤干细胞(CSC)自我更新有关，并在膀胱癌中被激活，但其对BCSC维持的影响尚不清楚。在这项研究中，我们制备了一种抗人膀胱癌CD44(+)细胞的单抗(BCMab1)，它识别异常糖基化的整合素α3β1。BCMab1与抗CD44抗体相结合，鉴定了BCMab1(+)CD44(+)细胞亚群具有干细胞样特性。基因表达分析表明，Hedgehog通路在BCMab1(+)CD44(+)亚群中被激活，是BCSC自我更新所必需的。此外，糖基转移酶GALNT1在BCMab1(+)CD44(+)细胞中高表达，并与膀胱癌的临床病理特征相关。从机制上讲，GALNT1介导SHH的O-连接糖基化促进其激活，这对BCSCs的自我更新维持和膀胱肿瘤的发生是必不可少的。最后，膀胱内注射GALNT1 siRNA和SHH抑制剂环丙胺对膀胱癌的生长有很强的抑制作用。综上所述，我们的发现确定了人类膀胱肿瘤中的BCSC亚群，似乎对GALNT1和SHH信号的抑制有反应，从而突出了预防膀胱癌患者典型的快速复发的潜在策略。(C)2016年AACR。
The existence of bladder cancer stem cells (BCSC) has been suggested to underlie bladder tumor initiation and recurrence. Sonic Hedgehog (SHH) signaling has been implicated in promoting cancer stem cell (CSC) self-renewal and is activated in bladder cancer, but its impact on BCSC maintenance is unclear. In this study, we generated a mAb (BCMab1) against CD44(+) human bladder cancer cells that recognizes aberrantly glycosylated integrin alpha 3 beta 1. The combination of BCMab1 with an anti-CD44 antibody identified a BCMab1(+)CD44(+) cell subpopulation as BCSCs with stem cell-like properties. Gene expression analysis revealed that the hedgehog pathway was activated in the BCMab1(+)CD44(+) subpopulation and was required for BCSC self-renewal. Furthermore, the glycotransferase GALNT1 was highly expressed in BCMab1(+)CD44(+) cells and correlated with clinicopathologic features of bladder cancers. Mechanistically, GALNT1 mediated O-linked glycosylation of SHH to promote its activation, which was essential for the self-renewal maintenance of BCSCs and bladder tumorigenesis. Finally, intravesical instillation of GALNT1 siRNA and the SHH inhibitor cyclopamine exerted potent antitumor activity against bladder tumor growth. Taken together, our findings identify a BCSC subpopulation in human bladder tumors that appears to be responsive to the inhibition of GALNT1 and SHH signaling, and thus highlight a potential strategy for preventing the rapid recurrence typical in patients with bladder cancer. (C)2016 AACR.