Loss of polarity protein Par3, via transcription factor Snail, promotes bladder cancer metastasis.
Loss of polarity protein Par3, via transcription factor Snail, promotes bladder cancer metastasis.
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通过转录因子 Snail 丧失极性蛋白 Par3 可促进膀胱癌转移
DOI：
10.1111/cas.14920
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发表时间：
2021-07
期刊：
影响因子：
5.7
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Wang S;Cai J;Zhang S;Dong M;Zhang L;Xu Y;Shen B;Chen S
膀胱癌（BLCA）仍然是全球泌尿生殖系统恶性肿瘤中癌症相关死亡的主要原因。BLCA转移是其预后不良的主要原因。在这项研究中，我们报道了分区缺陷3 （Par3）的表达降低，这是一种极性蛋白（Par3编码），与BLCA患者的肿瘤侵袭性表型和不良预后有关。在体外和体内，一致地，Par3的消融促进BLCA细胞的转移和侵袭。进一步的研究表明，锌指蛋白蜗牛通过结合Par3启动子近端E2 - box （CAGGTG）抑制Par3的表达。抑制GSK‐3β可促进Snail的表达和细胞核定位，进而降低Par3的表达，导致BLCA细胞转移和侵袭。此外，我们检测到Par3（936‐1356 aa）和ZO‐1（1372‐1748 aa）之间的相互作用，这参与了紧密连接的维持。总之，我们的研究结果表明，GSK‐3β/Snail/Par3/ZO‐1轴调控BLCA转移，而Snail是BLCA中Par3蛋白表达的主要调节因子。我们在这里报道(a)极性蛋白Par3在BLCA患者中经常丢失，并与肌肉侵袭性表型和不良预后相关；(b)体外和体内BLCA侵袭和转移需要Par3缺乏；(c) Snail通过结合Par3 E2‐box抑制Par3的表达；(d) Par3过表达可消除LiCl -或Snail -诱导的BLCA转移行为，提示GSK - 3β/Snail/Par3轴在调节BLCA转移中的作用。
Bladder cancer (BLCA) remains the leading cause of cancer‐related mortality among genitourinary malignancies worldwide. BLCA metastasis represents the primary reason for its poor prognosis. In this study, we report that decreased expression of partitioning defective 3 (Par3), a polarity protein (encoded by PARD3), is associated with tumor aggressive phenotypes and poor prognosis in BLCA patients. Consistently, ablation of Par3 promotes the metastasis and invasion of BLCA cells in vitro and in vivo. Further studies reveal that zinc finger protein Snail represses the expression of Par3 by binding to E2‐box (CAGGTG) of PARD3 promoter‐proximal. Inhibition of GSK‐3β promotes the expression and nuclear localization of Snail and then reduces the expression of Par3, resulting in the metastasis and invasion of BLCA cells. Moreover, we detected the interaction between Par3 (936‐1356 aa) and ZO‐1 (1372‐1748 aa), which is involved in the maintenance of tight junction. Together, our results demonstrate that the GSK‐3β/Snail/Par3/ZO‐1 axis regulates BLCA metastasis, and Snail is a major regulator for Par3 protein expression in BLCA. We report here that (a) polarity protein Par3 is frequently lost in BLCA patients and is associated with muscle‐invasive phenotypes and poor prognosis; (b) Par3 deficiency is required for BLCA invasion and metastasis in vitro and in vivo; (c) Snail suppresses Par3 expression through its binding to PARD3 E2‐box; and (d) overexpression of Par3 abolishes LiCl‐ or Snail‐induced BLCA metastatic behaviors, suggesting a role of the GSK‐3β/Snail/Par3 axis in regulating BLCA metastasis.