TGF-β-Induced Upregulation of malat1 Promotes Bladder Cancer Metastasis by Associating with suz12
TGF-β-Induced Upregulation of malat1 Promotes Bladder Cancer Metastasis by Associating with suz12
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DOI：
10.1158/1078-0432.ccr-13-1455
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发表时间：
2014-03-15
影响因子：
11.5
通讯作者：
Liu, Yong
中科院分区：
文献类型：
--
作者：
Fan, Yu;Shen, Bing;Liu, Yong
目的：转化生长因子-β通过诱导上皮-间充质转化(EMT)促进肿瘤侵袭和转移。然而，导致这一现象的潜在机制并不完全清楚。长非编码RNA(LncRNA)已被证明在癌症进展中发挥重要的调节作用。LncRNA MALAT1(转移相关肺腺癌转录本1)是肺癌细胞转移表型的关键调节因子。实验设计：因此，我们研究转化生长因子-β是否调节MALAT1的表达以促进膀胱癌的肿瘤转移。检测膀胱癌组织中MALAT1和EMT标志物的表达水平。通过细胞和动物模型评价MALAT1对膀胱癌转移的调控作用。结果：转化生长因子-β可诱导膀胱癌细胞MALAT1表达和EMT。MALAT1的过度表达与膀胱癌患者的不良生存密切相关。MALAT1和E-cadherin在体外和体内的表达呈负相关。MALAT1基因敲除可抑制转化生长因子-β诱导的EMT。MALAT1与ZEST12抑制因子(Suz12)相关，这种关联导致E-钙粘蛋白表达降低，N-钙粘蛋白和纤维连接蛋白表达增加。此外，靶向抑制MALAT1或Suz12可抑制由转化生长因子-β诱导的迁移和侵袭特性。最后，我们在动物模型中证实了MALAT1或suz12基因敲除抑制肿瘤转移。结论：MALAT1是转化生长因子-β诱导的EMT的重要介导者，MALAT1抑制可能是抑制膀胱癌进展的一种有前途的治疗选择。(C)2014年AACR。
Purpose: TGF-beta promotes tumor invasion and metastasis by inducing an epithelial-mesenchymal transition (EMT). However, the underlying mechanisms causing this are not entirely clear. Long noncoding RNAs (lncRNA) have been shown to play important regulatory roles in cancer progression. The lncRNA malat1 (metastasis associated lung adenocarcinoma transcript 1) is a critical regulator of the metastasis phenotype of lung cancer cells.Experimental Design: We, therefore, investigated whether TGF-beta regulates malat1 expression to promote tumor metastasis of bladder cancer. The expression levels of malat1 and EMT markers were assayed in specimens of bladder cancer. The role of malat1 in regulating bladder cancer metastasis was evaluated in cell and animal models.Results: TGF-beta induces malat1 expression and EMT in bladder cancer cells. malat1 overexpression is significantly correlated with poor survival in patients with bladder cancer. malat1 and E-cadherin expression is negatively correlated in vitro and in vivo. malat1 knockdown inhibits TGF-beta-induced EMT. malat1 is associated with suppressor of zeste 12 (suz12), and this association results in decrease of E-cadherin expression and increase of N-cadherin and fibronectin expression. Furthermore, targeted inhibition of malat1 or suz12 suppresses the migratory and invasive properties induced by TGF-beta. Finally, we demonstrated that malat1 or suz12 knockdown inhibits tumor metastasis in animal models.Conclusion: These data suggest that malat1 is an important mediator of TGF-beta-induced EMT, and suggest that malat1 inhibition may represent a promising therapeutic option for suppressing bladder cancer progression. (C)2014 AACR.