Knockdown of a novel lincRNA AATBC suppresses proliferation and induces apoptosis in bladder cancer
Knockdown of a novel lincRNA AATBC suppresses proliferation and induces apoptosis in bladder cancer
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新型 lincRNA AATBC 的敲低可抑制膀胱癌的增殖并诱导细胞凋亡
DOI：
10.18632/oncotarget.2833
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发表时间：
2015-01-20
期刊：
影响因子：
--
通讯作者：
Xie, Wenlian
中科院分区：
文献类型：
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作者：
Zhao, Fengjin;Lin, Tianxin;Xie, Wenlian
长基因间非编码RNA（lincRNA）在调节肿瘤的各种生物学过程中发挥重要作用，包括增殖和凋亡。然而，lincRNA在膀胱癌中的作用仍然难以捉摸。在这项研究中，我们发现了一种新的lincRNA，我们称之为AATBC。我们发现AATBC在膀胱癌患者组织中过表达，并与肿瘤分级和pT分期呈正相关。我们还发现，AATBC的抑制通过细胞周期蛋白D1，CDK 4，p18和磷酸化Rb介导的G1细胞周期导致细胞增殖停滞。此外，抑制AATBC通过内在凋亡信号通路诱导细胞凋亡，如通过半胱天冬酶-9和半胱天冬酶-3的活化所证明的。对信号通路的研究表明，AATBC敲低后的细胞凋亡是通过激活磷酸化JNK和抑制NRF 2介导的。此外，JNK抑制剂SP 600125可以减弱AATBC敲低所实现的凋亡效应，证实JNK信号转导参与诱导的凋亡。此外，小鼠异种移植模型显示，敲低AATBC导致抑制体内肿瘤发生。综上所述，我们的研究表明，AATBC可能通过调节细胞周期，内在凋亡信号，JNK信号和NRF 2在膀胱癌的促增殖和抗凋亡中发挥关键作用。AATBC可能成为膀胱癌潜在的治疗靶点和分子生物学标记物。
Long intergenic noncoding RNAs (lincRNAs) play important roles in regulating various biological processes in cancer, including proliferation and apoptosis. However, the roles of lincRNAs in bladder cancer remain elusive. In this study, we identified a novel lincRNA, which we termed AATBC. We found that AATBC was overexpressed in bladder cancer patient tissues and positively correlated with tumor grade and pT stage. We also found that inhibition of AATBC resulted in cell proliferation arrest through G1 cell cycle mediated by cyclin D1, CDK4, p18 and phosphorylated Rb. In addition, inhibition of AATBC induced cell apoptosis through the intrinsic apoptosis signaling pathway, as evidenced by the activation of caspase-9 and caspase-3. The investigation for the signaling pathway revealed that the apoptosis following AATBC knockdown was mediated by activation of phosphorylated JNK and suppression of NRF2. Furthermore, JNK inhibitor SP600125 could attenuate the apoptotic effect achieved by AATBC knockdown, confirming the involvement of JNK signaling in the induced apoptosis. Moreover, mouse xenograft model revealed that knockdown of AATBC led to suppress tumorigenesis in vivo. Taken together, our study indicated that AATBC might play a critical role in pro-proliferation and anti-apoptosis in bladder cancer by regulating cell cycle, intrinsic apoptosis signaling, JNK signaling and NRF2. AATBC could be a potential therapeutic target and molecular biomarker for bladder cancer.