Tumor suppressor lnc-CTSLP4 inhibits EMT and metastasis of gastric cancer by attenuating HNRNPAB-dependent Snail transcription.
Tumor suppressor lnc-CTSLP4 inhibits EMT and metastasis of gastric cancer by attenuating HNRNPAB-dependent Snail transcription.
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肿瘤抑制因子lnc-CTSLP4通过减弱HNRNPAB依赖的Snail转录来抑制胃癌的EMT和转移
DOI：
10.1016/j.omtn.2021.02.003
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发表时间：
2021-03-05
期刊：
影响因子：
--
通讯作者：
Su L
中科院分区：
文献类型：
--
作者：
Pan T;Yu Z;Jin Z;Wu X;Wu A;Hou J;Chang X;Fan Z;Li J;Yu B;Li F;Yan C;Yang Z;Zhu Z;Liu B;Su L
肿瘤转移是胃癌治疗的重要障碍，而上皮细胞向间质细胞转化（EMT）过程在胃癌转移的启动中起着关键作用。因此，本研究的目的是研究lnc-CTSLP 4在胃癌进展过程中的EMT过程中的调节。我们发现lnc-CTSLP 4在胃癌组织中的表达明显低于癌旁组织，其表达水平与胃癌局部浸润、TNM分期、淋巴结转移及预后密切相关。功能丧失和获得试验表明，lnc-CTSLP 4抑制GC细胞迁移，入侵，和EMT在体外，以及在体内腹膜传播。机制分析表明，lnc-CTSLP 4可以与Hsp 90 α/异质核核糖核蛋白AB（HNRNPAB）复合物结合，并招募E3-遍在蛋白连接酶ZFP 91来诱导HNRNPAB的降解，从而抑制Snail的转录激活，最终逆转GC细胞的EMT。综上所述，我们的研究结果表明，lnc-CTSLP 4在GC肿瘤组织中显著下调，并通过与Hsp 90 α相互作用和招募E3泛素连接酶ZFP 91来减弱HNRNPAB依赖的Snail转录，从而抑制GC细胞的转移潜力，这表明lnc-CTSLP 4可以作为转移性GC的预后生物标志物和治疗靶点。lnc-CTSLP 4在胃癌组织中表达显著下调，并通过与Hsp 90 α相互作用和募集E3-泛素连接酶ZFP 91而减弱HNRNPAB依赖的Snail转录，从而抑制胃癌细胞的转移潜能，表明lnc-CTSLP 4可作为转移性胃癌的预后生物标志物和治疗靶点。
Tumor metastasis is a crucial impediment to the treatment of gastric cancer (GC), and the epithelial-to-mesenchymal transition (EMT) program plays a critical role for the initiation of GC metastasis. Thus, the aim of this study is to investigate the regulation of lnc-CTSLP4 in the EMT process during GC progression. We found that lnc-CTSLP4 was significantly downregulated in GC tumor tissues compared with adjacent non-tumor tissues, and its levels in GC tumor tissues were closely correlated with tumor local invasion, TNM stage, lymph node metastasis, and prognosis of GC patients. Loss- and gain-of-function assays indicated that lnc-CTSLP4 inhibited GC cell migration, invasion, and EMT in vitro, as well as peritoneal dissemination in vivo. Mechanistic analysis demonstrated that lnc-CTSLP4 could bind with Hsp90α/heterogeneous nuclear ribonucleoprotein AB (HNRNPAB) complex and recruit E3-ubiquitin ligase ZFP91 to induce the degradation of HNRNPAB, thus suppressing the transcriptional activation of Snail and ultimately reversing EMT of GC cells. Taken together, our results suggest that lnc-CTSLP4 is significantly downregulated in GC tumor tissues and inhibits metastatic potential of GC cells by attenuating HNRNPAB-dependent Snail transcription via interacting with Hsp90α and recruiting E3 ubiquitin ligase ZFP91, which shows that lnc-CTSLP4 could serve as a prognostic biomarker and therapeutic target for metastatic GC. lnc-CTSLP4 is significantly downregulated in GC tumor tissues and inhibits metastatic potential of GC cells by attenuating HNRNPAB-dependent Snail transcription via interacting with Hsp90α and recruiting E3-ubiquitin ligase ZFP91, which shows that lnc-CTSLP4 could serve as a prognostic biomarker and therapeutic target for metastatic GC.
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