CRTC1-MAML2 fusion-induced lncRNA LINC00473 expression maintains the growth and survival of human mucoepidermoid carcinoma cells.
CRTC1-MAML2 fusion-induced lncRNA LINC00473 expression maintains the growth and survival of human mucoepidermoid carcinoma cells.
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DOI：
10.1038/s41388-017-0104-0
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发表时间：
2018-04
期刊：
影响因子：
8
通讯作者：
Wu L
中科院分区：
文献类型：
--
作者：
Chen Z;Lin S;Li JL;Ni W;Guo R;Lu J;Kaye FJ;Wu L
粘液表皮样癌（MEC）发生在许多腺组织中，是最常见的恶性唾液腺癌。MEC与独特的t（11;19）易位特异性相关，并且所产生的CRTC 1-MAML 2融合是MEC起始和维持的主要致癌驱动因素。然而，CRTC 1-MAML 2致癌功能的分子基础仍然非常有限。通过基因表达谱分析，我们观察到，LINC 00473，一个长的非编码RNA（lncRNA），是在CRTC 1-MAML 2耗尽的人MEC细胞的顶部下调的目标。lncRNA属于一类新的非编码RNA，在肿瘤发生和发展中具有新兴作用，但仍缺乏表征。在这项研究中，我们研究了LINC 00473在人MEC中介导CRTC 1-MAML 2致癌活性的作用。我们发现LINC 00473转录在人CRTC 1-MAML 2阳性MEC细胞系和原发性MEC肿瘤中被显著诱导，并且与CRTC 1-MAML 2 RNA水平密切相关。LINC 00473诱导依赖于CRTC 1-MAML 2激活CREB介导的转录的能力。LINC 00473的消耗显著降低了人MEC细胞的体外增殖和存活，并阻断了人MEC异种移植模型中的体内肿瘤生长。RNA原位杂交分析表明，LINC 00473在人MEC细胞中的主要核定位模式。此外，基因表达谱显示LINC 00473缺失导致癌细胞生长和存活中重要基因的差异表达。LINC 00473可能部分通过其结合cAMP信号传导途径组分NONO的能力来调节基因表达，从而增强CRTC 1-MAML 2激活CREB介导的转录的能力。我们的总体结果表明，LINC 00473是CRTC 1-MAML 2癌蛋白的下游靶点和重要介质。因此，LINC 00473作为人CRTC 1-MAML 2阳性MEC的有希望的生物标志物和治疗靶标。
Mucoepidermoid carcinoma (MEC) arises in many glandular tissues and contributes to the most common malignant salivary gland cancers. MEC is specifically associated with a unique t(11;19) translocation and the resulting CRTC1-MAML2 fusion is a major oncogenic driver for MEC initiation and maintenance. However, the molecular basis underlying the CRTC1-MAML2 oncogenic functions remain very limited. Through gene expression profiling analysis, we observed that LINC00473, a long noncoding RNA (lncRNA), was the top down-regulated target in CRTC1-MAML2-depleted human MEC cells. LncRNAs belong to a new class of non-coding RNAs with emerging roles in tumorigenesis and progression, but remain poorly characterized. In this study, we investigated the role of LINC00473 in mediating CRTC1-MAML2 oncogenic activity in human MEC. We found that LINC00473 transcription was significantly induced in human CRTC1-MAML2-positive MEC cell lines and primary MEC tumors, and was tightly correlated with the CRTC1-MAML2 RNA level. LINC00473 induction was dependent on the ability of CRTC1-MAML2 to activate CREB-mediated transcription. Depletion of LINC00473 significantly reduced the proliferation and survival of human MEC cells in vitro and blocked the in vivo tumor growth in a human MEC xenograft model. RNA in situ hybridization analysis demonstrated a predominantly nuclear localization pattern for LINC00473 in human MEC cells. Furthermore, gene expression profiling revealed that LINC00473 depletion resulted in differential expression of genes important in cancer cell growth and survival. LINC00473 likely regulates gene expression in part through its ability to bind to a cAMP signaling pathway component NONO, enhancing the ability of CRTC1-MAML2 to activate CREB-mediated transcription. Our overall results demonstrate that LINC00473 is a downstream target and an important mediator of the CRTC1-MAML2 oncoprotein. Therefore, LINC00473 acts as a promising biomarker and therapeutic target for human CRTC1-MAML2-positive MECs.
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非编码 RNA LINC00473 响应 cAMP 信号传导，介导人子宫内膜基质细胞的蜕膜化。
影响因子：
4.6
作者：
Liang XH;Deng WB;Liu YF;Liang YX;Fan ZM;Gu XW;Liu JL;Sha AG;Diao HL;Yang ZM
通讯作者：
Yang ZM
影响因子：
14.9
作者：
Moran VA;Perera RJ;Khalil AM
通讯作者：
Khalil AM
影响因子：
4.6
作者：
Dinh TA;Vitucci EC;Wauthier E;Graham RP;Pitman WA;Oikawa T;Chen M;Silva GO;Greene KG;Torbenson MS;Reid LM;Sethupathy P
通讯作者：
Sethupathy P
影响因子：
8
作者：
Chen, Z.;Chen, J.;Wu, L.
通讯作者：
Wu, L.
DOI：
10.1073/pnas.1319176111
发表时间：
2014-08-12
影响因子：
11.1
作者：
Amelio, Antonio L.;Fallahi, Mohammad;Conkright, Michael D.
通讯作者：
Conkright, Michael D.