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 remains elusive. Through gene expression profiling analysis, we observed that LINC00473, a long non-coding 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.

中文翻译：

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CRTC1-MAML2融合诱导的lncRNA LINC00473的表达维持了人类粘液表皮样癌细胞的生长和存活。

粘液表皮样癌（MEC）发生在许多腺体组织中，并导致最常见的恶性唾液腺癌。MEC与唯一的t（11; 19）易位特别相关，并且所产生的CRTC1-MAML2融合体是MEC启动和维持的主要致癌驱动因素。但是，CRTC1-MAML2致癌功能的分子基础仍然难以捉摸。通过基因表达谱分析，我们观察到LINC00473，一种长的非编码RNA（lncRNA），是CRTC1-MAML2缺失的人MEC细胞中最高的下调靶标。LncRNA属于一类新的非编码RNA，在肿瘤的发生和发展中起着新的作用，但仍表征不佳。在这项研究中，我们调查了LINC00473在介导人MEC中的CRTC1-MAML2致癌活性中的作用。我们发现LINC00473转录在人CRTC1-MAML2阳性MEC细胞系和原发性MEC肿瘤中被明显诱导，并且与CRTC1-MAML2 RNA水平紧密相关。LINC00473的诱导取决于CRTC1-MAML2激活CREB介导的转录的能力。LINC00473的耗尽在人MEC异种移植模型中显着降低了体外人MEC细胞的增殖和存活，并阻止了体内肿瘤的生长。RNA原位杂交分析证明了人MEC细胞中LINC00473的主要核定位模式。此外，基因表达谱分析显示，LINC00473耗竭导致对癌细胞生长和存活重要的基因差异表达。LINC00473可能部分地通过其与cAMP信号通路成分NONO结合的能力来调节基因表达，从而增强CRTC1-MAML2激活CREB介导的转录的能力。我们的总体结果表明，LINC00473是CRTC1-MAML2癌蛋白的下游靶标和重要介体。因此，LINC00473可作为人类CRTC1-MAML2阳性MEC的有前途的生物标志物和治疗靶标。