Cancer is characterized by genomic instability leading to deletion or amplification of oncogenes or tumor suppressors. However, most of the altered regions are devoid of known cancer drivers. Here, we identify lncRNAs frequently lost or amplified in cancer. Among them, we found amplified lncRNA associated with lung cancer-1 (ALAL-1) as frequently amplified in lung adenocarcinomas. ALAL-1 is also overexpressed in additional tumor types, such as lung squamous carcinoma. The RNA product of ALAL-1 is able to promote the proliferation and tumorigenicity of lung cancer cells. ALAL-1 is a TNFα− and NF-κB–induced cytoplasmic lncRNA that specifically interacts with SART3, regulating the subcellular localization of the protein deubiquitinase USP4 and, in turn, its function in the cell. Interestingly, ALAL-1 expression inversely correlates with the immune infiltration of lung squamous tumors, while tumors with ALAL-1 amplification show lower infiltration of several types of immune cells. We have thus unveiled a pro-oncogenic lncRNA that mediates cancer immune evasion, pointing to a new target for immune potentiation.

中文翻译：

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拷贝数变化分析揭示lncRNA ALAL-1作为肺癌免疫逃避的调节因子

癌症的特征是基因组不稳定，导致癌基因或肿瘤抑制基因的缺失或扩增。然而，大多数改变的区域缺乏已知的癌症驱动因素。在这里，我们鉴定了癌症中经常丢失或扩增的 lncRNA。其中，我们发现与肺癌-1 (ALAL-1) 相关的扩增 lncRNA 在肺腺癌中经常扩增。ALAL-1 在其他肿瘤类型中也过度表达，例如肺鳞癌。ALAL-1的RNA产物能够促进肺癌细胞的增殖和致瘤性。ALAL-1 是一种 TNFα− 和 NF-κB 诱导的细胞质 lncRNA，与 SART3 特异性相互作用，调节蛋白质去泛素酶 USP4 的亚细胞定位，进而调节其在细胞中的功能。有趣的是，ALAL-1 表达与肺鳞状肿瘤的免疫浸润呈负相关，而 ALAL-1 扩增的肿瘤显示几种类型免疫细胞的浸润较低。因此，我们揭示了一种介导癌症免疫逃避的促癌lncRNA，为免疫增强指明了新的靶点。