Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Institute of Health Research of Navarra, Pamplona, Spain.
J Cell Biol. 2020 Sep 7;219(9). doi: 10.1083/jcb.201908078.
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.
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，我们鉴定出在癌症中经常丢失或扩增的 lncRNAs。在这些 lncRNAs 中，我们发现扩增的与肺癌相关的长非编码 RNA-1（ALAL-1）在肺腺癌中经常扩增。ALAL-1 在其他肿瘤类型中也过表达，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，它特异性地与 SART3 相互作用，调节蛋白去泛素化酶 USP4 的亚细胞定位，并进而调节其在细胞中的功能。有趣的是，ALAL-1 的表达与肺鳞癌的免疫浸润呈负相关，而扩增 ALAL-1 的肿瘤显示出几种免疫细胞浸润程度较低。我们因此揭示了一种促进癌发生的 lncRNA，它介导了癌症的免疫逃逸，为免疫增强提供了一个新的靶点。
