Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.
Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Bologna, Italy.
PLoS One. 2022 Jan 11;17(1):e0261464. doi: 10.1371/journal.pone.0261464. eCollection 2022.
The expression of non-coding RNAs (ncRNAs) is dysregulated in human cancers. The transcribed ultraconserved regions (T-UCRs) express long ncRNAs involved in human carcinogenesis. T-UCRs are non-coding genomic sequence that are 100% conserved across humans, rats and mice. Conservation of genomic sequences across species intrinsically implies an essential functional role and so we considered the expression of T-UCRs in lung cancer. Using a custom microarray we analyzed the global expression of T-UCRs. Among these T-UCRs, the greatest variation was observed for antisense ultraconserved element 83 (uc.83-), which was upregulated in human lung cancer tissues compared with adjacent non cancerous tissues. Even though uc.83- is located within the long intergenic non-protein coding RNA 1876 (LINC01876) gene, we found that the transcribed uc.83- is expressed independently of LINC01876 and was cloned as a 1143-bp RNA gene. In this study, functional analysis confirmed important effects of uc.83- on genes involved in cell growth of human cells. siRNA against uc.83- decreased the growth of lung cancer cells while the upregulation through a vector overexpressing the uc.83- RNA increased cell proliferation. We also show the oncogenic function of uc.83- is mediated by the phosphorylation of AKT and ERK 1/2, two important biomarkers of lung cancer cell proliferation. Based on our findings, inhibition against uc.83- could be a future therapeutic treatment for NSCLC to achieve simultaneous blockade of pathways involved in lung carcinogenesis.
非编码 RNA（ncRNAs）的表达在人类癌症中失调。转录的超保守区域（T-UCRs）表达涉及人类致癌作用的长 ncRNAs。T-UCRs 是 100%在人类、大鼠和小鼠中保守的非编码基因组序列。跨物种基因组序列的保守性内在地意味着其具有重要的功能作用，因此我们考虑了 T-UCRs 在肺癌中的表达。我们使用定制的微阵列分析了 T-UCRs 的全局表达。在这些 T-UCRs 中，观察到反义超保守元件 83（uc.83-）的变化最大，与相邻的非癌组织相比，其在人类肺癌组织中上调。尽管 uc.83- 位于长基因间非蛋白编码 RNA 1876（LINC01876）基因内，但我们发现转录的 uc.83- 独立于 LINC01876 表达，并被克隆为 1143bp RNA 基因。在这项研究中，功能分析证实了 uc.83- 对参与人类细胞生长的基因有重要影响。针对 uc.83- 的 siRNA 降低了肺癌细胞的生长，而通过过表达 uc.83- RNA 的载体上调则增加了细胞增殖。我们还表明，uc.83- 的致癌功能是通过 AKT 和 ERK 1/2 的磷酸化介导的，AKT 和 ERK 1/2 是肺癌细胞增殖的两个重要生物标志物。基于我们的发现，针对 uc.83- 的抑制可能成为 NSCLC 的未来治疗方法，以同时阻断参与肺癌发生的途径。
