Multi-Omics Study Reveals Nc886/vtRNA2‑1 as a Positive Regulator of Prostate Cancer Cell Immunity

Noncoding RNA 886 has emerged as a pivotal regulatory RNA with distinct functions across tissues, acting as a regulator of protein activity by directly binding to protein partners. While it is well recognized as a tumor suppressor in prostate cancer, the underlying molecular mechanisms remain elusive. To discover the principal pathways regulated by nc886 in prostate cancer, we used a transcriptomic and proteomic approach analyzing malignant DU145, LNCaP, PC3, and benign RWPE-1 prostate cell line models transiently transfected with in vitro transcribed nc886 or antisense oligonucleotides. Multiomics revelead a significant enrichment of immune system-related pathways across the cell lines, including cytokines and interferon signaling. The interferon response provoked by nc886 was validated by functional assays. The invariability of PKR phosphorylation and NF-κB activity in the gain/loss of nc886 function experiments and the positive regulation of innate immunity suggest a PKR-independent mechanism of nc886 action. Accordingly, the GSEA of the PRAD-TCGA data set revealed immune stimulation as the nc886 most associated node also in the clinical setting. Our study showed that the reduction of nc886 leads to a blunted immune response in prostate cancer.

非编码RNA 886（Noncoding RNA 886，以下简称nc886）已成为一类关键的调控RNA，在不同组织中发挥独特功能，可通过直接结合蛋白质伴侣调控蛋白活性。尽管其作为前列腺癌肿瘤抑制因子已得到广泛认可，但其潜在分子机制仍未明确。为探明nc886在前列腺癌中调控的核心通路，本研究采用转录组学与蛋白质组学联用策略，分析了分别瞬时转染体外转录nc886或反义寡核苷酸的恶性前列腺细胞系DU145、LNCaP、PC3及良性前列腺细胞系RWPE-1模型。多组学分析显示，各细胞系中均显著富集免疫系统相关通路，涵盖细胞因子与干扰素信号通路。nc886诱导的干扰素应答已通过功能实验得到验证。在nc886功能获得与功能缺失实验中，蛋白激酶R（Protein Kinase R，简称PKR）磷酸化水平与核因子κB（Nuclear Factor κB，简称NF-κB）活性均无显著变化，加之天然免疫受到正向调控，这表明nc886的作用机制不依赖于PKR。据此，对PRAD-TCGA数据集的基因集富集分析（Gene Set Enrichment Analysis，简称GSEA）结果显示，在临床队列中免疫激活同样是与nc886关联最紧密的生物学节点。本研究证实，nc886表达下调会导致前列腺癌患者体内免疫应答减弱。