Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Tianwen Avenue No. 288, Nan'an District, Chongqing, 400010, China.
Chongqing University, Three Gorges Hospital, No. 165 Xincheng Road, Wanzhou District, Chongqing, 404100, China.
Cell Mol Biol Lett. 2022 Jun 3;27(1):43. doi: 10.1186/s11658-022-00343-7.
The pivotal role of long noncoding RNAs (lncRNAs) in cancer immune responses has been well established. This study was conducted with the aim of exploring the molecular mechanism of lncRNA small nucleolar RNA host gene 12 (SNHG12) in immune escape of non-small cell lung cancer (NSCLC).
Expression of lncRNA SNHG12, programmed cell death receptor ligand 1 (PD-L1), ubiquitin-specific protease 8 (USP8), and human antigen R (HuR) in NSCLC tissues and cells was measured, and their binding relationship was determined. NSCLC cell proliferation and apoptosis were assessed. Peripheral blood mononuclear cells (PBMCs) were co-cultured with NSCLC cells. The ratio of CD8 T cells, PBMC proliferation, and inflammatory factors were determined. lncRNA SNHG12 localization was assessed via subcellular fractionation assay. The half-life period of mRNA was determined using actinomycin D. Xenograft tumor models were established to confirm the role of lncRNA SNHG12 in vivo.
LncRNA SNHG12 was found to be prominently expressed in NSCLC tissues and cells, which was associated with a poor prognosis. Silencing lncRNA SNHG12 resulted in the reduction in proliferation and the promotion of apoptosis of NSCLC cells, while simultaneously increasing PBMC proliferation and the ratio of CD8 T cells. Mechanically, the binding of lncRNA SNHG12 to HuR improved mRNA stability and expression of PD-L1 and USP8, and USP8-mediated deubiquitination stabilized the protein level of PD-L1. Overexpression of USP8 or PD-L1 weakened the inhibition of silencing lncRNA SNHG12 on the immune escape of NSCLC. Silencing lncRNA SNHG12 restricted tumor growth and upregulated the ratio of CD8 T cells by decreasing USP8 and PD-L1.
LncRNA SNHG12 facilitated the immune escape of NSCLC by binding to HuR and increasing PD-L1 and USP8 levels.
长链非编码 RNA（lncRNA）在癌症免疫反应中的关键作用已得到充分证实。本研究旨在探讨 lncRNA 小核仁 RNA 宿主基因 12（SNHG12）在非小细胞肺癌（NSCLC）免疫逃逸中的分子机制。
检测 NSCLC 组织和细胞中 lncRNA SNHG12、程序性细胞死亡受体配体 1（PD-L1）、泛素特异性蛋白酶 8（USP8）和人抗原 R（HuR）的表达，并确定它们的结合关系。评估 NSCLC 细胞增殖和凋亡。将外周血单核细胞（PBMCs）与 NSCLC 细胞共培养，测定 CD8 T 细胞比例、PBMC 增殖和炎症因子。通过亚细胞分离测定 lncRNA SNHG12 的定位。使用放线菌素 D 测定 mRNA 的半衰期。建立异种移植肿瘤模型以确认 lncRNA SNHG12 在体内的作用。
发现 lncRNA SNHG12 在 NSCLC 组织和细胞中明显表达，与预后不良相关。沉默 lncRNA SNHG12 导致 NSCLC 细胞增殖减少，凋亡增加，同时增加 PBMC 增殖和 CD8 T 细胞比例。机制上，lncRNA SNHG12 与 HuR 的结合提高了 PD-L1 和 USP8 的 mRNA 稳定性和表达，USP8 介导的去泛素化稳定了 PD-L1 的蛋白水平。USP8 或 PD-L1 的过表达削弱了沉默 lncRNA SNHG12 对 NSCLC 免疫逃逸的抑制作用。沉默 lncRNA SNHG12 通过降低 USP8 和 PD-L1 来限制肿瘤生长并增加 CD8 T 细胞的比例。
lncRNA SNHG12 通过与 HuR 结合并增加 PD-L1 和 USP8 水平促进 NSCLC 的免疫逃逸。
