Molecular mechanism of lncRNA SNHG12 in immune escape of non-small cell lung cancer through the HuR/PD-L1/USP8 axis

Abstract

Background 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). Methods 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. Results 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. Conclusion LncRNA SNHG12 facilitated the immune escape of NSCLC by binding to HuR and increasing PD-L1 and USP8 levels.

Transcriptomic profiling of Indian breast cancer patients revealed subtype-specific mRNA and lncRNA signatures

“…SNHG1, SNHG12, and SNHG16 regulate Treg cells and promote immune escape ( Pei et al, 2018 , 1; Tamang et al, 2019 , 12; Ni et al, 2020 , 1; Pi et al, 2021 ). Blocking SNHG12 might cause depolarization of refractory immune cells that are primed by tumor in non–small-cell lung cancer ( Huang et al, 2022 , 12). SNHG12 is known to promote immune escape in ovarian cancer cells ( Qian et al, 2020 , 12).…”

SnoRNA and lncSNHG: Advances of nucleolar small RNA host gene transcripts in anti-tumor immunity

“…Tumor cells promote PD-1/PD-L1 immune checkpoint triggering through upregulation of lncSNHGs, which can lead to apoptosis of CD4 + T cells ( 110 ), CD8 + T cells ( 111 ), and reduced infiltration ( 113 ). Particularly, lncSNHG12 is reported to reduce peripheral blood mononuclear cell proliferation and the ratio of CD8 + T cells by human antigen R (HuR)/ubiquitin-specific protease 8 (USP8) axis ( 114 ). LncSNHGs can also function as communication mediators between tumor cells and immune killer cells.…”

“…LncSNHGs can also stabilize PD-L1 expression by participating in protein ubiquitination. lncSNHG12 binds to HuR and enhances the expression of PD-L1 with USP8, which improves PD-L1 stability by preventing ubiquitin-dependent degradation ( 114 ). CD73, an ectonucleotidase, is believed to be another key immune checkpoint molecule.…”

“…In addition, silencing the expression of lncSNHG15 could inhibit the proliferation and the migration of breast cancer, thus negating cisplatin resistance and providing novel therapeutic strategies for breast cancer ( 132 ). Silencing lncSNHG12 can restrict tumor growth and upregulate the ratio of CD8 + T cells, suggesting lncSNHG12 could be a potential therapeutic target ( 114 ). The circulating lncRNAs could be a source of cancer liquid biopsy biomarkers, lncSNHG2(GAS)in the plasma is suggested to be a diagnostic biomarker for multiple myeloma ( 133 ).…”

Epigenetic modifications: Critical participants of the PD‑L1 regulatory mechanism in solid tumors (Review)

“…Additionally, lncRNA PVT1 promotes PD-L1 expression in ovarian cancer by upregulating STAT3 phosphorylation levels (151). Furthermore, lncRNA small nucleolar RNA host gene 12 promotes non-small cell lung cancer (NSCLC) cell proliferation and immune escape by increasing the expression stability of PD-L1 through binding of the human antigen R gene (152).…”