Siglec15 facilitates the progression of non-small cell lung cancer and is correlated with spinal metastasis

Abstract

Background: Non-small cell lung cancer (NSCLC) frequently metastasizes to bone, leading to poor prognosis. Siglec15 has been identified as a newly discovered immune checkpoint and exists in a variety of tumors. However, the expression and function of Siglec15 in NSCLC and bone metastasis remains largely unclear.Methods: Siglec15 expression in NSCLC and the correlation between Siglec15 expression and the clinicopathological factors of patients with NSCLC were analyzed using The Cancer Genome Atlas (TCGA) dataset. Correlation analysis between Siglec15 and bone metastasis-related genes expression was based on the Molecular Signatures Database (MSigDB). Western blotting and immunohistochemistry were applied to detect Siglec15 expression in NSCLC and spinal metastasis. Human A549 and mouse CMT167 cells were transfected with Siglec15 siRNA to investigate its biological functions in NSCLC proliferation, migration, and invasion. The immune-related signaling pathways and correlations between Siglec15 and tumor-infiltrating immune cells and different immune checkpoints in the NSCLC tumor microenvironment (TME) were analyzed using Estimating Relative Subsets of RNA Transcripts (CIBERSORT) and gene set enrichment analysis (GSEA). To demonstrate Siglec15 in NSCLC cell-mediated T cell suppression and investigate the potential mechanism of Siglec15 silencing in antitumor immunity, we used a T cell killing assay in vitro and the high-throughput sequencing approach.Results: Siglec15 expression was positively associated with the tumor stage and lymph node metastasis, and was markedly up-regulated in NSCLC bone metastasis. Functionally, Siglec15 knockdown inhibited the proliferation, migration, and invasion of NSCLC cells (A549 and CMT167 cell lines). A total of eight kinds of tumor-infiltrating immune cells were found to have a strong association with the Siglec15 expression in NSCLC cases. The expression of previously discovered immune checkpoints was higher in the high Siglec15 expression NSCLC group. Furthermore, an in vitro T cell killing assay showed that the down-regulation of Siglec15 in tumor cells could enhance the antitumor immune responses of CD8 + T cells. High-throughput sequencing revealed the potential molecular mechanisms underlying the Siglec15mediated immunosuppression effect of tumor cells on immune cells.

The expression of two immunosuppressive SIGLEC family molecules in papillary thyroid cancer and their effect on prognosis

“…In addition, SIGLEC15 expression may be associated with distinct prognoses in various cancer types. For example, there was no correlation between the SIGLEC15 expression and the prognoses of gastric cancer and non-small cell lung cancer [43,44]. However, its high expression could indicate a good prognosis for pancreatic ductal adenocarcinoma and a poor prognosis for renal carcinoma [21,45].…”

The Proliferative Role of Immune Checkpoints in Tumors: Double Regulation

“…Through CCK8 and colony formation assay, SIGLEC-15 demonstrates involvement in NSCLC cell proliferation. The knockdown of SIGLEC-15 inhibits tumor proliferation, but the underlying mechanisms remain unclear currently [ 90 ].…”

Immunoregulatory framework and the role of miRNA in the pathogenesis of NSCLC – A systematic review

“…According to genomic research, Lung cancer has thousands of somatic mutations, copy number changes, and genome duplications. Due to exposure to tobacco carcinogens and germline genomic instability, lung cancer has a high somatic mutation rate, also the NSCLC initial tumors have a significant level of genetic variability ( 35 , 36 ). Oncogenes, tumour suppressors, cyclins, cyclin-dependent kinases, and defects in cell cycle regulation are the main molecular mechanisms generating genomic instability in lung cancer.…”

“…PD-L1 and siglec-15 expression are mutually exclusive and function as important immune suppressors. Monoclonal antibody NC 318 targets Siglec-15 to restore immune system normalcy ( 35 ). It has been proposed that interleukin 8 (IL-8) promotes immunological evasion.…”