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Siglec-15: a potential regulator of osteoporosis, cancer, and infectious diseases.

ABSTRACT: Siglec-15 is a member of the Siglec family of glycan-recognition proteins, primarily expressed on a subset of myeloid cells. Siglec-15 has been known to be involved in osteoclast differentiation, and is considered to be a potential therapeutic target for osteoporosis. Recent studies revealed unexpected roles of Siglec-15 in microbial infection and the cancer microenvironment, expanding the potential pathophysiological roles of Siglec-15. Chemical biology has advanced our understanding of the nature of Siglec-15 ligands, but the exact nature of Siglec-15 ligand depends on the biological context, leaving plenty of room for further exploration.

SUBMITTER: Angata T

PROVIDER: S-EPMC6941304 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Siglec-15: a potential regulator of osteoporosis, cancer, and infectious diseases.

Angata Takashi T

Journal of biomedical science 20200103 1

Siglec-15 is a member of the Siglec family of glycan-recognition proteins, primarily expressed on a subset of myeloid cells. Siglec-15 has been known to be involved in osteoclast differentiation, and is considered to be a potential therapeutic target for osteoporosis. Recent studies revealed unexpected roles of Siglec-15 in microbial infection and the cancer microenvironment, expanding the potential pathophysiological roles of Siglec-15. Chemical biology has advanced our understanding of the nat ...[more]

PMID: 31900164

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Project description:Lymph node metastasis indicates a poor prognosis in colorectal cancer. To better understand the underlying mechanisms of lymph node metastasis, we analyzed transcriptome characteristics of the pre-metastatic lymph node, a putative microenvironment favorable for the seeding and proliferation of cancer cells. Thus, we tried to compare and elucidate the transcriptional and immune characteristics of sentinel lymph nodes (SNs) with matched non-sentinel lymph nodes (NSNs) in colorectal cancer patients. In this study, a total of 38 pairs of SNs and NSNs were collected, in which 26 pairs of non-metastatic lymph nodes were subjected to RNA-seq and bioinformatics analysis for the gene expression profiles. There were 16 differentially expressed genes between SNs and NSNs being identified, including 9 upregulated and 7 downregulated genes in SN. Gene Ontology (GO) classification analysis revealed that the differentially expressed genes were mainly involved in leukocyte differentiation, chemokine secretion, and immune system regulation. In the meantime, gene set enrichment analysis (GSEA) showed that immune-related signaling pathways, such as transforming growth factor beta (TGF-β) signaling and tumor necrosis factor alpha (TNF-α)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, were enriched in NSN, while cell proliferation-related signaling pathways were enriched in SN, including MYC signaling and G2M checkpoint signaling. We further identified SIGLEC15 as a top upregulated gene in SN. However, RNAscope assay showed that SIGLEC15 was not largely co-expressed with M2 macrophage marker CD163. We then selected eight pairs of lymph nodes for further cytological studies. Flow cytometry analysis revealed that Siglec-15 was expressed on all myeloid cell subsets. The relative expression of SEGLEC15 (SN/NSN) was correlated with the microsatellite instability (MSI) status in colorectal cancer patients. Further studies found that small interfering ribonucleic acid (siRNA)-mediated silencing of SLGLEC15 can enhance the anti-tumor function of T cells, as indicated by cytokine release analysis. In conclusion, we presented here a first report on the gene expression profiling of the pre-metastatic lymph node in colorectal cancer. The findings in this study suggest that SIGLEC15 plays an important role in SN immunosuppression. SEGLEC15 silencing could be a therapeutic strategy for restoring T cell function in tumor SNs.

Project description:Vaccines used to prevent infections have long been known to stimulate immune responses to cancer as illustrated by the approval of the Bacillus Calmette-Guérin (BCG) vaccine to treat bladder cancer since the 1970s. The recent approval of immunotherapies has rejuvenated this research area with reports of anti-tumor responses with existing infectious diseases vaccines used as such, either alone or in combination with immune checkpoint inhibitors. Here, we have reviewed and summarized research activities using approved vaccines to treat cancer. Data supporting a cancer therapeutic use was found for 16 vaccines. For 10 (BCG, diphtheria, tetanus, human papillomavirus, influenza, measles, pneumococcus, smallpox, typhoid and varicella-zoster), clinical trials have been conducted or are ongoing. Within the remaining 6, preclinical evidence supports further evaluation of the rotavirus, yellow fever and pertussis vaccine in carefully designed clinical trials. The mechanistic evidence for the cholera vaccine, combined with the observational data in colorectal cancer, is also supportive of clinical translation. There is limited data for the hepatitis B and mumps vaccine (without measles vaccine). Four findings are worth highlighting: the superiority of intravesical typhoid vaccine instillations over BCG in a preclinical bladder cancer model, which is now the subject of a phase I trial; the perioperative use of the influenza vaccine to limit and prevent the natural killer cell dysfunction induced by cancer surgery; objective responses following intratumoral injections of measles vaccine in cutaneous T-cell lymphoma; objective responses induced by human papillomavirus vaccine in cutaneous squamous cell carcinoma. All vaccines are intended to induce or improve an anti-tumor (immune) response. In addition to the biological and immunological mechanisms that vary between vaccines, the mode of administration and sequence with other (immuno-)therapies warrant more attention in future research.

Dataset Information

Siglec-15: a potential regulator of osteoporosis, cancer, and infectious diseases.

Publications

Siglec-15: a potential regulator of osteoporosis, cancer, and infectious diseases.

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