Siglec‐15 promotes the migration of liver cancer cells by repressing lysosomal degradation of CD44

Liu, Weitao; Ji, Zongfei; Wu, Bangwei; Huang, Sijing; Chen, Qihang; Chen, Xiaoning; Wei, Yuanyan; Jiang, Jianhai

doi:10.1002/1873-3468.14169

Cited by 20 publications

(16 citation statements)

References 32 publications

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“…Since Siglec15 has the unique function of mediating tumor cells immune escape and osteoclast differentiation, we hypothesized that Siglec15 may play an important role in NSCLC bone metastasis. Many previous studies also have demonstrated that Siglec15 is a tumorpromoting gene that is overexpressed in many primary malignancies, including osteosarcoma, kidney cancer, and liver cancer (25)(26)(27). Yet, the expression of Siglec15 in malignant tumor bone metastasis remains unclear.…”

Section: Discussionmentioning

confidence: 99%

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

Liang¹,

Chen²,

Hu³

et al. 2022

Ann Transl Med

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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.

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Section: Discussionmentioning

confidence: 99%

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

Liang¹,

Chen²,

Hu³

et al. 2022

Ann Transl Med

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“…CD44 is a ligand for Siglec-15 ( 124 ). In the presence of CD44 N-glycan α-(2,6)-linked sialic acid modifications, Siglec-15 interacts with CD44 and mediates liver cancer progression and metastasis by preventing CD44 lysosome-mediated degradation ( 125 ).…”

Section: Cd44 Terminal Sialic Acids On Tumors Regulate Their Binding ...mentioning

confidence: 99%

CD44 Glycosylation as a Therapeutic Target in Oncology

Liao

Wang

et al. 2022

Front. Oncol.

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The interaction of non-kinase transmembrane glycoprotein CD44 with ligands including hyaluronic acid (HA) is closely related to the occurrence and development of tumors. Changes in CD44 glycosylation can regulate its binding to HA, Siglec-15, fibronectin, TM4SF5, PRG4, FGF2, collagen and podoplanin and activate or inhibit c-Src/STAT3/Twist1/Bmi1, PI3K/AKT/mTOR, ERK/NF-κB/NANOG and other signaling pathways, thereby having a profound impact on the tumor microenvironment and tumor cell fate. However, the glycosylation of CD44 is complex and largely unknown, and the current understanding of how CD44 glycosylation affects tumors is limited. These issues must be addressed before targeted CD44 glycosylation can be applied to treat human cancers.

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“…On March 5, 2019, the sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) was described as a novel immunosuppressive molecule in Nature Medicine by Professor Lieping Chen (34). The latest research shows that Siglec-15 promotes the migration of liver cancer cells by repressing the lysosomal degradation of CD44 (35). The T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) is another immune checkpoint involved in tumor immune surveillance (36).…”

Section: Antibody-based Therapy Immune Checkpoint Inhibitors (Icis)mentioning

confidence: 99%

Immunotherapy for Hepatocellular Carcinoma: Current Status and Future Prospects

Liu

Liang

et al. 2021

Front. Immunol.

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Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer with poor prognosis. Surgery, chemotherapy, and radiofrequency ablation are three conventional therapeutic options that will help only a limited percentage of HCC patients. Cancer immunotherapy has achieved dramatic advances in recent years and provides new opportunities to treat HCC. However, HCC has various etiologies and can evade the immune system through multiple mechanisms. With the rapid development of genetic engineering and synthetic biology, a variety of novel immunotherapies have been employed to treat advanced HCC, including immune checkpoint inhibitors, adoptive cell therapy, engineered cytokines, and therapeutic cancer vaccines. In this review, we summarize the current landscape and research progress of different immunotherapy strategies in the treatment of HCC. The challenges and opportunities of this research field are also discussed.

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Siglec‐15 promotes the migration of liver cancer cells by repressing lysosomal degradation of CD44

Cited by 20 publications

References 32 publications

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

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

CD44 Glycosylation as a Therapeutic Target in Oncology

Immunotherapy for Hepatocellular Carcinoma: Current Status and Future Prospects

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