The Interaction between Collagen 1 and High Mannose Type CD133 Up-Regulates Glutamine Transporter SLC1A5 to Promote the Tumorigenesis of Glioblastoma Stem Cells.

Targeting the niche components surrounding glioblastoma stem cells (GSCs) helps to develop more effective glioblastoma treatments. However, the mechanisms underlying the crosstalk between GSCs and microenvironment remain largely unknown. Clarifying the extracellular molecules binding to GSCs marker CD133 helps to elucidate the mechanism of the communication between GSCs and the microenvironment. Here, it is found that the extracellular domain of high mannose type CD133 physically interacts with Collagen 1 (COL1) in GSCs. COL1, mainly secreted by cancer-associated fibroblasts, is a niche component for GSCs. COL1 enhances the interaction between CD133 and p85 and activates Akt phosphorylation. Activation of Akt pathway increases transcription factor ATF4 protein level, subsequently enhances SLC1A5-dependent glutamine uptake and glutathione synthesis. The inhibition of CD133-COL1 interaction or down-regulation of SLC1A5 reduces COL1-accelerated GSCs self-renewal and tumorigenesis. Analysis of glioma samples reveals that the level of COL1 is correlated with histopathological grade of glioma and the expression of SLC1A5. Collectively, COL1, a niche component for GSCs, enhances the tumorigenesis of GSCs partially through CD133-Akt-SLC1A5 signaling axis, providing a new mechanism underlying the cross-talk between GSCs and extracellular matrix (ECM) microenvironment.

Loss of α-1,2-mannosidase MAN1C1 promotes tumorigenesis of intrahepatic cholangiocarcinoma through enhancing CD133-FIP200 interaction.

CD133 is widely used as a marker to isolate tumor-initiating cells in many types of cancers. The structure of N-glycan on CD133 is altered during the differentiation of tumor-initiating cells. However, the relationship between CD133 N-glycosylation and stem cell characteristics remains elusive. Here, we found that the level of α-1,2-mannosylated CD133 was associated with the level of stemness genes in intrahepatic cholangiocarcinoma (iCCA) tissues. α-1,2-mannosylated CD133+ cells possessed the characteristics of tumor-initiating cells. The loss of the Golgi α-mannosidase I coding gene MAN1C1 resulted in the formation of α-1,2-mannosylated CD133 in iCCA-initiating cells. Mechanistically, α-1,2-mannosylation promoted the cytoplasmic distribution of CD133 and enhanced the interaction between CD133 and the autophagy gene FIP200, subsequently promoting the tumorigenesis of α-1,2-mannosylated CD133+ cells. Analysis of iCCA samples showed that the level of cytoplasmic CD133 was associated with poor iCCA prognosis. Collectively, α-1,2-mannosylated CD133 is a functional marker of iCCA-initiating cells.

Siglec15 promotes the migration of thyroid carcinoma cells by enhancing the EGFR protein stability.

PURPOSE: Sialic acid-bound immunoglobulin-like lectin 15 (Siglec15) has emerged as a novel therapeutic target in tumor immunotherapy. This study is designed to investigate the function and mechanism of Siglec15 in thyroid carcinoma (THCA). MATERIALS AND METHODS: The information on patients with THCA from TGCA and GEO database were used to analyze the expression of Siglec15 in THCA. THCA cells were treated with Siglec15-mFc, a recombinant fusion protein consisting of the extracellular domain of human Siglec15 and murine IgG Fc. THP-1 cells expressing human Siglec15 and its mutant were co-cultured with THCA cells to mimic the contact between Siglec15-expressing tumor-associated macrophages and THCA cells. Wound-healing assay and transwell migration assay were used to examine the migration abilities of BCPAP and C643 cells. Pull-down assay was performed to examine the interaction between Siglec15 and epidermal growth factor receptor (EGFR) on the cancer cells. Cycloheximide (CHX) assay was used to evaluate the stability of the protein. RESULTS: The expression of Siglec15 in thyroid carcinoma tissues is higher than in normal tissues. Siglec15 promotes the migration of THCA cells by binding to EGFR in a sialic acid-dependent manner and increases EGFR protein expression. Inhibition of the EGFR pathway blocks the effect of Siglec15 on the migration of THCA cells. CONCLUSIONS: Our findings reveals that Siglec15 promotes the migration of thyroid carcinoma cells by enhancing the EGFR protein stability.