Brain metastasis is a major cause of death in breast cancer patients. The greatest event for brain metastasis is the breaching of the blood-brain barrier (BBB) by cancer cells. The role of exosomes in cancer metastasis is clear, whereas the role of exosomes in the integrity of the BBB is unknown. Here, we established a highly brain metastatic breast cancer cell line by three cycles of in vivo selection. The effect of exosomes on the BBB was evaluated in vitro by tracking, transepithelial/transendothelial electrical resistance (TEER), and permeability assays. BBB-associated exosomal long noncoding RNA (lncRNA) was selected from the GEO dataset and verified by real-time PCR, TEER, permeability, and Transwell assays. The cells obtained by the in vivo selection showed higher brain metastatic capacity in vivo and higher migration and invasion in vitro compared to the parental cells. Exosomes from the highly brain metastatic cells were internalized by brain microvascular endothelial cells (BMECs), which reduced TEER and increased permeability of BBB. The exosomes derived from the highly metastatic cells promoted invasion of the breast cancer cells in the BBB model. lncRNA GS1-600G8.5 was highly expressed in the highly brain metastatic cells and their exosomes, as compared to the samples with reduced metastatic behavior. Silencing of GS1-600G8.5 significantly abrogated the BBB destructive effect of exosomes. GS1-600G8.5-deficient exosomes failed to promote the infiltration of cancer cells through the BBB. Furthermore, BMECs treated with GS1-600G8.5-deprived exosomes expressed higher tight junction proteins than those treated with the control exosomes. These data suggest the exosomes derived from highly brain metastatic breast cancer cells might destroy the BBB system and promote the passage of cancer cells across the BBB, by transferring lncRNA GS1-600G8.5.
Here, we aim to explore whether tribbles pseudokinase 3 (TRIB3) enhances glioma cell stemness. TRIB3 was overexpressed in glioma tissues and cell-formed spheres, positively correlated with the size and grade. Additionally, TRIB3 expression displayed a negative correlation with the overall survival rate of glioma patients. Moreover, TRIB3 knockdown reduced the stemness of nonadherent spheres, evident by the decreased sphere-forming ability, stemness master expression, and ALDH1 activity, while TRIB3 overexpression enhanced the stemness of adherent cells, which was rescued by β-catenin knockdown. Mechanistically, TRIB3 activated β-catenin signaling via physically interacting with β-catenin. This study suggests that the TRIB3-β-catenin interaction is responsible for glioma cell stemness. K E Y W O R D Sβ-catenin, glioma, stemness, TRIB3, Wnt
Plenty of evidence has shown that endocytosis plays a key role in cancer progression; however, its effects in the progression of cancer stem cells (CSCs) are still fragmentary. In the present study, we firstly identified that mammalian Eps15 homology domain protein 1 (EHD1), an endocytic and metastasis‐associated gene, was upregulated in the 3D non‐adherent spheres derived from glioma cells compared to that in the corresponding parental cells. Further functional experiments revealed that EHD1 knockdown reduced the CSC‐like traits of glioma cells, which were evident by the decrease of sphere‐formation ability, ALDH1 activity, and CSC markers' expression. Additionally, EHD1 knockdown attenuated the tumor‐initiating ability of glioma cells in vivo. Furthermore, it was shown that EHD1 bound to CD44, enhanced CD44 stability, and prevented its total ubiquitination. Indeed, overexpression of CD44 rescued the inhibitory effects of EHD1 knockdown on the CSC‐like traits of glioma cells. Finally, through the online dataset analysis, we found that EHD1 indeed exhibited a higher level in glioma tissues relative to that in normal tissues, and a positive correlation with CSC markers' expression in glioma tissues. Notably, EHD1 expression was negatively correlated with the overall survival and relapse‐free survival of glioma patients. Thus, this work indicates that EHD1 might be a potent target for glioma progression, especially through breaking the EHD1–CD44 interaction.
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