Cleaved CD44 intracellular domain supports activation of stemness factors and promotes tumorigenesis of breast cancer
Copyright policy )Cleaved CD44 intracellular domain supports activation of stemness factors and promotes tumorigenesis of breast cancer
CD44 plays a role in the progression of tumors and is expressed in cancer stem cells (CSCs). However, the mechanisms underlying the crosstalk of CD44 with stemness genes in CSC maintenance remains unclear. In this study, we demonstrated how the cleaved intracellular domain of CD44 (CD44ICD) activates stemness factors such as Nanog, Sox2 and Oct4, and contributes to the tumorigenesis of breast cancer. We have found that the overexpression of CD44ICD increased mammosphere formation in breast cancer cells. Treatment with a γ-secretase inhibitor (GSI), which blocks the cleavage of CD44ICD, interfered with mammosphere formation. Interestingly, CD44ICD decreased the expression levels and nuclear localization of stemness factors, but overexpression of CD44ICD reversed these effects. In addition, we showed that nuclear localization of CD44ICD is important for transcriptional activation of the stemness factors. Furthermore, CD44ICD-overexpressed cells exhibited strong tumorigenecity and greater metastatic potential than did the control cells or CD44-depleted cells in vivo in mice models. Taken together, it was supposed that CD44 promotes tumorigenesis through the interaction and nuclear-translocation of its intracellular domain and stemness factors. We suggest that the prevention of cleavage and nuclear-translocation of CD44ICD is a potential target in treating breast cancer.
- Yonsei University Korea (Republic of)
- Yonsei University Health System Korea (Republic of)
- Yonsei University Medical Library Korea (Republic of)
- Yonsei University College of Medicine
Lung Neoplasms, Hyaluronan Receptors/genetics, Hyaluronan Receptors/chemistry, Neoplasm/biosynthesis, Mice, Neoplasm Proteins/physiology*, Neoplasm Proteins/genetics, Protein Interaction Mapping, CD44, Hyaluronan Receptors/biosynthesis, Octamer Transcription Factor-3/metabolism, Tumor, Neoplastic Stem Cells/pathology, Breast Neoplasms/pathology*, Nanog Homeobox Protein, SOXB1 Transcription Factors/metabolism, Active Transport, Specific Pathogen-Free Organisms, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Hyaluronan Receptors, Small Interfering/genetics, Neoplastic Stem Cells, Heterografts, Female, RNA Interference, Recombinant Fusion Proteins/metabolism, Transcription, Octamer Transcription Factor-3/genetics, Neoplastic Stem Cells/metabolism*, Protein Structure, 570, Active Transport, Cell Nucleus, 610, Breast Neoplasms, Transfection, Cell Line, breast cancer, Genetic, Cell Line, Tumor, Homeodomain Proteins/metabolism, Animals, Humans, RNA, Messenger, Lung Neoplasms/secondary, Neoplasm Proteins/biosynthesis, Cell Nucleus, Homeodomain Proteins, Neoplastic, Messenger/biosynthesis, Protein Structure, Tertiary, Gene Expression Regulation, Breast Neoplasms/metabolism, Hyaluronan Receptors/physiology*, SOXB1 Transcription Factors/genetics, RNA, Cellular, Homeodomain Proteins/genetics, Spheroids, Octamer Transcription Factor-3, Neoplasm Proteins/chemistry, Tertiary
Lung Neoplasms, Hyaluronan Receptors/genetics, Hyaluronan Receptors/chemistry, Neoplasm/biosynthesis, Mice, Neoplasm Proteins/physiology*, Neoplasm Proteins/genetics, Protein Interaction Mapping, CD44, Hyaluronan Receptors/biosynthesis, Octamer Transcription Factor-3/metabolism, Tumor, Neoplastic Stem Cells/pathology, Breast Neoplasms/pathology*, Nanog Homeobox Protein, SOXB1 Transcription Factors/metabolism, Active Transport, Specific Pathogen-Free Organisms, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Hyaluronan Receptors, Small Interfering/genetics, Neoplastic Stem Cells, Heterografts, Female, RNA Interference, Recombinant Fusion Proteins/metabolism, Transcription, Octamer Transcription Factor-3/genetics, Neoplastic Stem Cells/metabolism*, Protein Structure, 570, Active Transport, Cell Nucleus, 610, Breast Neoplasms, Transfection, Cell Line, breast cancer, Genetic, Cell Line, Tumor, Homeodomain Proteins/metabolism, Animals, Humans, RNA, Messenger, Lung Neoplasms/secondary, Neoplasm Proteins/biosynthesis, Cell Nucleus, Homeodomain Proteins, Neoplastic, Messenger/biosynthesis, Protein Structure, Tertiary, Gene Expression Regulation, Breast Neoplasms/metabolism, Hyaluronan Receptors/physiology*, SOXB1 Transcription Factors/genetics, RNA, Cellular, Homeodomain Proteins/genetics, Spheroids, Octamer Transcription Factor-3, Neoplasm Proteins/chemistry, Tertiary
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