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- Title
Notch activation promotes bone metastasis via SPARC inhibition in adenoid cystic carcinoma.
- Authors
Zhang, Ye; Liu, Xiaoxiao; Zhu, Lijing; Zhou, Zheng; Cui, Yajuan; Zhou, Chuan‐Xiang; Li, Tie‐jun
- Abstract
Objectives: We aimed to investigate bone metastasis induced by Notch signalling pathway dysregulation and to demonstrate that SPARC is a potential therapeutic target in adenoid cystic carcinoma (AdCC) with Notch dysregulation. Materials and Methods: This retrospective study enrolled 144 AdCC patients. RNA‐sequencing and enrichment analyses were performed using 32 AdCC samples. Osteonectin/SPARC and the Notch activation indicator Notch intracellular domain (NICD) were detected using immunohistochemistry. Cell proliferation and migration assays were conducted using stably NICD over‐expressing cells. The effect of SPARC on osteoclast differentiation in NICD cells was investigated using western blotting, quantitative reverse transcription PCR, tartrate‐resistant acid phosphatase staining and resorption assays. Results: RNA‐sequencing analysis showed that genes down‐regulated in Notch‐mutant AdCCs, such as SPARC, were enriched in ossification and osteoblast differentiation. Most (75/110, 68.2%) Notch1‐wild‐type AdCCs showed SPARC over‐expression, whereas 30 out of 34 (88.2%) Notch1‐mutant tumours showed low SPARC expression. SPARC over‐expression was then found negatively to be correlated with NICD expression in 144 AdCCs. NICD over‐expression promoted cell growth, migration and osteoclast differentiation, which could be partly reversed by exogenous SPARC. Conclusions: Notch activation in AdCC contributes to bone metastasis through SPARC inhibition. The study results suggest that SPARC may represent a prognostic biomarker and potential therapeutic target.
- Subjects
CHINA; BONE resorption; CELL migration; PEARSON correlation (Statistics); IN vitro studies; OSTEOBLASTS; ACADEMIC medical centers; MOUTH tumors; SURVIVAL rate; RESEARCH funding; HEAD &; neck cancer; CELL proliferation; BONE growth; FISHER exact test; TUMOR markers; GLYCOPROTEINS; CELLULAR signal transduction; CANCER patients; RETROSPECTIVE studies; REVERSE transcriptase polymerase chain reaction; NEOVASCULARIZATION inhibitors; CHI-squared test; SALIVARY gland tumors; DESCRIPTIVE statistics; BONE metastasis; ADENOID cystic carcinoma; IMMUNOHISTOCHEMISTRY; CELL lines; MESSENGER RNA; KAPLAN-Meier estimator; LOG-rank test; FACE diseases; WESTERN immunoblotting; GENE expression profiling; MICROBIOLOGICAL assay; PAROTID gland tumors; GENETIC mutation; CELL differentiation; FACTOR analysis; MICROSCOPY; STAINS &; staining (Microscopy); TUMORS; DATA analysis software; CONFIDENCE intervals; SEQUENCE analysis; OVERALL survival; CHEMICAL inhibitors
- Publication
Oral Diseases, 2024, Vol 30, Issue 3, p1220
- ISSN
1354-523X
- Publication type
Article
- DOI
10.1111/odi.14573