Affiliation:
1. Department of Oral Pathology Peking University School and Hospital of Stomatology Beijing China
2. National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices Beijing China
3. Research Unit of Precision Pathologic Diagnosis in Tumors of the Oral and Maxillofacial Regions Chinese Academy of Medical Sciences (2019RU034) Beijing China
Abstract
AbstractObjectivesWe 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 MethodsThis 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.ResultsRNA‐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.ConclusionsNotch 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.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Beijing Municipality
Subject
General Dentistry,Otorhinolaryngology
Cited by
1 articles.
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