RESUMEN
We previously reported that extracellular matrix protein 1 isoform a (ECM1a) promotes epithelial ovarian cancer (EOC) through autocrine signaling by binding to cell surface receptors αXß2. However, the role of ECM1a as a secretory molecule in the tumor microenvironment is rarely reported. In this study, we constructed murine Ecm1-knockout mice and human ECM1a-knockin mice and further generated orthotopic or peritoneal xenograft tumor models to mimic the different metastatic stages of EOC. We show that ECM1a induces oncogenic metastasis of orthotopic xenograft tumors, but inhibits early-metastasis of peritoneal xenograft tumors. ECM1a remodels extracellular matrices (ECM) and promotes remote metastases by recruiting and transforming bone marrow mesenchymal stem cells (BMSCs) into platelet-derived growth factor receptor beta (PDGFRß+) cancer-associated fibroblasts (CAFs) and facilitating the secretion of angiopoietin-like protein 2 (ANGPTL2). Competing with ECM1a, ANGPTL2 also binds to integrin αX through the P1/P2 peptides, resulting in negative effects on BMSC differentiation. Collectively, this study reveals the dual functions of ECM1a in remodeling of TME during tumor progression, emphasizing the complexity of EOC phenotypic heterogeneity and metastasis.
Asunto(s)
Proteína 2 Similar a la Angiopoyetina , Fibroblastos Asociados al Cáncer , Proteínas de la Matriz Extracelular , Ratones Noqueados , Neoplasias Ováricas , Microambiente Tumoral , Animales , Femenino , Neoplasias Ováricas/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Humanos , Proteínas de la Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/genética , Ratones , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Línea Celular Tumoral , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/genética , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Proteínas Similares a la Angiopoyetina/metabolismo , Proteínas Similares a la Angiopoyetina/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Metástasis de la NeoplasiaRESUMEN
Osteoporosis (OP) is a common disease among older adults. The promotion of osteoblast differentiation plays a crucial role in alleviating OP symptoms. Extracellular matrix protein 1 (ECM1) has been reported to be closely associated with osteogenic differentiation. In this study, we constructed U2OS cell lines with ECM1 knockdown and ECM1a overexpression based on knockdown, and identified the target miRNA (miR-1260b) by sequencing. Overexpression of miR-1260b promoted the osteogenic differentiation of U2OS and MG63 cells, as demonstrated by increased alkaline phosphatase (ALP) activity, matrix mineralization, and Runt-Related Transcription Factor 2 (RUNX2), Osteopontin (OPN), Collagen I (COL1A1), and Osteocalcin (OCN) protein expressions, whereas low expression of miR-1260b had the opposite effect. In addition, miR-1260b expression was decreased in OP patients than in non-OP patients. Next, we predicted the target gene of miRNA through TargetScan and miRDB and found that miR-1260b negatively regulated GDP dissociation inhibitor 1 (GDI1) by directly binding to its 3'-untranslated region. Subsequent experiments revealed that GDI1 overexpression decreased ALP activity and calcium deposit, reduced RUNX2, OPN, COL1A1, and OCN expression levels, and reversed the effects of miR-1260b on osteogenic differentiation. In conclusion, ECM1-related miR-1260b promotes osteogenic differentiation by targeting GDI1 in U2OS and MG63 cells. Thus, this study has significant implication for osteoporosis treatment.