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Signals from the Metastatic Niche Regulate Early and Advanced Ovarian Cancer Metastasis through miR-4454 Downregulation
- Source :
- Molecular cancer research : MCR. 18(8)
- Publication Year :
- 2019
-
Abstract
- Treatment of ovarian cancer is limited by extensive metastasis and yet it remains poorly understood. We have studied the critical step of metastatic colonization in the context of the productive interactions with the metastatic microenvironment with a goal of identifying key regulators. By combining miRNA expression analysis using an organotypic 3D culture model of early ovarian cancer metastasis with that of matched primary and metastatic tumors from 42 patients with ovarian cancer, we identified miR-4454 as a key regulator of both early colonization and advanced metastasis in patients with ovarian cancer. miR-4454 was downregulated in the metastasizing ovarian cancer cells through paracrine signals from microenvironmental fibroblasts, which promoted migration, invasion, proliferation, and clonogenic growth in ovarian cancer cells as well as their ability to penetrate through the outer layers of the omentum. Stable overexpression of miR-4454 decreased metastasis in ovarian cancer xenografts. Its mechanism of action was through the upregulation of its targets, secreted protein acidic and cysteine rich (SPARC) and BCL2 associated athanogene 5 (BAG5), which activated focal adhesion kinase (FAK) signaling, promoted mutant p53 gain of function by its stabilization, and inhibited apoptosis. Because microenvironment-induced downregulation of miR-4454 is essential for early and advanced metastasis, targeting it could be a promising therapeutic approach. Implications: This study identifies a miRNA, miR-4454, which is downregulated by signals from the microenvironment and promotes early and advanced ovarian cancer metastasis through its effects on FAK activation, mutant p53 stabilization, and apoptosis inhibition.
- Subjects :
- 0301 basic medicine
Cancer Research
Down-Regulation
Context (language use)
Biology
Metastasis
Focal adhesion
03 medical and health sciences
Mice
0302 clinical medicine
Downregulation and upregulation
Cell Movement
Cell Line, Tumor
microRNA
medicine
Tumor Microenvironment
Animals
Humans
Osteonectin
Neoplasm Metastasis
Clonogenic assay
Molecular Biology
Adaptor Proteins, Signal Transducing
Cell Proliferation
Ovarian Neoplasms
Tumor microenvironment
Protein Stability
medicine.disease
Gene Expression Regulation, Neoplastic
MicroRNAs
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Focal Adhesion Kinase 1
Mutation
Cancer research
Female
Tumor Suppressor Protein p53
Ovarian cancer
Neoplasm Transplantation
Subjects
Details
- ISSN :
- 15573125
- Volume :
- 18
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Molecular cancer research : MCR
- Accession number :
- edsair.doi.dedup.....44fea0ff9c935707a50d34b952941a6d