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Exosomal Transfer of Stromal Cell-Derived miR21 Confers Taxol Resistance in High-grade Serous Ovarian Cancer Cells Through Down-Regulation of APAF1.

ABSTRACT: Advanced ovarian cancer usually spreads to the visceral adipose tissue of the omentum. However, the stromal cell-derived molecular determinants that modulate ovarian cancer growth have not been characterized. Here, we identified significantly higher levels of miR21 in exosomes and tissue lysate isolated from cancer associated adipocytes (CAA) and fibroblasts (CAF) compared to those from ovarian cancer cells. Functional studies and transcriptome analysis on miR21 transfected SKOV3 ovarian cancer cells revealed that miR21 could be transferred from CAA or CAF to ovarian cancer cells and modulate ovarian cancer apoptosis and chemoresistance through binding to its direct target APAF1. These data suggest that malignant phenotype of metastatic ovarian cancer cells can be modulated by miR21 delivered by exosomes derived from neighboring stromal cells in the omental tumor microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE51457 | GEO | 2016/03/21

SECONDARY ACCESSION(S): PRJNA223235

REPOSITORIES: GEO

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Project description:Ovarian cancer is the fifth most common form of cancer in women in the United States. Among different types of ovarian cancer, epithelial ovarian cancer is the most common and is highly lethal, however, prognostic and predictive markers, which can be used to predict chemoresponse and patient survival, have not been thoroughly explored. One critically important yet often overlooked component to the tumor progression process is the tumor microenvironment. Primarily composed of fibroblasts and extracellular matrix proteins (ECM) as well as endothelial cells and lymphocytic infiltrate, the tumor microenvironment has been shown to directly affect cell growth, migration, and differentiation through secreted proteins, cell-cell interactions and matrix remodeling (Tlsty and Coussens, 2006). The tumor microenvironment has the potential to promote tumor initiation of normal epithelial cells and facilitate progression of malignant cells, thereby, presenting a unique approach to diagnosing, understanding and treating cancer. Using a whole-genome oligonucleotide array platform to perform transcriptome profiling on the fibroblastic stromal component microdissected from a series of advanced stage high-grade serous ovarian adenocarcinomas, we identified a transcriptome signature for the ovarian cancer associated fibroblast (CAF). We further functionally characterized one of the identified genes, MFAP5, and we showed that stromal MFAP5 is a prognostic marker associated with poor patient survival. In addition to that, to investigate the signaling machanism and the effect of MFAP5 treatment on ovarian cancer cells, transcriptome profiling of MFAP5 treated OVCA432 high-grade serous ovarian cancer cells was performed. Further functional studies showed that stromal MFAP5 modulated ovarian cancer cell motility and invasion potential. High grade serous ovarian cancer cell line OVCA432 was used. Total RNA was isolated from control samples and MFAP5 treated cancer cell samples at 48 hours post-treatment. Followed by cDNA synthesis, IVT and biotin labeling, samples were then hybridized onto Affymetrix Human genome U133 plus 2.0 microarrays. For each treatment group, three independent samples were prepared for the microarray experiment.

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Exosomal Transfer of Stromal Cell-Derived miR21 Confers Taxol Resistance in High-grade Serous Ovarian Cancer Cells Through Down-Regulation of APAF1.

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