Abstract
The different prostate cancer (PCa) cell populations (bulk and cancer stem cells, CSCs) release exosomes that contain miRNAs that could modify the local or premetastatic niche. The analysis of the differential expression of miRNAs in exosomes allows evaluating the differential biological effect of both populations on the niche, and the identification of potential biomarkers and therapeutic targets. Five PCa primary cell cultures were established to originate bulk and CSCs cultures. From them, exosomes were purified by precipitation for miRNAs extraction to perform a comparative profile of miRNAs by next generation sequencing in an Illumina platform. 1839 miRNAs were identified in the exosomes. Of these 990 were known miRNAs, from which only 19 were significantly differentially expressed: 6 were overexpressed in CSCs and 13 in bulk cells exosomes. miR-100-5p and miR-21-5p were the most abundant miRNAs. Bioinformatics analysis indicated that differentially expressed miRNAs are highly related with PCa carcinogenesis, fibroblast proliferation, differentiation and migration, and angiogenesis. Besides, miRNAs from bulk cells affects osteoblast differentiation. Later, their effect was evaluated in normal prostate fibroblasts (WPMY-1) where transfection with miR-100-5p, miR-21-5p and miR-139-5p increased the expression of metalloproteinases (MMPs) -2, -9 and -13 and RANKL and fibroblast migration. The higher effect was achieved with miR21 transfection. As conclusion, miRNAs have a differential pattern between PCa bulk and CSCs exosomes that act collaboratively in PCa progression and metastasis. The most abundant miRNAs in PCa exosomes are interesting potential biomarkers and therapeutic targets.
Highlights
Prostate cancer (PCa) is a major health concern, representing the second leading cause of cancer related death in men in developed countries, and the main cause of cancer death in elderly men
MiRNA were isolated from total RNA, obtaining enriched fractions, mainly around 30 and 60 nucleotides (Figure 1B)
The main population is constituted by clones of bulk cells, and a small population are CSCs [23]
Summary
Prostate cancer (PCa) is a major health concern, representing the second leading cause of cancer related death in men in developed countries, and the main cause of cancer death in elderly men. In PCa, it has been proposed that stem cells with cancer characteristics ( called cancer stem cells or CSCs) give rise and maintain tumor growth These are a subset of cells into the tumor with abilities of selfrenewal, giving rise to other malignant clones including transient amplifying cells (responsible for the bulk tumor proliferation) that repopulate the tumor after radio- and chemo-therapies and are responsible for development of castration-resistant disease [5,6,7]. The www.impactjournals.com/oncotarget recruitment of stromal fibroblasts, denominated cancer associated fibroblasts (CAFs) triggers matrix remodeling, and produces growth factors that promote tumor growth and progression. This communication is achieved among others, by the release of exosomes from cancer cells [8, 9]
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