miR‐34a is an intracellular and exosomal predictive biomarker for response to docetaxel with clinical relevance to prostate cancer progression

Abstract

BACKGROUND. Docetaxel-resistance limits successful treatment of castration resistant prostate cancer. We previously demonstrated that extracellular vesicles (exosomes) may play a role in regulating docetaxel resistance. Here, we investigated intracellular and extracellular (exosomal) miRNAs related to docetaxel resistance. METHODS. Following global miRNA profiling of cell line models of docetaxel-resistance and their corresponding exosomes, we investigated the clinical relevance of four selected miRNAs (miR-598, miR-34a, miR-146a, miR-148a) in four publically available clinical cohorts representing both primary and advanced disease in tissue and urine specimens. One of these miRNAs, miR-34a was selected for functional evaluation by miRNA inhibition and over-expression in vitro. We further assessed the panel of miRNAs for their combined clinical relevance as a biomarker signature by examining their common predicted targets. RESULTS. A strong correlation was found between the detection of miRNAs in exosomes and their corresponding cells of origin. Of the miRNAs chosen for further validation and clinical assessment, decreased miR-34a levels showed substantial clinical relevance and so was chosen for further analysis. Manipulating miR-34a in prostate cancer cells confirms that this miRNA regulates BCL-2 and may, in part, regulate response to docetaxel. When combined, these miRNAs are predicted to regulate a range of common mRNA targets, two of which (e.g., SNCA, SCL7A5) demonstrate a strong relationship with prostate cancer progression and poor prognosis. CONCLUSIONS. This study supports the extracellular environment as an important source of minimally invasive predictive biomarkers representing their cellular origin. Using miR-34a as example, we showed that biomarkers identified in this manner may also hold functional relevance.

Cisplatin-resistant lung cancer cell–derived exosomes increase cisplatin resistance of recipient cells in exosomal miR-100–5p-dependent manner

“…16 More importantly, exosomes-shuttling miRNAs probably conferred this resistance delivery. Followed by these studies, more and more evidence confirmed this observation in other cancers including breast cancer, prostate cancer, hepatocellular cancer, [17][18][19][20] and so on. However, similar to our previous study, most of these literatures mainly reported this phenomenon and few researchers 13 conduct in-depth study and systematically explore its detailed mechanism.…”

miRNAs as novel biomarkers in the management of prostate cancer

“…Unfortunately, there is not a consensus in miRNAs selected for these studies neither congruence with results published in blood. On the other hand, miRNAs were not associated with biochemical recurrence [123], PSA serum levels [126] or Gleason score [122,126], although according to Lewis et al [49], miR-888 measured in supernatant, but not in pellet, is associated with high-grade PCa. Finally, the value of miRNAs in the detection of PCa could increase in association with other tests.…”

“…However, no studies are currently available about miRNAs in urinary exosomes in PCa, even when they have been widely explored in benign nephropathies [119,120]. Table 4 presents published results about miRNAs in urine, showing AUCs between 0.639 and 0.769 [49,86,88,98,[121][122][123][124][125][126][127][128]. Unfortunately, there is not a consensus in miRNAs selected for these studies neither congruence with results published in blood.…”

Exosomal microRNAs in liquid biopsies: future biomarkers for prostate cancer

“…Regarding other important factors, it has been observed that the miRNAs content of exosomes plays a role in docetaxel resistance. mir-34a that was significantly decreased in prostate cancer versus normal tissues as well as in urine, regulates BCL-2 and may in part, regulate the response to docetaxel [76,77].…”