Abstract
MicroRNAs (miRNAs) are small (∼22 nucleotide) non-coding RNAs that regulate a myriad of biological processes and are frequently dysregulated in cancer. Cancer-associated microRNAs have been detected in serum and plasma and hold promise as minimally invasive cancer biomarkers, potentially for assessing disease characteristics in patients with metastatic disease that is difficult to biopsy. Here we used miRNA profiling to identify cancer-associated miRNAs that are differentially expressed in sera from patients with metastatic castration resistant prostate cancer (mCRPC) as compared to healthy controls. Of 365 miRNAs profiled, we identified five serum miRNAs (miR-141, miR-200a, miR-200c, miR-210 and miR-375) that were elevated in cases compared to controls across two independent cohorts. One of these, miR-210, is a known transcriptional target of the hypoxia-responsive HIF-1α signaling pathway. Exposure of cultured prostate cancer cells to hypoxia led to induction of miR-210 and its release into the extracellular environment. Moreover, we found that serum miR-210 levels varied widely amongst mCRPC patients undergoing therapy, and correlated with treatment response as assessed by change in PSA. Our results suggest that (i) cancer-associated hypoxia is a frequent, previously under-appreciated characteristic of mCRPC, and (ii) serum miR-210 may be further developed as a predictive biomarker in patients with this distinct disease biology.
Highlights
The natural history of patients with metastatic castration resistant prostate cancer varies widely, suggesting a heterogeneous disease biology in this patient population
Invasive approaches that can help stratify patients on the basis of distinct tumor biology could help inform choice of therapy, which is especially relevant with the recent introduction of multiple new effective treatments for metastatic castration resistant prostate cancer (mCRPC)
Specific miRNAs have been found to regulate a variety of critical processes in tumor physiology, including angiogenesis [3], epithelial-to-mesenchymal transition [4], metastasis [5] and the tumor response to hypoxia [6]. miRNAs have been demonstrated to be effective tissue-based cancer biomarkers–in diagnosing cancers of unknown tissue origin and in predicting clinical outcomes[7,8,9]
Summary
The natural history of patients with metastatic castration resistant prostate cancer (mCRPC) varies widely, suggesting a heterogeneous disease biology in this patient population. We used a candidate miRNA approach to identify significant elevation of miR-141 in serum from patients with metastatic castration-resistant prostate cancer (mCRPC) [1].
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