Circulating microRNA profiling identifies a subset of metastatic prostate cancer patients with evidence of cancer-associated hypoxia.
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.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Heather H
HH
Cheng
Patrick S
PS
Mitchell
Evan M
EM
Kroh
Alexander E
AE
Dowell
Lisly
L
Chéry
Javed
J
Siddiqui
Peter S
PS
Nelson
Robert L
RL
Vessella
Beatrice S
BS
Knudsen
Arul M
AM
Chinnaiyan
Kenneth J
KJ
Pienta
Colm
C
Morrissey
Muneesh
M
Tewari
D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D009362:Neoplasm Metastasis; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D015203:Reproducibility of Results; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; C543800:MIRN210 microRNA, human; D035683:MicroRNAs