Dysregulation of kallikrein-related peptidases in renal cell carcinoma: potential targets of miRNAs.
Renal cell carcinoma (RCC) accounts for 3% of all adult malignancies and currently no diagnostic marker exists. Kallikrein-related peptidases (KLKs) have been implicated in numerous cancers including ovarian, prostate, and breast carcinoma. KLKs 5, 6, 10, and 11 have decreased expression in RCC when compared to normal kidney tissue. Our bioinformatic analysis indicated that the KLK 1, 6, and 7 genes have decreased expression in RCC. We experimentally verified these results and found that decreased expression of KLKs 1 and 3 were significantly associated with the clear cell RCC subtype (p<0.001). An analysis of miRNAs differentially expressed in RCC showed that 61 of the 117 miRNAs that were reported to be dysregulated in RCC were predicted to target KLKs. We experimentally validated two targets using two independent approaches. Transfection of miR-224 into HEK-293 cells resulted in decreased KLK1 protein levels. A luciferase assay demonstrated that hsa-let-7f can target KLK10 in the RCC cell line ACHN. Our results, showing differential expression of KLKs in RCC, suggest that KLKs could be novel diagnostic markers for RCC and that their dysregulation could be under miRNA control. The observation that KLKs could represent targets for miRNAs suggests a post-transcriptional regulatory mechanism with possible future therapeutic applications.
White
Nicole M
NM
Department of Laboratory Medicine and the Keenan Research Center in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Bui
Anna
A
Mejia-Guerrero
Salvador
S
Chao
Julie
J
Soosaipillai
Antoninus
A
Youssef
Youssef
Y
Mankaruos
Marina
M
Honey
R John
RJ
Stewart
Robert
R
Pace
Kenneth T
KT
Sugar
Linda
L
Diamandis
Eleftherios P
EP
Doré
Jules
J
Yousef
George M
GM
D014408:Biomarkers, Tumor / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D002869:Chromosome Aberrations; D019295:Computational Biology; D019143:Evolution, Molecular; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007610:Kallikreins / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010802:Phylogeny; D015203:Reproducibility of Results
D014408:Biomarkers, Tumor; D035683:MicroRNAs; D007610:Kallikreins