Argonaute, Dicer, and Drosha are up-regulated along tumor progression in serous ovarian carcinoma.
MicroRNAs are posttranscriptional regulators of messenger RNA synthesis that are intracellularly processed and transferred by the microRNA-regulating machinery consisting of Drosha, Dicer, and Argonaute. The present study analyzed the expression and clinical role of the microRNA-regulating machinery in advanced-stage ovarian carcinoma. Drosha, Dicer, Argonaute 1, and Argonaute 2 messenger RNA levels were analyzed in 144 specimens (82 effusions, 33 primary carcinomas, and 29 solid metastases) using quantitative polymerase chain reaction. Dicer, Argonaute 1, and Argonaute 2 protein levels were analyzed in 103 of the above specimens by Western blotting. Argonaute 1, Argonaute 2, and Drosha messenger RNAs were overexpressed in effusions compared with primary carcinomas and solid metastases (P<.001), whereas Argonaute 1 protein expression was highest in solid metastases (P=.004). Significantly higher expression of all 4 messenger RNAs was found in effusions compared with primary carcinomas (P<.001 to P=.006), whereas Argonaute 2 messenger RNA (P=.002), Drosha messenger RNA (P=.009), and Dicer protein (P=.006) were overexpressed in solid metastases compared with primary carcinomas. Drosha, Dicer, Argonaute 1, and Argonaute 2 messenger RNAs and protein levels in effusions were unrelated to clinicopathologic parameters. In primary carcinomas, higher levels of 3 messenger RNAs were significantly associated with high-grade histology (P=.003 for Dicer and P=.01 for Drosha and Argonaute 1). Higher Argonaute 2 messenger RNA levels in prechemotherapy effusions were related to shorter progression-free survival (P=.049), a finding that retained its significance in multivariate Cox analysis (P=.046). In conclusion, Drosha, Dicer, Argonaute 1, and Argonaute 2 are differentially expressed at different metastatic sites in ovarian carcinoma compared with primary carcinomas, suggesting a role for these molecules in tumor progression. Their clinical role in metastatic ovarian carcinoma merits further research.
Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Olga
O
Vaksman
Thea Eline
TE
Hetland
Claes G
CG
Trope'
Reuven
R
Reich
Ben
B
Davidson
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060565:Argonaute Proteins / Q000235:genetics* / Q000378:metabolism; D001202:Ascitic Fluid / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010996:Pleural Effusion / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
C115848:AGO1 protein, human; C466422:AGO2 protein, human; D060565:Argonaute Proteins; D014408:Biomarkers, Tumor; D039642:Eukaryotic Initiation Factors; D012333:RNA, Messenger; C408087:DICER1 protein, human; C517918:DROSHA protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases