Abstract
Prostate carcinoma (CaP) is a leading cause of cancer-related death in men. We have previously determined the microRNA (miRNA) profile of primary CaP in comparison with nontumor prostate tissue. miRNAs are small, noncoding RNAs that inhibit protein synthesis on a posttranscriptional level by binding to the 3'-untranslated region (3'-UTR) of their target genes. In primary CaP tissue, we have previously found by miRNA sequencing that miR-375 and miR-200c were upregulated 9.1- and 4.5-fold, respectively. A computational analysis predicted the 3'-UTR of the SEC23A gene as a potential target for both miR-375 and miR-200c. Here, we show that the 3'-UTR of SEC23A mRNA is indeed a target for miR-375 and miR-200c and that both miRNAs downregulate Sec23A protein expression when ectopically expressed in human 293T cells. In primary samples of CaP, we found a direct correlation between reduction of SEC23A mRNA and overexpression of miR-375 but not of miR-200c. The reduced levels of Sec23A protein were inversely correlated to the increased amount of miR-375 in the LNCaP and DU145 CaP cell lines when compared with normal prostate fibroblasts. In primary CaP, we also detected decreased amounts of Sec23A protein when compared with corresponding normal prostate tissue. Ectopically overexpressed Sec23A in LNCaP and DU145 CaP cells significantly reduced the growth properties, indicating that Sec23A might play a role in the induction or growth of prostate carcinoma. Sec23A overexpression reduced cell growth but did not induce apoptosis, whereas inhibition of Sec23A stimulated cell proliferation.
Highlights
The underlying molecular defects leading to prostate carcinoma (CaP) are still poorly understood
We had previously established the miRNA profile of primary CaP by deep sequencing and had found that miR-375 and miR-200c were upregulated 9.1- and 4.5-fold in tumor tissue. These findings had been confirmed by Northern blotting for both miRNAs [5] and by quantitative RT-PCR (qRT-PCR) analyses, using a set of 26 corresponding pairs of tumor and nontumor prostate tissue, only for miR-375
Because we showed that the miRNAs miR-375 and miR-200c were upregulated in CaP and that SEC23A 30-untranslated region (30-UTR) was a regulative target for both miRNAs, we analyzed the expression of Sec23A in CaP cell lines
Summary
The underlying molecular defects leading to prostate carcinoma (CaP) are still poorly understood. The deregulation of microRNAs (miRNA) has recently been described as a mechanism contributing to the induction and growth of various tumors MiRNAs are short noncoding RNAs of about 19 to 25 nucleotides which preferentially bind to specific sequences. Authors' Affiliations: 1Department of Virology, Saarland University Medical School, Homburg/Saar; 2University Clinic of Urology and 3Department of Pathology, Friedrich-Alexander-University Erlangen-Nu€rnberg; 4Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nu€rnberg, Erlangen; 5Helmholtz Zentrum Mu€nchen, Institute of Molecular Immunology, Service Unit Monoclonal Antibodies, Munich; and 6University Clinic of Urology, University Regensburg, Regensburg, Germany. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).
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