Role of 8q Amplification and MicroRNAs in Prostate Cancer
Acta Universitatis Tamperensis No. 1733
By Jalava Sanni
Tampere University Press
$87.50 Paper original
Despite extensive research in recent years, the molecular mechanisms underlying prostate cancer initiation and progression are not fully understood. Key chromosomal aberrations have been identified, yet many of the target genes remain elusive. Castration-resistant prostate cancer (CRPC) is a lethal disease that emerges after hormonal therapy. So far, the only gene known to be involved in the formation of CRPC is the androgen receptor (AR). A gain of the long arm of chromosome 8 is one of the most common findings in CRPC; in fact, 60-90% of these tumors harbor this particular gain. In addition, 8q gain is associated with poor prognosis in prostatectomy-treated patients. Several minimal regions have been identified, suggesting the existence of multiple target genes. Four of the putative target genes (EIF3H, TCEB1, KIAA0196 and RAD21) within the 8q gain region have been functionally evaluated. Of these, TCEB1, located at 8q21, was shown to promote invasion and to affect the anchorage-independent growth of prostate cancer cells. Furthermore, TCEB1 overexpression enhanced the growth of murine fibroblasts. These data indicate that TCEB1 is a putative target gene for gain of the minimal 8q21 region.
microRNAs (miRNA) are short, non-coding RNAs that negatively regulate gene expression and can function as tumor suppressor miRs or oncomiRs. To address whether miRNAs are involved in prostate cancer progression, their expression was investigated in two different clinical datasets (102 samples and 54 samples). A panel of 25 miRNAs was able to distinguish aggressive from less aggressive tumors.
Androgen-regulated miRNAs involved in CRPC were identified by combining information on androgen receptor binding sites (ARBS) and CRPC miRNA expression profiles. Twenty-eight miRNAs were deregulated in CRPC and contained ARBS. Exogenous overexpression of miR-32 and miR-148a enhanced the growth of an androgen-responsive cell line; miR-32 accomplished this by reducing apoptosis. The expression of these two miRNAs was demonstrated to be up-regulated by androgens and increased in CRPC. In addition, ARBS were detected in close proximity to these miRNAs. BTG2 and PIK3IP1 were identified as target genes for miR-32 and miR-148a, respectively. BTG2 expression was markedly decreased in CRPC, and the loss of BTG2 expression was associated with shorter progression-free survival in prostatectomy-treated patients.
In conclusion, TCEB1, miR-148a and miR-32 were demonstrated to possess oncogenic functions in prostate cancer. They are all overexpressed in CRPC and, in initial cell-based studies, affected invasion, proliferation and apoptosis. miR-32 and miR-148a were determined to be androgen-regulated. In addition, miRNA expression profiling was effective in predicting the prognosis of prostatectomy-treated patients. However, additional studies are necessary to evaluate the role of miRNAs as prognostic indicators in prostate cancer.
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