miR-221 Is Down-regulated In TMPRSS2:ERG Fusion-positive Prostate Cancer

Prostate cancer exists along a biological continuum that ranges from clinically insignificant to extremely aggressive disease. Although clinically localized prostate cancer is largely manageable by surgery, with patients rarely developing clinical recurrence, recurrent disease remains essentially incurable. Because of this difference in treatment options, it is critical to establish specific biomarkers to differentiate between different stages of disease not only to determine presence of disease, but also to differentiate between indolent and aggressive cancer. The most common class of prostate cancer biomarker thus far are gene fusions resulting from chromosomal rearrangements. Numerous recurrent chromosomal rearrangements have been identified that are generally characterized by the fusion of various 5′ regulatory elements to E twenty-six (ETS) transcription factors, leading to high expression of these oncogenic transcription factors. Transmembrane protease serine 2: ETS-related gene (TMPRSS2:ERG), present in over 50% of all prostate cancers, is the most commonly identified fusion gene (1). TMPRSS2 is an androgen-responsive, prostate-specific serine protease of unknown function, and ERG is a member of the ETS transcription factor family and is rarely detected in normal prostate tissue (2). The consequences of ERG overexpression, and its correlation to the progression of prostate cancer remains unclear. What is known is that androgen stimulation induces the over-expression of an mRNA containing the ERG ORF and 3′ UTR when ERG is fused to the TMPRSS2 5′ UTR. In vitro studies have shown that over-expression of ERG stimulates cell migration and invasion, while its knockdown decreases the invasive properties of VCaP cells (3). In addition, it has been shown by our laboratory and others that TMPRSS2:ERG fusion mRNAs are present in prostate tumours but seldom in normal prostate cells. Thus, detection of abnormally high ERG expression could, at least theoretically, be a potential diagnostic and/or prognostic marker for prostate cancer. Although the chromosomal alterations seem to be important in the development of prostate neoplastic development, they alone may not be sufficient to induce cancer formation (2). An active area of prostate cancer research is to find biomarkers that are predictive of recurrence in patients in order to aid oncologists in treatment or non-treatment decisions. TMPRSS2:ERG has been repeatedly, but not unanimously, associated with a poorer prognosis in prostate cancer patients and our laboratory, in collaboration with other groups, has previously demonstrated that prostate cancer patients with the TMPRSS2:ERG gene fusion have a higher risk of recurrence (4), while others have reported no association between this chromosomal rearrangement and clinical outcome (5). The reasons for this lack of congruity between findings are unclear and the value of TMPRSS2:ERG as an independent prognostic biomarker of prostate cancer remains contentious; however, it is possible technical discrepancies may be an important factor, such as institutional inconsistencies in disease staging, or statistical variations, such as disparate cohort sizes (1). In fact, studies that show an absence of clinical correlation between fusion and prognosis highlight the importance of finding out how the fusion may be epigenetically regulated. MicroRNAs (miRNAs) have received considerable attention in recent years as possible biomarkers not only in prostate cancer, but also in various cancer subtypes. They are small, single-stranded, noncoding RNA molecules that regulate mRNA function by binding to the 3′ UTR of mRNAs to which they are partially complementary, thereby repressing translation (6). MiRNAs are known to be involved in almost every cellular function, including early development (7), differentiation (8), apoptosis (9), and cell cycle regulation (10); as such, it is not surprising that miRNAs have also been linked to cancer, since misregulation of any of these important cellular functions can lead to cancer (11). Aberrant expression of miRNAs has been found in prostate cell lines, xenografts, and clinical tissues. Since the majority of cancer deaths are caused by complications from metastasis, miRNAs that specifically regulate cancer metastasis (metastamirs) are of particular interest. The study of miRNAs as biomarkers and their exact involvement in the formation and/or progression of prostate cancer is still at its early stages, and more research is needed to evaluate the potential use of miRNAs as diagnostic and prognostic markers of prostate cancer. Given that miRNAs and fusion genes have been independently linked to prostate disease and progression, we set out to study the possible connection between miRNA regulation, prostate cancer recurrence, and TMPRSS2:ERG gene fusion status. We used a large cohort of men with clinically localized prostate cancer who were treated with radical prostatectomy and had long-term follow-ups. We assessed whether miR-221, a metastasis-promoting miRNA (12) located on the X chromosome that is differentially expressed in recurrent prostate cancers, is also associated with TMPRSS2:ERG fusion gene. Thereby, our study may prove applicable to future use of these regulators as surrogate biomarkers of prostate cancer.