|Year : 2018 | Volume
| Issue : 1 | Page : 28-34
MicroRNAs differentially expressed in prostate cancer of African-American and European-American men
Ernest K Amankwah
Department of Oncology, Johns Hopkins School of Medicine, Cancer and Blood Disorders Institute, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA
|Date of Submission||02-Jan-2018|
|Date of Acceptance||08-Feb-2018|
|Date of Web Publication||26-Feb-2018|
Dr. Ernest K Amankwah
Johns Hopkins All Children's Hospital, 501 6th Avenue South, St. Petersburg, FL 33701
Source of Support: None, Conflict of Interest: None
African-American (AA) men have higher rates of prostate cancer incidence and mortality compared with European-American (EA) men. Although several socioeconomic and environmental factors may contribute to the disparity, recent studies suggest a biological component, including differential microRNA (miRNA) expression, to the disparity. miRNAs comprise a large family of about 22-nucleotide-long nonprotein coding RNAs that regulate gene expression posttranscriptionally and participate in the regulation of almost every known cellular process investigated to date. miRNAs have been associated with prostate cancer progression, and recent studies indicate that they are differentially expressed between AA and EA. They could therefore contribute, at least in part, to the disparity in prostate cancer between the two groups. In this review, existing evidence on differential miRNA expression between AA and EA prostate cancer patients or cell lines is summarized.
Keywords: African-American, European-American, microRNA, prostate cancer, race
|How to cite this article:|
Amankwah EK. MicroRNAs differentially expressed in prostate cancer of African-American and European-American men. Cancer Transl Med 2018;4:28-34
|How to cite this URL:|
Amankwah EK. MicroRNAs differentially expressed in prostate cancer of African-American and European-American men. Cancer Transl Med [serial online] 2018 [cited 2018 Dec 14];4:28-34. Available from: http://www.cancertm.com/text.asp?2018/4/1/28/226168
| Introduction|| |
Prostate cancer is the most common nonskin malignancy among men worldwide. An estimated 903,500 new cases and 258,400 deaths occur annually worldwide. In the US, an estimated 242,000 new cases and 28,000 deaths occurred in 2016. The incidence rate of prostate cancer for African-American (AA) men in the US is nearly 1.6 times that of European-American (EA) men, and AA men are 2.4 times more likely to die from the disease. AA prostate cancer patients are generally diagnosed at an earlier age with higher Gleason scores, prostate-specific antigen (PSA) levels, and the incidence of palpable disease., Furthermore, a large percentage of AAs develop a more aggressive form of the disease.
Several socioeconomic, cultural, and environmental factors have been suggested to contribute to the disparity in prostate cancer incidence and mortality. For instance, inequities in healthcare access strongly affect the disparity. Other factors such as attitudes toward healthcare, income, education, and type and aggressiveness of treatment have also been suggested as potential explanations for the disparity. However, adjustment for the various postulated socioeconomic and environmental factors does not completely eliminate the differences in incidence and mortality, although attenuates them. Indeed, the proportion of the disparity that can be explained by environmental and socioeconomic factors is small, suggesting the existence of potential biological differences.
| Potential Biological Mechanisms for Prostate Cancer Disparity|| |
Multiple biological differences have been proposed to explain prostate cancer racial differences. More recently, genomic analyses have identified multiple genetic variants that may contribute to the disparity.,,,,,,,,,,,,,,,,,, For example, single nucleotide polymorphisms (SNPs) in MET, TP63, ALDH1A1 are reported to be associated with prostate cancer risk in AA, but not EA, while different SNPs in EGFR are associated with risk in AA and EA men. Furthermore, SNPs at 3p12, 8q24, and 19q13 are associated with prostate cancer aggressiveness in EA only, AA, and EA or AA only; and SNPs in KLK3 are associated with levels of serum PSA in AA men only.
In addition to genetic differences, a number of studies have shown differential gene and protein expression patterns in AA and EA prostate cancer samples. For instance, differential cancer-related gene expression in AA patients contributes to a higher prostate cancer grade in AA compared to EA men., Expression of mRNA of ERG is relatively lower among AA than EA prostate cancer tumors. Elevated EGFR protein expression that is associated with Gleason score and androgen independence is more frequent in AA than in EA prostate cancer. Other studies suggest a potential role of DNA hypermethylation in racial differences between AA and EA prostate cancer patients., AA compared to EA men seem to have higher methylation of key genes involved in cancer such as APC and RARB with APC associated with increased risk of higher grade prostate cancer in AA men and RARB methylation associated with increased risk of prostate cancer in AA men. Hypermethylation of other genes such as AR, RAR β 2, SPARC, TIMP3, and NKX2-5 has been observed in AA men with prostate cancer compared to EA men.
MicroRNA (miRNA) expression is another epigenetic mechanism, similar to DNA methylation, that affects gene regulation and may occur differentially among races. However, very little is known about the differential expression of miRNA between AA and EA prostate cancer patients. In this review, we summarize the existing evidence on differential expression of miRNA between AA and EA prostate cancer samples or cell lines.
| Microrna Biogenesis|| |
miRNAs are a large family of about 22-nucleotide-long RNAs that do not code for proteins and regulate gene expression posttranscriptionally. Although they are nonprotein coding, miRNAs are transcribed in the nucleus as separate transcription units or as part of composite transcription units. The primary transcript of a miRNA (pri-miRNA) has a stem-loop structure and is processed further by Drosha and Dicer. Drosha cleaves the pri-miRNA in the nucleus to generate a 60–70-nucleotide precursor miRNA, which is transported to the cytoplasm by exportin 5. In the cytoplasm, Dicer cleaves off the terminal loop to generate a mature duplex miRNA (miRNA/miRNA*). The resulting duplex forms a complex with RNA induced silencing complex (RISC) assembly pathway that includes duplex unwinding and preferential binding of one strand of the duplex to Argonaute 2 effector protein., The bound miRNA directs the effector protein to mostly the 3′ untranslated regions (3'-UTR) or occasionally to coding regions or 5'-UTR of target mRNA resulting in mRNA degradation or translational repression.,, Functional studies indicate that miRNAs participate in the regulation of key cellular processes.,
| Microrna and Prostate Cancer|| |
miRNA expression is deregulated in an increasing number of human cancers, including prostate cancer. Deregulation of miRNA in cancer may be attributed to translocation, loss or gain of a chromosomal region; changes in miRNA processing; epigenetic alterations; and/or aberrant expression and activation of transcriptional factors. miRNAs can be functionally classified as oncogenic or tumor suppressive depending on whether they affect the expression of oncogenes or tumor suppressor genes. miRNAs that are usually upregulated and impede the expression of tumor suppressor genes are referred to as oncogenic miRNAs or onco-miRs. Examples of onco-miRs in prostate cancer are miR-21, miR-125b, miR-106b, miR-221, and miR-222 that stimulate growth by downregulating their target genes as well as induce invasion and motility of prostate tumor cells.,, On the contrary, miRNAs that are usually down-regulated or deleted to promote tumor progression are referred to as tumor suppressor miRNAs. Examples of tumor suppressive miRNAs in prostate cancer are miR-15a/16-1 cluster, miR-101, miR-34a, miR-146a, miR-145, miR-23b, and miR-205. They are either deleted or downregulated in prostate cancer tumor or cell lines and their ectopic expression usually induce cell cycle arrest and interfere with cell migration or invasion.,
Numerous studies have evaluated dysregulation of miRNA expression in prostate cancer to understand their role in the onset and progression of the disease. These studies have identified a number of differentially expressed miRNAs and suggested that miRNAs might play a role in the risk and progression of prostate cancer.,,,,,,,,,,,, Feng et al. recently showed that expression of several miRNAs in the miR-17–92 cluster were elevated in prostate cancer tissues and cell lines compared to benign prostate tissue and the elevated expression was positively associated with Gleason grade. In another recent study, Zhong et al. showed that the expression of miR-199a-5p is lower in prostate adenocarcinoma and ectopic expression increased apoptosis, but decreased cell proliferation, motility, and tumor angiogenesis in prostate cancer cell lines. Earlier work by Porkka et al. showed differential expression of miRNAs between benign and carcinoma samples with eight upregulated and 22 down-regulated miRNAs in carcinoma compared to benign samples. In another study, Ozen et al. also showed differential expression of miRNA between benign prostate tumor and carcinoma samples. They observed that compared to benign peripheral zone tissue, clinically localized prostate cancer samples had downregulation of several paralogous miRNAs, including let-7b-g, let-7i, miR-26a-b, and miR29a-c. Ambs et al. observed differential miRNA expression, including miR-99b, between primary prostate tumors and nontumor samples as well as between organ-confined tumor and extraprostatic disease, providing additional evidence for the role of miRNAs in the development and progression of prostate cancer. miR-193a-3p expression level is lower in prostate cancer cell lines compared to normal prostate epithelium cell line and its downregulation promotes invasion, migration, and bone metastasis while its ectopic expression inhibits cell proliferation in prostate cancer.,
Other studies have evaluated the potential relationship between miRNA expression and clinicopathological features, progression, and recurrence of the disease. Pesta et al. observed a difference in expression of miR-20a between patients with a Gleason score of 7–10 and those with a Gleason score of 0–6, possibly suggesting a role of miR-20a in prostate cancer progression. miR-20b expression was recently shown to be elevated in prostate cancer tissues compared to adjacent normal prostate tissues and knockdown of its expression impeded the growth and migration of prostate cancer cell line PC-3. Similarly, Prueitt et al. observed upregulation of 19 miRNAs (particularly miR-224) and downregulation of 34 mRNAs in patients with perineural invasions compared to those with no invasion, revealing a potential role of miRNAs in prostate cancer progression. Amankwah et al. showed that miR-21 is associated with prostate cancer recurrence and that the association was more pronounced among obese compared to nonobese men. Similar differential expression has been observed between matched tumor and adjacent normal prostate samples. Schaefer et al. compared miRNA expression profile between matched tumor and adjacent normal tissues from 76 radical prostatectomy tissue samples and observed that a combination of the expression of miR-205 and miR-183 could correctly classify 84% of malignant and nonmalignant samples. In the same study, a higher expression of miR-96 was observed to be associated with prostate cancer recurrence after radical prostatectomy. More recently, Nordby et al. showed that expression of miR-205 was lower in tumor epithelium compared to normal epithelium. However, they observed no association between miR-205 expression and primary tumor epithelium or recurrence. Contrarily, elevated expression of miR-205 in normal epithelium was associated with biochemical recurrence suggesting a potential crosstalk between normal and tumor epithelium in prostate cancer.
A progressive downregulation of miR-221 is observed in aggressive and metastatic prostate cancer compared to benign hyperplastic prostate tissue. In this study, downregulation of miR-221 correlated with Gleason score and clinical recurrence. Tong et al. observed a 48 miRNA signature that could predict biochemical recurrence after prostatectomy. These miRNAs included miR-221, miR-23b, miR-100, miR-145, and miR-222 that were downregulated in recurrent compared to nonrecurrent samples.
Findings from studies that examined differential expression of miRNAs in serum or plasma have been similar to those of tissue. Moltzahn et al. identified serum miRNA signatures that included oncogenic and tumor suppressive miRNAs by examining sera from 48 healthy men and untreated prostate cancer patients. A higher level of serum miR-21 is observed in patients with androgen-dependent prostate cancer and hormone-refractory prostate cancer whose PSA level is > 4 ng/mL, but no difference in expression is observed between benign prostatic hyperplasia, localized cancer, and androgen-dependent prostate cancer with PSA level < 4 ng/mL. This observation may suggest a potential role of miR-21 in the transition to hormone refractory disease. In another study, miR-375 and miR-141 were upregulated in prostate cancer tumor tissue compared to normal tissue. Both miRNAs were also upregulated in the sera of metastatic patients compared to patients with localized disease and the expression correlated with high Gleason score or lymph node positive status. One previous study also showed that the expression of miR-141 in the sera of patients could distinguish patients with prostate cancer from healthy controls.
Although several previous studies have shown an association between miRNA expression and prostate cancer risk and progression, few of them compared the expression of miRNAs between AA and EA prostate cancer patients. The evidence accumulated from these few studies are summarized in [Table 1].
|Table 1: miRNAs differentially expressed between Africa-American and European-American prostate cancer|
Click here to view
| Studies Comparing Microrna Expression between African American and European American|| |
Hashimoto et al. compared the expression of miR-24 between 81 AA and 51 EA patient samples. They observed an association between miR-24 expression and race with EA more than eight times likely to have a higher expression of miR-24 compared to AA. Further evaluation of the miR-24 expression in cell lines revealed that miR-24 expression was down-regulation in an AA prostate cancer cell line (MDA-PCa-2b) than CA cell line (DU-145). Overexpression of miR-24 reduced cell viability in both cell lines but was more pronounced in AA compared to EA. Similarly, overexpression of miR-24 increased apoptosis in both cell lines, but was more pronounced (> 11-fold) and occurred later (6 days after transfection) in MDA-PCa-2b than DU-145 (3-fold and at day 4 after transfection) cell lines. Interestingly, while cleaved Caspase-3 was upregulated in AA cells, it was downregulated in EA cell line suggesting different mechanisms of apoptosis regulation in the two cell lines. Although the studied cell lines had different androgen receptor (AR) status (DU-145 is AR − and MDA-PCa-2b is AR +), differential expression of miR-24 may potentially contribute to the disparity in prostate cancer aggressiveness between AA and EA and warrants further investigation.
Srivastava et al. compared serum miRNA expression between six AA and six EA patients in a discovery set and validated the expression of three miRNAs (miR-25, miR-101, and miR-628-5p) in 36 AA (24 prostate cancer and 12 healthy control samples) and 36 EA (16 prostate cancer and 20 healthy control samples). They observed a significantly decreased expression of miR-101 in the serum of EA prostate cancer patients compared to EA controls, but no difference in expression of miR-101 was observed in AA prostate cancer cases compared with AA controls. However, the expression levels of miR-25 and miR-628-5p were significantly lower in prostate cancer cases compared to controls, irrespective of race.
Theodore et al. performed differential expression analysis of miRNAs in prostate cancer tissue samples from 20 AAs and 19 EAs and observed generally lower expression of miR-152 in AA compared to EA with half of the AA patients having a significantly lower miR-152 expression compared to only a third of EA patients. In the same study, they observed that 47 miRNAs were differentially expressed between AA and EA cell lines. They selected 11 out of the 47 candidate miRNAs to evaluate their association with prostate cancer aggressiveness in a prostate cancer cell line progression model. Differential expression for five (miR-132, miR-376b, miR-410, and miR-152 and miR-363) out of the 11 candidates were confirmed and decreased expression of four (miR-132, miR-376b, miR-410, and miR-152) of the five was correlated with the increased metastatic potential of the cell lines. In addition, ectopic expression of miR-152 inhibited cell proliferation in both AA (MDA-PCa-2b) and EA (PC-3 and LNCaP) cell lines but decreased expression of ABCD3 and SOS1 in the MDA-PCa-2b cell line. This latter finding is important because ABCD3 and SOS1 have been previously implicated in AA prostate cancer.
Wang et al. performed miRNA profiling on 14 AA prostate cancer cases, 14 normal-matched AA, 13 EA prostate cancer cases and 13 normal-matched EA controls and observed differential expression for 10, 33, and 29 miRNAs between AA cases versus EA cases, AA cases versus AA controls and EA cases versus EA controls, respectively. Eleven of the miRNAs were differentially expressed between both AA cases versus AA controls as well as EA cases versus EA controls, 22 were specific for AA, and 18 were specific for EA. Additional pathway analysis showed that AA-specific miRNAs regulated EGFR (or ERBB) signaling. Mechanistic assays revealed that manipulation of miR-mRNA pairings led to improved sensitization to docetaxel-induced cytotoxicity in the AA cell line, suggesting a race-specific effect.
In a previous study, Theodore et al. examined the expression of miR-26a expression in AA (RC77N/E, RC77T/E and MDA-2Pca-2b) and EA (PrEC, RC-92a, and PC-3) cell lines at different pathological stages: nonmalignant, malignant, and metastatic, respectively. Although they observed a general increase in miR-26a expression from nonmalignant to metastatic in both AA and EA cell lines, when the AA cell lines were compared to EA cell lines at the same pathological stage, there was a 2.3-fold, 13.3-fold, and 2.4-fold increase for miR-26a expression in the nonmalignant, malignant, and metastatic cell lines, respectively.
| Conclusion|| |
Racial disparity in prostate cancer risk and progression between AA and EA is multifactorial encompassing socioeconomic, cultural, and environmental factors, inequities in health care access, attitudes toward healthcare, type and aggressiveness of treatment, and biological differences. Multiple biological mechanisms have been proposed to explain the disparity, including genetic variants, differential gene, and protein expression patterns and DNA hypermethylation. Recent emerging evidence suggests that miRNA expression could also contribute to the disparity. Findings from existing limited number of studies on the differential expression of miRNAs between AA and EA prostate cancer patients and cell lines suggest that miR-24, miR-101, miR-152, and miR-26a may play a potential role in prostate cancer disparity between AA and EA.
miRNA expression has been studied extensively in cancer risk and progression and promising candidates for diagnosis and prognosis of prostate cancer have been suggested with only a few candidates in clinical trials or preclinical studies. miRNAs possess several features that make them attractive candidates for diagnostic and prognostic markers. These features include the ability to influence numerous biological pathways; the ease of extraction from several biological samples including plasma, serum, urine, and saliva; and their stability under many storage conditions. However, the pervasive expression of several known miRNAs hinders the specific delivery of miRNAs for therapeutic modulation. Therefore, additional research is needed in this area for translation of miRNAs to the clinic. Van Rooij et al. recently provided excellent suggestions on potential delivery modes that the research community can pursue, including encapsulation of miRNAs in lipid-based formulations and conjugation to targeting bioactive molecules. These strategies could improve targeted delivery of miRNAs and enhance their clinical use.
Since emerging evidence suggests miRNAs could be differentially expressed between races, future studies should include or indicate the race/ethnicity of the study population. The currently identified differentially expressed candidates between AA and EA need to be validated in larger independent studies. The evaluation of other miRNAs as potential candidates is also imperative. In addition, mechanistic studies are warranted to serve as the impetus for the evaluation of the therapeutic potential of these candidate miRNAs. Future studies are also needed to evaluate differential expression of miRNAs between other different racial and ethnic groups.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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