|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 Sep 19];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.
| References|| |
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin
2011; 61 (2): 69–90.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin
2016; 66 (1): 7–30.
Powell IJ. Epidemiology and pathophysiology of prostate cancer in African-American men. J Urol
2007; 177 (2): 444–9.
Moul JW, Sesterhenn IA, Connelly RR, Douglas T, Srivastava S, Mostofi FK, McLeod DG. Prostate-specific antigen values at the time of prostate cancer diagnosis in African-American men. JAMA
1995; 274 (16): 1277–81.
Powell IJ, Banerjee M, Novallo M, Sakr W, Grignon D, Wood DP, Pontes JE. Prostate cancer biochemical recurrence stage for stage is more frequent among African-American than white men with locally advanced but not organ-confined disease. Urology
2000; 55 (2): 246–51.
Evans S, Metcalfe C, Ibrahim F, Persad R, Ben-Shlomo Y. Investigating black-white differences in prostate cancer prognosis: a systematic review and meta-analysis. Int J Cancer
2008; 123 (2): 430–5.
Rebbeck TR. Prostate cancer disparities by race and ethnicity: from nucleotide to neighborhood. Cold Spring Harb Perspect Med
2017. doi: 10.1101/cshperspect.a030387.
Kumar S, Singh R, Malik S, Manne U, Mishra M. Prostate cancer health disparities: an immuno-biological perspective. Cancer Lett
2018; 414: 153–65.
Barnholtz-Sloan JS, Raska P, Rebbeck TR, Millikan RC. Replication of GWAS “Hits” by race for breast and prostate cancers in European Americans and African Americans. Front Genet
2011; 2: 37.
Bensen JT, Xu Z, Smith GJ, Mohler JL, Fontham ET, Taylor JA. Genetic polymorphism and prostate cancer aggressiveness: a case-only study of 1,536 GWAS and candidate SNPs in African-Americans and European-Americans. Prostate
2013; 73 (1): 11–22.
Beuten J, Gelfond JA, Franke JL, Shook S, Johnson-Pais TL, Thompson IM, Leach RJ. Single and multivariate associations of MSR1, ELAC2, and RNASEL with prostate cancer in an ethnic diverse cohort of men. Cancer Epidemiol Biomarkers Prev
2010; 19 (2): 588–99.
Bonilla C, Hooker S, Mason T, Bock CH, Kittles RA. Prostate cancer susceptibility loci identified on chromosome 12 in African Americans. PLoS One
2011; 6 (2): e16044.
Chung CC, Hsing AW, Yeboah E, Biritwum R, Tettey Y, Adjei A, Cook MB, De Marzo A, Netto G, Tay E, Boland JF, Yeager M, Chanock SJ. A comprehensive resequence-analysis of 250 kb region of 8q24.21 in men of African ancestry. Prostate
2014; 74 (6): 579–89.
Conti DV, Wang K, Sheng X, Bensen JT, Hazelett DJ, Cook MB, Ingles SA, Kittles RA, Strom SS, Rybicki BA, Nemesure B, Isaacs WB, Stanford JL, Zheng W, Sanderson M, John EM, Park JY, Xu J, Stevens VL, Berndt SI, Haiman CA; PRACTICAL/ELLIPSE Consortium. Two novel susceptibility loci for prostate cancer in men of African ancestry. J Natl Cancer Inst
2017; 109 (8): djx084.
Gusev A, Shi H, Kichaev G, Pomerantz M, Li F, Long HW, Ingles SA, Kittles RA, Strom SS, Rybicki BA, Nemesure B, Isaacs WB, Zheng W, Pettaway CA, Yeboah ED, Tettey Y, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Chokkalingam AP, John EM, Murphy AB, Signorello LB, Carpten J, Leske MC, Wu SY, Hennis AJ, Neslund-Dudas C, Hsing AW, Chu L, Goodman PJ, Klein EA, Witte JS, Casey G, Kaggwa S, Cook MB, Stram DO, Blot WJ, Eeles RA, Easton D, Kote-Jarai Z, Al Olama AA, Benlloch S, Muir K, Giles GG, Southey MC, Fitzgerald LM, Gronberg H, Wiklund F, Aly M, Henderson BE, Schleutker J, Wahlfors T, Tammela TL, Nordestgaard BG, Key TJ, Travis RC, Neal DE, Donovan JL, Hamdy FC, Pharoah P, Pashayan N, Khaw KT, Stanford JL, Thibodeau SN, McDonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Wokolorczyk D, Kluzniak W, Cannon-Albright L, Teerlink C, Brenner H, Dieffenbach AK, Arndt V, Park JY, Sellers TA, Lin HY, Slavov C, Kaneva R, Mitev V, Batra J, Spurdle A, Clements JA, Teixeira MR, Pandha H, Michael A, Paulo P, Maia S, Kierzek A; Practical Consortium, Conti DV, Albanes D, Berg C, Berndt SI, Campa D, Crawford ED, Diver WR, Gapstur SM, Gaziano JM, Giovannucci E, Hoover R 3rd
, Hunter DJ, Johansson M, Kraft P, Le Marchand L, Lindström S, Navarro C, Overvad K, Riboli E, Siddiq A, Stevens VL, Trichopoulos D, Vineis P, Yeager M, Trynka G, Raychaudhuri S, Schumacher FR, Price AL, Freedman ML, Haiman CA, Pasaniuc B. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation. Nat Commun
2016; 7: 10979.
Haiman CA, Chen GK, Blot WJ, Strom SS, Berndt SI, Kittles RA, Rybicki BA, Isaacs WB, Ingles SA, Stanford JL, Diver WR, Witte JS, Chanock SJ, Kolb S, Signorello LB, Yamamura Y, Neslund-Dudas C, Thun MJ, Murphy A, Casey G, Sheng X, Wan P, Pooler LC, Monroe KR, Waters KM, Le Marchand L, Kolonel LN, Stram DO, Henderson BE. Characterizing genetic risk at known prostate cancer susceptibility loci in African Americans. PLoS Genet
2011; 7 (5): e1001387.
Haiman CA, Chen GK, Blot WJ, Strom SS, Berndt SI, Kittles RA, Rybicki BA, Isaacs WB, Ingles SA, Stanford JL, Diver WR, Witte JS, Hsing AW, Nemesure B, Rebbeck TR, Cooney KA, Xu J, Kibel AS, Hu JJ, John EM, Gueye SM, Watya S, Signorello LB, Hayes RB, Wang Z, Yeboah E, Tettey Y, Cai Q, Kolb S, Ostrander EA, Zeigler-Johnson C, Yamamura Y, Neslund-Dudas C, Haslag-Minoff J, Wu W, Thomas V, Allen GO, Murphy A, Chang BL, Zheng SL, Leske MC, Wu SY, Ray AM, Hennis AJ, Thun MJ, Carpten J, Casey G, Carter EN, Duarte ER, Xia LY, Sheng X, Wan P, Pooler LC, Cheng I, Monroe KR, Schumacher F, Le Marchand L, Kolonel LN, Chanock SJ, Van Den Berg D, Stram DO, Henderson BE. Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21. Nat Genet
2011; 43 (6): 570–3.
Haiman CA, Han Y, Feng Y, Xia L, Hsu C, Sheng X, Pooler LC, Patel Y, Kolonel LN, Carter E, Park K, Le Marchand L, Van Den Berg D, Henderson BE, Stram DO. Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population. PLoS Genet
2013; 9 (3): e1003419.
Han Y, Hazelett DJ, Wiklund F, Schumacher FR, Stram DO, Berndt SI, Wang Z, Rand KA, Hoover RN, Machiela MJ, Yeager M, Burdette L, Chung CC, Hutchinson A, Yu K, Xu J, Travis RC, Key TJ, Siddiq A, Canzian F, Takahashi A, Kubo M, Stanford JL, Kolb S, Gapstur SM, Diver WR, Stevens VL, Strom SS, Pettaway CA, Al Olama AA, Kote-Jarai Z, Eeles RA, Yeboah ED, Tettey Y, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Chokkalingam AP, Isaacs WB, Chen C, Lindstrom S, Le Marchand L, Giovannucci EL, Pomerantz M, Long H, Li F, Ma J, Stampfer M, John EM, Ingles SA, Kittles RA, Murphy AB, Blot WJ, Signorello LB, Zheng W, Albanes D, Virtamo J, Weinstein S, Nemesure B, Carpten J, Leske MC, Wu SY, Hennis AJ, Rybicki BA, Neslund-Dudas C, Hsing AW, Chu L, Goodman PJ, Klein EA, Zheng SL, Witte JS, Casey G, Riboli E, Li Q, Freedman ML, Hunter DJ, Gronberg H, Cook MB, Nakagawa H, Kraft P, Chanock SJ, Easton DF, Henderson BE, Coetzee GA, Conti DV, Haiman CA. Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions. Hum Mol Genet
2015; 24 (19): 5603–18.
Hoffmann TJ, Van Den Eeden SK, Sakoda LC, Jorgenson E, Habel LA, Graff RE, Passarelli MN, Cario CL, Emami NC, Chao CR, Ghai NR, Shan J, Ranatunga DK, Quesenberry CP, Aaronson D, Presti J, Wang Z, Berndt SI, Chanock SJ, McDonnell SK, French AJ, Schaid DJ, Thibodeau SN, Li Q, Freedman ML, Penney KL, Mucci LA, Haiman CA, Henderson BE, Seminara D, Kvale MN, Kwok PY, Schaefer C, Risch N, Witte JS. A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences. Cancer Discov
2015; 5 (8): 878–91.
Ledet EM, Sartor O, Rayford W, Bailey-Wilson JE, Mandal DM. Suggestive evidence of linkage identified at chromosomes 12q24 and 2p16 in African American prostate cancer families from Louisiana. Prostate
2012; 72 (9): 938–47.
Martin DN, Starks AM, Ambs S. Biological determinants of health disparities in prostate cancer. Curr Opin Oncol
2013; 25 (3): 235–41.
Sun J, Purcell L, Gao Z, Isaacs SD, Wiley KE, Hsu FC, Liu W, Duggan D, Carpten JD, Grönberg H, Xu J, Chang BL, Partin AW, Walsh PC, Isaacs WB, Zheng SL. Association between sequence variants at 17q12 and 17q24.3 and prostate cancer risk in European and African Americans. Prostate
2008; 68 (7): 691–7.
Wang Y, Freedman JA, Liu H, Moorman PG, Hyslop T, George DJ, Lee NH, Patierno SR, Wei Q. Associations between RNA splicing regulatory variants of stemness-related genes and racial disparities in susceptibility to prostate cancer. Int J Cancer
2017; 141 (4): 731–43.
Wang Y, Ray AM, Johnson EK, Zuhlke KA, Cooney KA, Lange EM. Evidence for an association between prostate cancer and chromosome 8q24 and 10q11 genetic variants in African American men: the Flint Men's Health Study. Prostate
2011; 71 (3): 225–31.
Whitman EJ, Pomerantz M, Chen Y, Chamberlin MM, Furusato B, Gao C, Ali A, Ravindranath L, Dobi A, Sesterhenn IA, McLeod DG, Srivastava S, Freedman M, Petrovics G. Prostate cancer risk allele specific for African descent associates with pathologic stage at prostatectomy. Cancer Epidemiol Biomarkers Prev
2010; 19 (1): 1–8.
Xu Z, Bensen JT, Smith GJ, Mohler JL, Taylor JA. GWAS SNP replication among African American and European American men in the North Carolina-Louisiana prostate cancer project (PCaP). Prostate
2011; 71 (8): 881–91.
Wallace TA, Prueitt RL, Yi M, Howe TM, Gillespie JW, Yfantis HG, Stephens RM, Caporaso NE, Loffredo CA, Ambs S. Tumor immunobiological differences in prostate cancer between African-American and European-American men. Cancer Res
2008; 68 (3): 927–36.
Guo Y, Sigman DB, Borkowski A, Kyprianou N. Racial differences in prostate cancer growth: apoptosis and cell proliferation in Caucasian and African-American patients. Prostate
2000; 42 (2): 130–6.
Yamoah K, Johnson MH, Choeurng V, Faisal FA, Yousefi K, Haddad Z, Ross AE, Alshalafa M, Den R, Lal P, Feldman M, Dicker AP, Klein EA, Davicioni E, Rebbeck TR, Schaeffer EM. Novel biomarker signature that may predict aggressive disease in African American men with prostate cancer. J Clin Oncol
2015; 33 (25): 2789–96.
Antonarakis ES, Carducci MA, Eisenberger MA. Novel targeted therapeutics for metastatic castration-resistant prostate cancer. Cancer Lett
2010; 291 (1): 1–13.
Rybicki BA, Rundle A, Kryvenko ON, Mitrache N, Do KC, Jankowski M, Chitale DA, Trudeau S, Belinsky SA, Tang D. Methylation in benign prostate and risk of disease progression in men subsequently diagnosed with prostate cancer. Int J Cancer
2016; 138 (12): 2884–93.
Rubicz R, Zhao S, Geybels M, Wright JL, Kolb S, Klotzle B, Bibikova M, Troyer D, Lance R, Ostrander EA, Feng Z, Fan JB, Stanford JL. DNA methylation profiles in African American prostate cancer patients in relation to disease progression. Genomics
2016. doi: 10.1016/j. ygeno. 2016.02.004.
Tang D, Kryvenko ON, Mitrache N, Do KC, Jankowski M, Chitale DA, Trudeau S, Rundle A, Belinsky SA, Rybicki BA. Methylation of the RARB gene increases prostate cancer risk in black Americans. J Urol
2013; 190 (1): 317–24.
Kwabi-Addo B, Wang S, Chung W, Jelinek J, Patierno SR, Wang BD, Andrawis R, Lee NH, Apprey V, Issa JP, Ittmann M. Identification of differentially methylated genes in normal prostate tissues from African American and Caucasian men. Clin Cancer Res
2010; 16 (14): 3539–47.
Enokida H, Shiina H, Urakami S, Igawa M, Ogishima T, Pookot D, Li LC, Tabatabai ZL, Kawahara M, Nakagawa M, Kane CJ, Carroll PR, Dahiya R. Ethnic group-related differences in CpG hypermethylation of the GSTP1 gene promoter among African-American, Caucasian and Asian patients with prostate cancer. Int J Cancer
2005; 116 (2): 174–81.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell
2004; 116 (2): 281–97.
Meister G, Landthaler M, Patkaniowska A, Dorsett Y, Teng G, Tuschl T. Human argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol Cell
2004; 15 (2): 185–97.
Tomari Y, Zamore PD. MicroRNA biogenesis: drosha can't cut it without a partner. Curr Biol
2005; 15 (2): R61–4.
Bartel DP, Chen CZ. Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nat Rev Genet
2004; 5 (5): 396–400.
Pang Y, Young CY, Yuan H. MicroRNAs and prostate cancer. Acta Biochim Biophys Sin (Shanghai)
2010; 42 (6): 363–9.
Rigoutsos I. New tricks for animal microRNAS: targeting of amino acid coding regions at conserved and nonconserved sites. Cancer Res
2009; 69 (8): 3245–8.
Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet
2010; 11 (9): 597–610.
Qu W, Ma F, Xu B. Role of Exosome microRNA in breast cancer. Cancer Transl Med
2017; 3 (5): 167–73.
Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer
2006; 6 (11): 857–66.
Li T, Li D, Sha J, Sun P, Huang Y. MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells. Biochem Biophys Res Commun
2009; 383 (3): 280–5.
DeVere White RW, Vinall RL, Tepper CG, Shi XB. MicroRNAs and their potential for translation in prostate cancer. Urol Oncol
2009; 27 (3): 307–11.
Shi XB, Xue L, Yang J, Ma AH, Zhao J, Xu M, Tepper CG, Evans CP, Kung HJ, deVere White RW. An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells. Proc Natl Acad Sci U S A
2007; 104 (50): 19983–8.
Bonci D, Coppola V, Musumeci M, Addario A, Giuffrida R, Memeo L, D'Urso L, Pagliuca A, Biffoni M, Labbaye C, Bartucci M, Muto G, Peschle C, De Maria R. The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med
2008; 14 (11): 1271–7.
Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B, Laxman B, Cao X, Jing X, Ramnarayanan K, Brenner JC, Yu J, Kim JH, Han B, Tan P, Kumar-Sinha C, Lonigro RJ, Palanisamy N, Maher CA, Chinnaiyan AM. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science
2008; 322 (5908): 1695–9.
Feng S, Qian X, Li H, Zhang X. Combinations of elevated tissue miRNA-17-92 cluster expression and serum prostate-specific antigen as potential diagnostic biomarkers for prostate cancer. Oncol Lett
2017; 14 (6): 6943–9.
Guo J, Xiao Z, Yu X, Cao R. miR-20b promotes cellular proliferation and migration by directly regulating phosphatase and tensin homolog in prostate cancer. Oncol Lett
2017; 14 (6): 6895–900.
Jin M, Zhang T, Liu C, Badeaux MA, Liu B, Liu R, Jeter C, Chen X, Vlassov AV, Tang DG. miRNA-128 suppresses prostate cancer by inhibiting BMI-1 to inhibit tumor-initiating cells. Cancer Res
2014; 74 (15): 4183–95.
Kanwal R, Plaga AR, Liu X, Shukla GC, Gupta S. MicroRNAs in prostate cancer: functional role as biomarkers. Cancer Lett
2017; 407: 9–20.
Liu Y, Xu X, Xu X, Li S, Liang Z, Hu Z, Wu J, Zhu Y, Jin X, Wang X, Lin Y, Chen H, Mao Y, Luo J, Zheng X, Xie L. MicroRNA-193a-3p inhibits cell proliferation in prostate cancer by targeting cyclin D1. Oncol Lett
2017; 14 (5): 5121–8.
Luu HN, Lin HY, Sorensen KD, Ogunwobi OO, Kumar N, Chornokur G, Phelan C, Jones D, Kidd L, Batra J, Yamoah K, Berglund A, Rounbehler RJ, Yang M, Lee SH, Kang N, Kim SJ, Park JY, Di Pietro G. miRNAs associated with prostate cancer risk and progression. BMC Urol
2017; 17 (1): 18.
Nordby Y, Richardsen E, Ness N, Donnem T, Patel HR, Busund LT, Bremnes RM, Andersen S. High miR-205 expression in normal epithelium is associated with biochemical failure – An argument for epithelial crosstalk in prostate cancer? Sci Rep
2017; 7 (1): 16308.
Paziewska A, Mikula M, Dabrowska M, Kulecka M, Goryca K, Antoniewicz A, Dobruch J, Borowka A, Rutkowski P, Ostrowski J. Candidate diagnostic miRNAs that can detect cancer in prostate biopsy. Prostate
2018; 78 (3): 178–85.
Sita-Lumsden A, Dart DA, Waxman J, Bevan CL. Circulating microRNAs as potential new biomarkers for prostate cancer. Br J Cancer
2013; 108 (10): 1925–30.
Sun D, Layer R, Mueller AC, Cichewicz MA, Negishi M, Paschal BM, Dutta A. Regulation of several androgen-induced genes through the repression of the miR-99a/let-7c/miR-125b-2 miRNA cluster in prostate cancer cells. Oncogene
2014; 33 (11): 1448–57.
Vanacore D, Boccellino M, Rossetti S, Cavaliere C, D'Aniello C, Di Franco R, Romano FJ, Montanari M, La Mantia E, Piscitelli R, Nocerino F, Cappuccio F, Grimaldi G, Izzo A, Castaldo L, Pepe MF, Malzone MG, Iovane G, Ametrano G, Stiuso P, Quagliuolo L, Barberio D, Perdonà S, Muto P, Montella M, Maiolino P, Veneziani BM, Botti G, Caraglia M, Facchini G. Micrornas in prostate cancer: an overview. Oncotarget
2017; 8 (30): 50240–51.
Wa Q, Li L, Lin H, Peng X, Ren D, Huang Y, He P, Huang S. Downregulation of miR19a3p promotes invasion, migration and bone metastasis via activating TGFbeta signaling in prostate cancer. Oncol Rep
2018; 39 (1): 81–90.
Zhong J, Huang R, Su Z, Zhang M, Xu M, Gong J, Chen N, Zeng H, Chen X, Zhou Q. Downregulation of miR-199a-5p promotes prostate adeno-carcinoma progression through loss of its inhibition of HIF-1alpha. Oncotarget
2017; 8 (48): 83523–38.
Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL, Visakorpi T. MicroRNA expression profiling in prostate cancer. Cancer Res
2007; 67 (13): 6130–5.
Ozen M, Creighton CJ, Ozdemir M, Ittmann M. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene
2008; 27 (12): 1788–93.
Ambs S, Prueitt RL, Yi M, Hudson RS, Howe TM, Petrocca F, Wallace TA, Liu CG, Volinia S, Calin GA, Yfantis HG, Stephens RM, Croce CM. Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res
2008; 68 (15): 6162–70.
Pesta M, Klecka J, Kulda V, Topolcan O, Hora M, Eret V, Ludvikova M, Babjuk M, Novak K, Stolz J, Holubec L. Importance of miR-20a expression in prostate cancer tissue. Anticancer Res
2010; 30 (9): 3579–83.
Prueitt RL, Yi M, Hudson RS, Wallace TA, Howe TM, Yfantis HG, Lee DH, Stephens RM, Liu CG, Calin GA, Croce CM, Ambs S. Expression of microRNAs and protein-coding genes associated with perineural invasion in prostate cancer. Prostate
2008; 68 (11): 1152–64.
Amankwah EK, Anegbe E, Park H, Pow-Sang J, Hakam A, Park JY. miR-21, miR-221 and miR-222 expression and prostate cancer recurrence among obese and non-obese cases. Asian J Androl
2013; 15 (2): 226–30.
Schaefer A, Jung M, Mollenkopf HJ, Wagner I, Stephan C, Jentzmik F, Miller K, Lein M, Kristiansen G, Jung K. Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma. Int J Cancer
2010; 126 (5): 1166–76.
Spahn M, Kneitz S, Scholz CJ, Stenger N, Rudiger T, Strobel P, Riedmiller H, Kneitz B. Expression of microRNA-221 is progressively reduced in aggressive prostate cancer and metastasis and predicts clinical recurrence. Int J Cancer
2010; 127 (2): 394–403.
Tong AW, Fulgham P, Jay C, Chen P, Khalil I, Liu S, Senzer N, Eklund AC, Han J, Nemunaitis J. MicroRNA profile analysis of human prostate cancers. Cancer Gene Ther
2009; 16 (3): 206–16.
Moltzahn F, Olshen AB, Baehner L, Peek A, Fong L, Stöppler H, Simko J, Hilton JF, Carroll P, Blelloch R. Microfluidic-based multiplex qRT-PCR identifies diagnostic and prognostic microRNA signatures in the sera of prostate cancer patients. Cancer Res
2011; 71 (2): 550–60.
Zhang HL, Yang LF, Zhu Y, Yao XD, Zhang SL, Dai B, Zhu YP, Shen YJ, Shi GH, Ye DW. Serum miRNA-21: elevated levels in patients with metastatic hormone-refractory prostate cancer and potential predictive factor for the efficacy of docetaxel-based chemotherapy. Prostate
2011; 71 (3): 326–31.
Brase JC, Johannes M, Schlomm T, Fälth M, Haese A, Steuber T, Beissbarth T, Kuner R, Sültmann H. Circulating miRNAs are correlated with tumor progression in prostate cancer. Int J Cancer
2011; 128 (3): 608–16.
Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O'Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A
2008; 105 (30): 10513–8.
Hashimoto Y, Shiina M, Kato T, Yamamura S, Tanaka Y, Majid S, Saini S, Shahryari V, Kulkarni P, Dasgupta P, Mitsui Y, Sumida M, Deng G, Tabatabai L, Kumar D, Dahiya R. The role of miR-24 as a race related genetic factor in prostate cancer. Oncotarget
2017; 8 (10): 16581–93.
Srivastava A, Goldberger H, Dimtchev A, Marian C, Soldin O, Li X, Collins SP, Suy S, Kumar D. Circulatory miR-628-5p is downregulated in prostate cancer patients. Tumour Biol
2014; 35 (5): 4867–73.
Theodore SC, Davis M, Zhao F, Wang H, Chen D, Rhim J, Dean-Colomb W, Turner T, Ji W, Zeng G, Grizzle W, Yates C. MicroRNA profiling of novel African American and Caucasian prostate cancer cell lines reveals a reciprocal regulatory relationship of miR-152 and DNA methyltranferase 1. Oncotarget
2014; 5 (11): 3512–25.
Wang BD, Ceniccola K, Yang Q, Andrawis R, Patel V, Ji Y, Rhim J, Olender J, Popratiloff A, Latham P, Lai Y, Patierno SR, Lee NH. Identification and functional validation of reciprocal microRNA-mRNA pairings in African American prostate cancer disparities. Clin Cancer Res
2015; 21 (21): 4970–84.
Theodore SC, Rhim JS, Turner T, Yates C. MiRNA 26a expression in a novel panel of African American prostate cancer cell lines. Ethn Dis
2010; 20 (1 Suppl 1): S1–96–100.
van Rooij E, Kauppinen S. Development of microRNA therapeutics is coming of age. EMBO Mol Med
2014; 6 (7): 851–64.