Unraveling the dark matter, long non-coding RNAs, in male reproductive diseases: A narrative review
Recent advances in human transcriptome have revealed the fundamental and functional roles of long non-coding RNA in the susceptibility to diverse diseases and pathological conditions. They participate in wide range of biological processes such as the modulating of chromatin structure, transcription, translation, and posttranslation modification. In addition, based on their unique expression profiles and their association with clinical abnormalities such as those of related to male reproductive diseases, they can be used to develop therapeutic methods and biomarkers for screening of the diseases. In this study, we will review the identified lncRNAs and their molecular functions in the pathogenesis of male reproductive diseases such as prostate cancer, benign prostatic hyperplasia, prostatitis, testicular cancer, varicocele, and sperm abnormalities.
Key words: Long noncoding RNA, Prostate cancer, Prostatic hyperplasia, Prostatitis, Varicocele, Sperm abnormalities.
 Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod Biol Endocrinol 2015; 13: 37.
 Cooper TG, Noonan E, Von Eckardstein S, Auger J, Baker HW, Behre HM, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update 2010; 16: 231– 245.
 Liu J, Cheng G, Yang H, Deng X, Qin Ch, Hua L, et al. Reciprocal regulation of long noncoding RNAs THBS4-003 and THBS4 control migration and invasion in prostate cancer cell lines. Mol Med Rep 2016; 14: 1451–1458.
 Xu X, Hou J, Lv J, Huang Y, Pu J, Wang L. Overexpression of lncRNA GAS5 suppresses prostatic epithelial cell proliferation by regulating COX-2 in chronic non-bacterial prostatitis. Cell Cycle 2019; 18: 923–931.
 Khademi Bami M, Dehghan Tezerjani M, Montazeri F, Ashrafzadeh Mehrjardi HR, Ghasemi-Esmailabad S, Sheikhha MH, et al. Tumor necrosis factor alpha- 308 G/A single nucleotide polymorphism and risk of sperm abnormalities in Iranian males. Int J Fertil Steril 2017; 11: 112–116.
 Ashrafzadeh HR, Nazari T, Dehghan Tezerjani M, Khademi Bami M, Ghasemi-Esmailabad S, Ghasemi N. Frequency of TNFR1 36 A/G gene polymorphism in azoospermic infertile men: A case-control study. Int J Reprod BioMed 2017; 15: 521–526.
 Hangauer MJ, Vaughn IW, McManus MT. Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic noncoding RNAs. Plos Genet 2013; 9: e1003569. 1– 13.
 Morceau F, Chateauvieux S, Gaigneaux A, Dicato M, Diederich M. Long and short non-coding RNAs as regulators of hematopoietic differentiation. Int J Mol Sci 2013; 14: 14744–14770.
 Kadali VN, Chandran Sh, Murthy S. Long Non-coding RNAs and their “orchestration” in cancers. Journal of Applied Biology & Biotechnology 2018; 6: 57–60.
 Tate PH, Bird AP. Effects of DNA methylation on DNA-binding proteins and gene expression. Curr Opin Genet Dev 1993; 3: 226–231.
 Nathan D, Sterner DE, Berger SL. Histone modifications: Now summoning sumoylation. Proc Natl Acad Sci USA 2003; 100: 13118–13120.
 Engreitz JM, Haines JE, Perez EM, Munson G, Chen J, Kane M, et al. Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature 2016; 539: 452–455.
 Evans JR, Feng FY, Chinnaiyan AM. The bright side of dark matter: lncRNAs in cancer. J Clin Invest 2016; 126: 2775–2782.
 Mukherjee A, Koli S, Reddy K. Regulatory non−coding transcripts in spermatogenesis: shedding light on ‘dark matter’. Andrology 2014; 2: 360–369.
 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394–424.
 Chen Q, Sun T, Wang F, Gong B, Xie W, Ma M, et al. Long noncoding RNA IGF2AS is acting as an epigenetic tumor suppressor in human prostate cancer. Urology 2019; 124: 310–318.
 Jiang CY, Gao Y, Wang XJ, Ruan Y, Bei XY, Wang XH, et al. Long non-coding RNA lnc-MX1-1 is associated with poor clinical features and promotes cellular proliferation and invasiveness in prostate cancer. Biochem Biophys Res Commun 2016; 470: 721–727.
 Qin X, Zhu W, Lu A, Wang G, Ye X, Weng G. Long noncoding RNA SAP30L-AS1 promotes prostate cancer growth through repressing SAP30L. Gene 2019; 690: 120–128.
 Zhao R, Sun F, Bei X, Wang X, Zhu Y, Jiang C, et al. Upregulation of the long non−coding RNA FALEC promotes proliferation and migration of prostate cancer cell lines and predicts prognosis of PCa patients. Prostate 2017; 77: 1107–1117.
 Wang J, Yang X, Li R, Wang L, Gu Y, Zhao Y, et al. Long non-coding RNA MYU promotes prostate cancer proliferation by mediating the miR-184/c-Myc axis. Oncol Rep 2018; 40: 2814–2825.
 Yang X, Wang L, Li R, Zhao Y, Gu Y, Liu S, et al. The long non-coding RNA PCSEAT exhibits an oncogenic property in prostate cancer and functions as a competing endogenous RNA that associates with EZH2. Biochem Biophys Res Commun 2018; 502: 262–268.
 Chen Y, Gu M, Liu Ch, Wan X, Shi Q, Chen Q, et al. Long noncoding RNA FOXC2-AS1 facilitates the proliferation and progression of prostate cancer via targeting miR-1253/EZH2. Gene 2019; 686: 37–42.
 Beaver LM, Kuintzle R, Buchanan A, Wiley MW, Glasser ST, Wong CP, et al. Long noncoding RNAs and sulforaphane: a target for chemoprevention and suppression of prostate cancer. J Nutr Biochem 2017; 42: 72–83.
 Wang J, Cheng G, Li X, Pan Y, Qin Ch, Yang H, et al. Overexpression of long non-coding RNA LOC400891 promotes tumor progression and poor prognosis in prostate cancer. Tumor Biol 2016; 37: 9603–9613.
 Liu T, Chi H, Chen J, Chen Ch, Huang Y, Xi H, et al. Curcumin suppresses proliferation and in vitro invasion of human prostate cancer stem cells by ceRNA effect of miR-145 and lncRNA-ROR. Gene 2017; 631: 29–38.
 Lemos AEG, Ferreira LB, Batoreu NM, de Freitas PP, Bonamino MH, Gimba ERP. PCA3 long noncoding RNA modulates the expression of key cancer-related genes in LNCaP prostate cancer cells. Tumour Biol 2016; 37: 11339–11348.
 Lee B, Mazar J, Aftab MN, Qi F, Shelley J, Li JL, et al. Long noncoding RNAs as putative biomarkers for prostate cancer detection. J Mol Diagn 2014; 16: 615–626.
 Zhang Ch, Liu Ch, Wu J, Zheng Y, Xu H, Cheng G, et al. Upregulation of long noncoding RNA LOC440040 promotes tumor progression and predicts poor prognosis in patients with prostate cancer. Onco Targets Ther 2017; 10: 4945–4954.
 Su W, Xu M, Chen X, Chen N, Gong J, Nie L, et al. Long noncoding RNA ZEB1-AS1 epigenetically regulates the expressions of ZEB1 and downstream molecules in prostate cancer. Molecular Cancer 2017; 16: 142.
 Orfanelli U, Jachetti E, Chiacchiera F, Grioni M, Brambilla P, Briganti A, et al. Antisense transcription at the TRPM2 locus as a novel prognostic marker and therapeutic target in prostate cancer. Oncogene 2015; 34: 2094–2102.
 Lavorgna G, Chiacchiera F, Briganti A, Montorsi F, Pasini D, Salonia A. Expression-profiling of apoptosis induced by ablation of the long ncRNA TRPM2-AS in prostate cancer cell. Genom Data 2015; 3: 4–5.
 Prensner JR, Iyer MK, Balbin OA, Dhanasekaran SM, Cao Q, Brenner JC, et al. Transcriptome sequencing across a prostate cancer cohort identifies PCAT- 1, an unannotated lincRNA implicated in disease progression. Nat Biotechnol 2011; 29: 742–749.
 Prensner JR, Chen W, Iyer MK, Cao Q, Ma T, Han S, et al. PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer. Cancer Res 2014; 74: 1651–1660.
 Prensner JR, Chen W, Han S, Iyer MK, Cao Q, Kothari V, et al. The long non-coding RNA PCAT-1 promotes prostate cancer cell proliferation through cMyc. Neoplasia 2014; 16: 900–908.
 Ylip A, Kivinummi K, Kohvakka A, Annala M, Latonen L, Scaravilli M, et al. Transcriptome sequencing reveals PCAT5 as a novel ERG-regulated long noncoding RNA in prostate cancer. Cancer Res 2015; 75: 4026–4031.
 Misawa A, Takayama KI, Fujimura T, Homma Y, Suzuki Y, Inoue S. Androgen−induced lncRNA POTEF−AS1 regulates apoptosis−related pathway to facilitate cell survival in prostate cancer cells. Cancer Sci 2017; 108: 373–379.
 Gu P, Chen X, Xie R, Han J, Xie W, Wang B, et al. lncRNA HOXD-AS1 regulates proliferation and chemo-resistance of castration-resistant prostate cancer via recruiting WDR5. Mol Ther 2017; 25: 1959–1973.
 Li J, Zhang Zh, Xiong L, Guo Ch, Jiang T, Zeng L, et al. SNHG1 lncRNA negatively regulates miR-199a- 3p to enhance CDK7 expression and promote cell proliferation in prostate cancer. Biochem Biophys Res Commun 2017; 487: 146–152.
 Misawa A, Takayama KI, Urano T, Inoue S. Androgeninduced long noncoding RNA (lncRNA) SOCS2- AS1 promotes cell growth and inhibits apoptosis in prostate cancer cells. J Biol Chem 2016; 291: 17861– 17880.
 Takayama KI, Horie−Inoue K, Katayama Sh, Suzuki T, Tsutsumi Sh, Ikeda K, et al. Androgen−responsive long noncoding RNA CTBP1−AS promotes prostate cancer. EMBO J 2013; 32: 1665–1680.
 Liu HT, Fang L, Cheng YX, Sun Q. LncRNA PVT1 regulates prostate cancer cell growth by inducing the methylation of miR−146a. Cancer Med 2016; 5: 3512–3519.
 Yang J, Li C, Mudd A, Gu X. LncRNA PVT1 predicts prognosis and regulates tumor growth in prostate cancer. Biosci Biotechnol Biochem 2017; 81: 2301– 2306.
 Zhu Y, Ren Sh, Jing T, Cai X, Liu Y, Wang F, et al. Clinical utility of a novel urine-based gene fusion TTTY15-USP9Y in predicting prostate biopsy outcome. Urol Oncol 2015; 33: 384. e9–e20.
 Ren Sh, Peng Zh, Mao JH, Yu Y, Yin Ch, Gao X, et al. RNA-seq analysis of prostate cancer in the Chinese population identifies recurrent gene fusions, cancer-associated long noncoding RNAs and aberrant alternative splicings. Cell Res 2012; 22: 806–821.
 Yao J, Kong D, Ye C, Chen R, Li L, Zeng T, et al. The long noncoding RNA TTTY15, which is located on the Y chromosome, promotes prostate cancer progression by sponging let-7. Eur Urol 2019; 76: 315–326.
 Shang W, Yang Y, Zhang J, Wu Q. Long noncoding RNA BDNF-AS is a potential biomarker and regulates cancer development in human retinoblastoma. Biochem Biophys Res Commun 2018; 497: 1142– 1148.
 Shen M, Xu Zh, Jiang K, Xu W, Chen Y, Xu ZH. Long noncoding nature brain-derived neurotrophic factor antisense is associated with poor prognosis and functional regulation in non-small cell lung caner. Tumour Biol 2017; 39: 1010428317695948. 1–9.
 Li W, Dou Zh, We Sh, Zhu Zh, Pan D, Jia Zh, et al. Long noncoding RNA BDNF-AS is associated with clinical outcomes and has functional role in human prostate cancer. Biomed Pharmacother 2018; 102: 1105–1110.
 Kino T, Hurt DE, Ichijo T, Nader N, Chrousos GP. Noncoding RNA gas5 is a growth arrest-and starvation-associated repressor of the glucocorticoid receptor. Sci Signal 2010; 3: ra8.
 Pickard MR, Mourtada-Maarabouni M, Williams GT. Long non-coding RNA GAS5 regulates apoptosis in prostate cancer cell lines. Biochim Biophys Acta 2013; 1832: 1613–1623.
 Xue D, Zhou C, Lu H, Xu R, Xu X, He X. LncRNA GAS5 inhibits proliferation and progression of prostate cancer by targeting miR-103 through AKT/mTOR signaling pathway. Tumour Biol 2016; 37: 16187– 16197.
 Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G. Genome regulation by polycomb and trithorax proteins. Cell 2007; 128: 735–745.
 Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Morales DR, et al. Many human large intergenic noncoding RNAs associate with chromatinmodifying complexes and affect gene expression. Proc Natl Acad Sci USA 2009; 106: 11667–11672.
 Zhang G, Han G, Zhang X, Yu Q, Li Z, Li Zh, et al. Long non-coding RNA FENDRR reduces prostate cancer malignancy by competitively binding miR- 18a-5p with RUNX1. Biomarkers 2018; 23: 435–445.
 Sakurai K, Reon BJ, Anaya J, Dutta A. The lncRNA DRAIC/PCAT29 locus constitutes a tumorsuppressive nexus. Mol Cancer Res 2015; 13: 828– 838.
 Li JB, Liu F, Zhang BP, Bai WK, Cheng W, Zhang YH, et al. LncRNA625 modulates prostate cancer cells proliferation and apoptosis through regulating the Wnt/β-catenin pathway by targeting miR-432. Eur Rev Med Pharmacol Sci 2017; 21: 2586–2595.
 Das M, Renganathan A, Dighe SN, Bhaduri U, Shettar A, Mukherjee G, et al. DDX5/p68 associated lncRNA LOC284454 is differentially expressed in human cancers and modulates gene expression. RNA Biol 2018; 15: 214–230.
 Lingadahalli Sh, Jadhao S, Sung YY, Chen M, Hu L, Chen X, et al. Novel lncRNA LINC00844 regulates prostate cancer cell migration and invasion through AR signaling. Mol Cancer Res 2018; 16: 1865–1878.
 White NM, Zhao SG, Zhang J, Rozycki EB, Dang HX, McFadden SD, et al. Multi-institutional analysis shows that low PCAT-14 expression associates with poor outcomes in prostate cancer. Eur Urol 2017; 71: 257–266.
 Luo G, Wang M, Wu X, Tao D, Xiao X, Wang L, et al. Long non-coding RNA MEG3 inhibits cell proliferation and induces apoptosis in prostate cancer. Cell Physiol Biochem 2015; 37: 2209–2220.
 Descazeaud A, Rubin MA, Hofer M, Setlur S, Nikolaief N, Vacherot F, et al. BPH gene expression profile associated to prostate gland volume. Diagn Mol Pathol 2008; 17: 207–213.
 McVary KT. BPH: epidemiology and comorbidities. Am J Manag Care 2006; 12: S122–S128.
 Armitage TG, Cooper EH, Newling DW, Robinson MR, Appleyard I. The value of the measurement of serum prostate specific antigen in patients with benign prostatic hyperplasia and untreated prostate cancer. Br J Urol 1988; 62: 584–589.
 Bokhorst LP, Bangma ChH, van Leenders GJ, Lous JJ, Moss SM, Schröder FH, et al. Prostate-specific antigen-based prostate cancer screening: Reduction of prostate cancer mortality after correction for nonattendance and contamination in the rotterdam section of the European randomized study of screening for prostate cancer. Eur Urol 2014; 65: 329–336.
 Bayat H, Narouie B, Ziaee SAM, Mowla SJ. Two long non−coding RNAs, Prcat17. 3 and Prcat38, could efficiently discriminate benign prostate hyperplasia from prostate cancer. Prostate 2018; 78: 812–818.
 Wang YH, Ji J, Wang BC, Chen H, Yang ZhH, Wang K, et al. Tumor-derived exosomal long noncoding RNAs as promising diagnostic biomarkers for prostate cancer. Cell Physiol Biochem 2018; 46: 532–545.
 Lässer C. Identification and analysis of circulating exosomal microRNA in human body fluids. Methods Mol Biol 2013; 1024: 109–128.
 Işin M, Uysaler E, Özgür E, Köseoğlu H, Şanl Ö, Yücel ÖB, et al. Exosomal lncRNA-p21 levels may help to distinguish prostate cancer from benign disease. Front Genet 2015; 6: 168.
 Alshahrani S, McGill J, Agarwal A. Prostatitis and male infertility. J Reprod Immunol 2013; 100: 30–36.
 McGlynn KA, Cook MB. Etiologic factors in testicular germ-cell tumors. Future Oncol 2009; 5: 1389–1402.
 De Toni L, Šabovic I, Cosci I, Ghezzi M, Foresta C, Garolla A. Testicular cancer: Genes, environment, hormones. Front Endocrinol 2019; 10: 408.
 van de Geijn GJM, Hersmus R, Looijenga LH. Recent developments in testicular germ cell tumor research. Birth Defects Res C 2009; 87: 96–113.
 Cost NG, Adibi M, Lubahn JD, Romman A, Raj GV, Sagalowsky AI, et al. Effect of testicular germ cell tumor therapy on renal function. Urology 2012; 80: 641–648.
 Liang M, Hu CK, He Ch, Zhou J, Liao Y. Upregulated lncRNA Gm2044 inhibits male germ cell development by acting as miR-202 host gene. Anim Cells Syst 2019; 23: 128–134.
 Sun WL, Kang T, Wang YY, Sun JP, Li Ch, Liu HJ, et al. Long noncoding RNA OIP5-AS1 targets Wnt-7b to affect glioma progression via modulation of miR- 410. Biosci Rep 2019; 39: BSR20180395. 1–11.
 Arunkumar G, Anand Sh, Raksha P, Dhamodharan Sh, Rao HPS, Subbiah Sh, et al. LncRNA OIP5-AS1 is overexpressed in undifferentiated oral tumors and integrated analysis identifies AS a downstream effector of stemness-associated transcription factors. Sci Rep 2018; 8: 7018. 1–13.
 Rezaei M, Emadi-Baygi M, Hoffmann MJ, Schulz WA, Nikpour P. Altered expression of LINC-ROR in cancer cell lines and tissues. Tumor Biol 2016; 37: 1763– 1769.
 Wang Y, Xu Zh, Jiang J, Xu Ch, Kang J, Xiao L, et al. Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal. Dev Cell 2013; 25: 69–80.
 Zhang A, Zhou N, Huang J, Liu Q, Fukuda K, Ma D, et al. The human long non-coding RNA-RoR is a p53 repressor in response to DNA damage. Cell Res 2013; 23: 340–350.
 Weidner W, Pilatz A, Altinkilic B. Andrology: varicocele: an update. Urologe A 2010; 49 (Suppl.): 163–165.
 Fretz PC, Sandlow JI. Varicocele: current concepts in pathophysiology, diagnosis, and treatment. Urol Clin North Am 2002; 29: 921–937.
 Santana VP, Miranda-Furtado CL, de Oliveira- Gennaro FG, Dos Reis RM. Genetics and epigenetics of varicocele pathophysiology: An overview. J Assist Reprod Genet 2017; 34: 839–847.
 Hollander MC, Alamo I, Fornace Jr AJ. A novel DNA damage-inducible transcript, gadd7, inhibits cell growth, but lacks a protein product. Nucleic Acids Res 1996; 24: 1589–1593.
 Fornace AJ, Alamo I, Hollander MC. DNA damageinducible transcripts in mammalian cells. Proc Natl Acad Sci USA 1988; 85: 8800–8804.
 Brookheart RT, Michel CI, Listenberger LL, Ory DS, Schaffer JE. The non-coding RNA gadd7 is a regulator of lipid-induced oxidative and endoplasmic reticulum stress. J Biol Chem 2009; 284: 7446–7454.
 Zhao J, Li H, Deng H, Zhu L, Zhou B, Yang M, et al. LncRNA gadd7, increased in varicocele patients, suppresses cell proliferation and promotes cell apoptosis. Oncotarget 2018; 9: 5105–5110.
 Hung AJ, King P, Schlegel PN. Uniform testicular maturation arrest: a unique subset of men with nonobstructive azoospermia. J Urol 2007; 178: 608– 612.
 Zhang X, Gao F, Fu J, Zhang P, Wang Y, Zeng X. Systematic identification and characterization of long non-coding RNAs in mouse mature sperm. PLoS One 2017; 12: e0173402.
 Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 2010; 464: 1071–1076.
 Tsai MCh, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 2010; 329: 689–693.
 Zhang L, Liu Zh, Li X, Zhang P, Wang J, Zhu D, et al. Low long non-coding RNA HOTAIR expression is associated with down-regulation of Nrf2 in the spermatozoa of patients with asthenozoospermia or oligoasthenozoospermia. Int J Clin Exp Pathol 2015; 8: 14198–14205.
 Chen K, Mai Z, Zhou Y, Gao X, Yu B. Low NRF2 mRNA expression in spermatozoa from men with low sperm motility. Tohoku J Exp Med 2012; 228: 259– 266.
 Zhang X, Zhang P, Song D, Xiong S, Zhang H, Fu J, et al. Expression profiles and characteristics of human lncRNA in normal and asthenozoospermia sperm. Biol Reprod 2018; 100: 982–993.