摘要：前列腺癌患者常在基础雄激素剥夺治疗后出现激素治疗抵抗,从而发展为去势抵抗型前列腺癌(castrationresistant prostate cancer,CRPC)。随着大量临床试验结果的公布,展现了恩杂卢胺作为二代抗雄药物对CRPC良好的治疗效果,显著延长患者总生存期。然而,30%的患者在接受恩杂卢胺治疗后出现药物耐药,给晚期前列腺癌患者治疗带来巨大挑战。非编码RNA (non-coding RNA,ncRNA)作为近年来分子生物学领域的研究热点,其广泛的生物学功能已介入众多疾病治疗进程中,大量研究揭示其在肿瘤发生发展、药物耐药中的关键作用。因此,阐明ncRNA与恩杂卢胺耐药性的相互关系可为深入了解恩杂卢胺耐药的发生和发展提供新思路,为逆转晚期前列腺癌治疗困境提供新靶点。本文着重阐述微小核糖核酸(microRNA,miRNA)、长链非编码RNA (long non-coding RNA,lncRNA)、环状RNA (circular,circRNA)和其他ncRNA在恩杂卢胺耐药进展中的调控机制,并系统分析其共性,为后续研究提供一定参考思路。

暂无相关信息！

[1]SIEGEL RL,MILLER KD,WAGLE NS,et al.Cancerstatistics,2023 [J].CA Cancer J Clin,2023,73(1):17-48.

[2]SUNG H,FERLAY J,SIEGEL RL,et al.Global cancer statistics 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J].CA Cancer J Clin,2021,71(3):209-249.

[3]GROSSFELD GD,CHANG JJ,BROERING JM,et al Under staging and under grading in a contemporary series of patients undergoing radical prostatectomy:results from the cancer of the prostate strategic urologic research endeavor database [J].J Urol,2001,165(3):851-856.

[4]ARMSTRONG AJ,SZMULEWITZ RZ,PETRYLAKDP,et al.ARCHES:a randomized,phase Ⅲ study ofandrogen deprivation therapy with enzalutamide or placeboinmen with metastatic hormone-sensitive prostate cancer [J].JClin Oncol,2019,37(32):2974-2986.

[5]DAVIS ID,MARTIN AJ,STOCKLER MR,et al.Enzalutamide with standard first-line therapy in metastaticprostate cancer [J].N Engl J Med,2019,381(2):121-131.

[6]VOGELZANG NJ.Enzalutamide-a major advance in thetreatment of metastatic prostate cancer [J].N Engl J Med,2012,367(13):1256-1257.

[7]STERNBERGCN,FIZAZI K,SAAD F,et al.Enzalutamideand survival in nonmetastatic,castration-resistant prostatecancer [J].N Engl J Med,2020,382(23):2197-2206.

[8]ARMSTRONG CM,GAO AC.Drug resistance in castrationresistant prostate cancer resistance mechanisms and emergingtreatment strategies [J].Am J Clin Exp Urol,2015,3(2):64-76.

[9]TODEN S,ZUMWALT TJ,GOEL A.Non-coding RNAsand potential therapeutic targeting in cancer [J].BiochimBiophys Acta Rev Cancer,2021,1875(1):188491.

[10]FLETCHER CE,SULPICE E,COMBE S,et al.Androgen receptor-modulatory microRNAs provide insightinto therapy resistance and therapeutic targets in advancedprostate cancer [J].Oncogene,2019,38(28):5700-5724.

[11]ANTONARAKIS ES,LU C,WANG H,e al.AR-V7and resistance to enzalutamide and abiraterone in prostatecancer[J].N Engl J Med,2014,371(11):1028-1038.

[12]HANSEN TB,KJEMS J,DAMGAARD CK.CircularRNA and miR-7 in cancer [J].Cancer Res,2013,73(18):5609-5612.

[13]WANG HT,YAO YH,LI BG,et al.Neuroendocrineprostate cancer (NEPC)progressing from conventional prostaticadenocarcinoma:factors associated with time to developmentof NEPC and survival from NEPC diagnosis-a systematicreview and pooled analysis [J].J Clin Oncol,2014,32(30):3383-3390.

[14]NAM RK,BENATAR T,AMEMIYA Y,et al.microRNA-652 induces NED in LNCaP and EMT in PC3prostate cancer cells [J].Oncotarget,2018,9(27):19159-19176

[15]BHAGIRATH D,LISTON M,PATEL N,et al.MicroRNA determinants of neuroendocrine differentiation in metastatic castration-resistant prostate cancer[J].Oncogene,2020,39(49):7209-7223.

[16]PACHNIS V,BELAYEW A,TILGHMAN SM.Locus unlinked to alpha-fetoproteinunder the control of the murine raf and rif genes [J].Proc Natl Acad Sci U S A,1984,81(17):5523-5527.

[17]CHEN G,WANG Z,WANG D,et al.LncRNA disease:a database for long-non-coding RNA-associated diseases [J]Nucleic Acids Res,2013,41:D983-D986.

[18]YAO M,SHI X,LI Y,et al.LINC00675 activates androgen receptor axis signaling pathway to promote castratonresistant prostate cancer progression [J].Cell Death Dis2020,11(8):638.

[19]TA HQ,WHITWORTH H,YIN Y,et al.Discovery ofa novel long noncoding RNA overlapping the LCK genethat regulates prostate cancer cell growth [J].Mol Cancer,2019,18(1):113.

[20]ZHANG B,ZHANG M,SHEN C,et al.LncRNAPCBP¹-AS1-mediated AR/AR-V7 deubiquitinationenhancesprostate cancer enzalutamide resistance [J].Cell Death Dis,2021,12(10):856.

[21]WANG R,SUN Y,LI L,et al.Preclinical study usingmalatl small interfering RNA or androgen receptor splicing varant7 degradation enhancer ASC-J9(R)to suppress enzalutamide-resistant prostate cancer progression [J].EurUrol,2017,72(5):835-844.

[22]HUANG S,LIA0 Q,LI W,et al.The IncRNA PTTG3Ppromotes the progression ofCRPC via upregulating PTTG1 [J].Bull Cancer,2021,108(4):359-368.

[23]HUARTE M,GUTTMAN M,FELDSER D,et al.Alarge intergenic noncoding RNA induced by p53 mediatesglobal gene repression in the p53 response [J].Cell,2010,142(3):409-419.

[24]MATHER RL,PAROLIA A,CARSON SE,et al.Theevolutionarily conserved long non-coding RNA LINC00261drives neuroendocrine prostate cancer poliferation and metastasisvia distinct nuclear and cytoplasmic mechanisms [J].MolOncol,2021,15(7):1921-1941.

[25]SANGER HL,KLOTZ G,RIESNER D,et al.Viroidsare single-stranded covalently closed circular RNA moleculesexisting as highly base-paired rod-like structures [J].ProcNatl Acad Sci U S A,1976,73(11):3852-3856.

[26]SALZMAN J,GAWAD C,WANG PL,et al.CircularRNAs are the predominant transcript isoform from hundredsof human genes in diverse cell types [J].PLoS One,2012,7(2):e30733.

[27]SHA J,XIA L,HAN Q,et al.Downregulation of circ-TRPS1 suppressed prostatic cancer prognoses by regulatingmiR-124-3p/EZH2 axis-mediated stemness [J].Am J Cancer Res,2020,10(12):4372-4385.

[28]XIE Y,DANG W,ZHANG S,et al.The role ofexosomal noncoding RNAs in cancer [J].Mol Cancer 2019,18(1):37.

[29]VO JN,CIESLIK M,ZHANG Y,et al.The landscapeofcircular RNA in cancer [J].Cell,2019,176(4):869-881.[30]ZHANG Y,SHI Z,LI Z,et al.Circ-0057553/miR-515-5pregulates prostate cancer cell proliferation,apoptosis,migration,nvasion and aerobic glycolysis by targeting YESI [J].OncoTargetsTher,2020,13:11289-11299.

[31]GREENE J,BAIRD AM,CASEY O,et al.CircularRNAs are differentially expressed in prostate cancer and arepotentially associated with resistance to enzalutamide [J]Sci Rep,2019,9(1):10739.

[32]WU G,SUN Y,XIANG Z,et al.Preclinical study usingcircular RNA 17 and micro RNA 181c-5p to suppress theenzalutamide-resistant prostate cancer progression [J].CellDeath Dis,2019,10(2):37.

[33]ZHANG Z,LEE JH,RUAN H,et al.Transcriptionallandscape and clinical utility of enhancer RNAs for eRNA-targeted therapy in cancer [J].Nat Commun,2019,10(1):4562.

[34 ZHAO Y,WANG L,REN S,et al.Activation ofP-TEFb by androgen receptor-regulated enhancer RNAsin castration-resistant prostate cancer [J].Cell Rep,2016,15(3):599-610.

[35]CREA F,QUAGLIATA L,MICHAEL A,et al.Integrated analysis of the prostate cancer small-nucleolar transcriptome reveals SNORA55 as a driver of prostate cancerprogression [J].Mol Oncol,2016,10(5):693-703.

[36]YI C,WAN X,ZHANG Y,et al.SNORA42 enhances prostate cancer cel viability,migration and EMT and is correlated with prostate cancer poor prognosis [J].Int J Biochem Cell Biol,2018,102:138-150.

尹皓立,徐石义,李俊,等.非编码RNA介导去势抵抗型前列腺癌对恩杂卢胺耐药的机制[J].泌尿外科杂志(电子版),2024,16(02):77-81.DOI:10.20020/j.CNKI.1674-7410.2024.02.13.

暂无相关信息！

前列腺癌是世界范围内最常见的男性恶性肿瘤之一。2023年，美国新发前列腺癌患者约28.8万例，为所有肿瘤第1位，死亡人数约3.4万例，高居第2位^[1]。随着人口老龄化现象加剧，前列腺癌发病率也逐年上升。2020年，我国新发前列腺癌患者约11万例，死亡人数约5万例，占所有肿瘤死因的2.8%^[2]。在高发病率和死亡率的背后，居高不下的晚期确诊率是目前临床面临的巨大挑战。有研究显示，近30%的前列腺癌患者在初诊时即晚期，5年生存率不足30%^[3]。晚期前列腺癌的治疗一直是前列腺癌研究领域的热点及难点。随着ARCHES^[4]和ENZAMET^[5]两项重磅临床研究结果显示，以恩杂卢胺(一种二代抗雄激素药物)为代表的新型内分泌治疗药物获批用于晚期前列腺癌的一线治疗，恩杂卢胺联合雄激素剥夺治疗(androgen deprivation treatment,ADT)能够有效延长转移性激素敏感性前列腺癌(metastatichormone-sensitive prostate cancer,mHSPC)患者的总生存期^[4-6]。类似的结果也出现在了PROSPER研究中，恩杂卢胺联合ADT治疗能够显著延长转移性去势抵抗型前列腺癌(metastatic castration-resistant prostate cancer,mCRPC)患者的无转移生存期，降低71%的死亡风险^[7]。虽然，恩杂卢胺为晚期前列腺癌患者带来了生存福音，但约30%的患者在接受恩杂卢胺治疗后短时间内出现药物抵抗，严重影响患者总生存期^[8]。目前，针对恩杂卢胺的耐药机制仍然不清，全面了解其机制有助于治疗方案的提升，改善治疗效果。人类基因组中不参与编码蛋白质的转录RNA被称为非编码RNA(non-coding RNA,ncRNA),约占98%。ncRNA早期被认为是转录过程中产生的错误，然而，随着研究不断深人，学者们发现其在细胞内具有重要生物学功能，可在表观遗传学、转录和转录后水平上调节基因表达。其强大的基因调节功能逐渐被揭露，现已成为分子生物学的重要研究领域之一。ncRNA根据其碱基长短分为短于200 bp的短链ncRNA(small ncRNA,sncRNA)和大于200 bp的长链ncRNA (long non-coding RNA,IncRNA),细分为微小核糖核酸(microRNA,miRNA)、IncRNA、环状RNA(circular,6cRNAs)和小核仁RNA(small nucleolar RNA,snoRNA)等，均在生物体内发挥重要作用。ncRNA作为生物体内强大的功能调节因子，参与肿瘤发生发展及药物耐药的多个环节^[9]。研究结果显示，部分ncRNA参与恩杂卢胺的耐药进程。本文对ncRNA失调在前列腺癌恩杂卢胺耐药中的调节作用的最新进展作一综述。

1 miRNA失调引起前列腺癌恩杂卢胺耐药

2 IncRNA失调引起前列腺癌恩杂卢胺耐药

3 circRNA失调引起前列腺癌恩杂卢胺耐药

4 增强子RNA及snoRNA失调引起前列腺癌恩杂卢胺耐药

5 总结及展望

恩杂卢胺是口服二代雄激素受体抑制剂，已成功获批用于晚期前列腺癌一线治疗，挽救数以万计前列腺癌患者生命。然而，恩杂卢胺耐药性的出现导致其对晚期前列腺癌长期治疗效果产生不利影响。NcRNA作为近年来研究热点在多种肿瘤进程中发挥关键作用，大量研究证实，ncRNA参与了恩杂卢胺耐药的方方面面。因此，揭示ncRNAs与恩杂卢胺耐药性的相互关系可为深入了解恩杂卢胺耐药的发生和发展提供新思路，为逆转晚期前列腺癌治疗困境提供新靶点。本文着重阐述miRNA、IncRNA、circRNA和其他ncRNA在恩杂卢胺耐药进展中的调控机制，并系统分析其共性，为后续研究提供一定参考思路。与其他机制相比，AR基因的表达及下游通路的激活在ncRNA介导的恩杂卢胺耐药性中至关重要。虽然一些ncRNA不直接靶向AR,但他们通过miRNA分子海绵效应或WNT/β-catenin通路来调节AR表达。此外，众多ncRNA通过促进肿瘤细胞神经内分泌化导致细胞产生药物耐药性，靶向这些异常表达的ncRNA或将成为逆转肿瘤神经内分泌化、逆转药物耐药的关键。CRPC的耐药性和转移性是临床预后的难题。早期准确的预测和诊断有利于临床医师了解疾病的演变情况，并及时做出适当的临床干预。综上，CRPC中ncRNA的异常表达有望于被开发为恩杂卢胺耐药的生物标志物，尽管大量实验数据表明ncRNAs治疗恩杂卢胺耐药具有良好的前景，但其临床转化仍是一个亟待解决的问题。此外，由于耐药的复杂性，可同时存在多种耐药机制，这将限制单一疗法的精确性。尽管具有挑战性，但随着临床前工作研究的深入，恩杂卢胺耐药性面临的挑战终将得到克服，ncRNAs在CRPC的耐药性、早期预测和治疗中的价值将不断体现。

暂无相关信息！

暂无相关信息！