摘要：膀胱癌(bladder cancer,BC)是泌尿系统常见恶性肿瘤之一,其具有高复发及高死亡率,目前临床主要治疗方案仍以手术联合化学治疗为主,患者对化疗药物的耐药导致肿瘤进展较快,故患者死亡率较高。非编码核糖核酸(non-coding ribonucleic acid,ncRNA)是一类不具备编码蛋白功能的核糖核酸(ribonucleic acid,RNA),ncRNA参与各系统疾病,其在BC中通过参与肿瘤细胞的各种生物学活动介导肿瘤的发展,同时,其在化学药物耐药发生过程中也发挥举足轻重的作用,本文就近年来ncRNA与BC化学药物耐药的相关性研究结果作一综述。

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膀胱癌(bladder cancer,BC)是泌尿系统最常见的恶性肿瘤之一，每年全球约有55万例新发病例^[1]。根据肿瘤浸润程度，分为非肌层浸润性膀胱癌(non muscle-invasive bladder cancer,NMIBC)及肌层浸润性膀胱癌(muscle invasive bladder cancer,MIBC)。NMIBC由于耐药导致复发率高达50%～70%,目前，有研究发现BC对顺铂(cisplatin,Cis)联合吉西他滨(gemcitabine,GEM)化疗最灵敏，但MIBC仍有50%以上会出现耐药^[2]。据统计，由于耐药可导致50%的患者在2～3年内进展为远处转移状态^[3]。因此，探索化疗耐药机制，可为BC药物治疗提供新的理论基础及治疗靶点^[4]。BC耐药机制主要包括药物外排、上皮-间质转化(epithelial-mesenchymaltransition,EMT)、细胞自噬、基因表观遗传学修饰等，降低摄取和积累药物、激活谷胱甘肽解毒系统、加强脱氧核糖核酸(deoxyribonucleicacid,DNA)修复及上调抗凋亡途径等^[5]。在各种耐药机制中均能够发现有基因参与，并在其中起到举足轻重的作用。核糖核酸(ribonucleic acid,RNA)按是否能够编码蛋白质分为两大类，包括编码蛋白质和非编码蛋白质。转录基因组约能编码20000多种蛋白质，但其只占整个转录基因组的2%,非编码RNA(non-coding RNA,ncRNA)占比则高达70%^[6-7]。经过多年研究，ncRNA在肿瘤细胞的各个生物学过程中发挥着重要作用，已成为近年来各个领域的研究热点。ncRNA目前发现的有非编码长链RNA(long non-coding RNA,IncRNA)、微小RNA(micro-RNA,miRNA)、环状RNA(circular RNA,circRNA),通过在肿瘤细胞转录前、中、后的水平，对肿瘤发生、发展、转移、耐药等产生影响^[6]。ncRNA种类繁多，有部分还能够通过参与膀胱癌干细胞(bladder cancer stem cells,BCSCs)的生物学行为来影响BC对化学药物的灵敏度。

1 IncRNA

1.1 IncRNA FOXD2-AS1通过药物外排实现BC耐药

1.2 IncRNA SNHG16通过影响肿瘤耐药细胞凋亡降低肿瘤化学药物灵敏度

1.3 肿瘤微环境与RNA HIF1A-AS2作用介导发生耐药  

1.4 lncRNA通过干扰BC干细胞影响肿瘤化学药物灵敏度  

2 circRNA

2.1 circ 0058063充当miR-335-5p海绵促进发生耐药

2.2 circ 0008399通过影响基因甲基化影响肿瘤细胞耐药

2.3 Hsa circ 0072309与MSH2蛋白作用增加肿瘤细胞化疗灵敏度

3 miRNA

3.1 miRNA影响肿瘤细胞凋亡及耐药

3.2 miRNA参与药物外排过程实现肿瘤细胞耐药

3.3 miRNA通过与IncRNA作用影响肿瘤细胞自噬诱导肿瘤细胞耐药

4 总结

目前，BC治疗方案仍以手术联合化学治疗为主，其高耐药率导致患者的治疗效果差，若能掌握BC的耐药机制，从机制中找到阻断或逆转耐药的方法、药物，有望改善BC的治疗效果，降低患者经济负担。ncRNA家族数量庞大，能够参与各个系统的疾病进程，并发挥促进或抑制疾病发展的作用。其能够在转录前、中、后通过联合相关基因、蛋白，通过调节相关信号通路，改变肿瘤微环境等方式在肿瘤耐药过程中发挥作用，既能够导致耐药产生，也能够逆转或阻止耐药结果。ncRNA只有数千道尔顿的重量，其分子量小，故相比于大分子药物更容易穿透组织屏障和细胞膜到达肿瘤细胞内部，且ncRNA含有许多氢键供体和受体，携带多个负电荷，具有良好的组织相容性，若能充分利用这一特性，可更好地实现靶向肿瘤细胞进入肿瘤细胞内，继而更有效地影响肿瘤细胞的生物学行为，提高治疗效果^[6]。然而，由于其家族庞大，涉及面广泛，相关作用机制相互交错成网，为研究带来了极大挑战，作用机制仍需更深层次的探索，力求发现最有效的靶点，提高BC化学药物灵敏度，改善BC预后。近10年来，对BC的治疗研究一直没有突破性进展，故目前手术和化学治疗仍为主要的治疗手段。免疫治疗在很多肿瘤治疗方面已被证实有效，然而，BC方面的免疫相关治疗尚在探索阶段，有学者证明了免疫检查点抑制剂在转移性MIBC中具有一定疗效，但国外很多回顾性研究发现，免疫治疗试验的应答率低于30%^[42]。相对于化疗组，接受免疫疗法单药治疗的患者的生存期更短^[42]。目前，仍有很多学者投身于免疫方面的研究，研究人员也期待在将来能够发现有效的治疗BC免疫药物。肿瘤微环境在癌症进展和治疗抗性中起着关键作用，而肿瘤微环境也能够影响ncRNA对BC的耐药。肿瘤微环境中的基质成分及分泌蛋白能够影响表观遗传学发生变化，如微环境发生改变导致成纤维细胞生长因子和IncRNA的突变，导致发生化学耐药性^[43]。肿瘤微环境改变还能够影响BCSCs的生物学行为，促进或抑制肿瘤进展和耐药。因此，可通过影响肿瘤微环境进而改变基因表观遗传、影响信号通路的信号传导、干扰肿瘤干细胞生物学行为，从而阻断、逆转耐药，提高BC治疗效果。综上所述，由于BC目前缺乏有效的靶向药物、免疫治疗方案、放疗等治疗手段，导致BC低治愈率、高复发率、疾病进展快。故在没有发现其他有效治疗手段前，明确耐药机制，并针对耐药机制找到相关靶向药物，阻断、逆转耐药结果，对改善BC治疗后果至关重要。

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