Research Progress of Exosomes-derived Long Non-coding RNA in Bladder Cancer
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摘要: 膀胱癌是最常见的泌尿系肿瘤之一，具有较高的发病率和复发率，开发一种高灵敏度和高特异性的无创性体外诊断检测技术对于膀胱癌的诊断和治疗具有重要的临床价值。外泌体是一种由许多细胞分泌的细胞外囊泡，通过递送细胞内信号物质（如蛋白质，核酸，非编码RNA等）在细胞间通讯中发挥关键作用。越来越多研究表明外泌体来源的长链非编码RNA在膀胱癌发生发展中发挥重要的调控作用，能够有效地反映肿瘤的进展和预后情况，有望成为一种新的肿瘤标记物。因此就外泌体来源的长链非编码RNA在膀胱癌发生发展及诊断方面的研究进展进行综述。Abstract: Bladder cancer is one of the most common urinary tumors with the high morbidity and recurrence rate. It is of great clinical value to develop a non-invasive detection technique with the high sensitivity and specificity in vitro for the diagnosis and treatment of bladder cancer. Exosomes are extracellular vesicles secreted by many cells and play a key role in intercellular communication by delivering intracellular signaling substances （such as proteins, nucleic acids, non-coding RNAs, etc.）. More and more studies have shown that exosomes-derived long non-coding RNA plays an important regulatory role in the development and progression of bladder cancer and can effectively reflect the progression and prognosis of tumors, which is expected to become a new tumor marker. Therefore, this paper reviews the research progress of exosomes-derived long non-coding RNA in the development and diagnosis of bladder cancer.
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Key words:
- Exosomes /
- Long non-coding RNA /
- Bladder cancer
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CTEPH为毛细血管前性肺动脉高压，目前归为肺动脉高压（pulmonary hypertension，PH）的第四类，也是可能治愈的一类PH。未接受治疗的CTEPH患者死亡率高，其3 a生存率约20%～30%[1]，5 a生存率常小于15%[2]，因而危害极大。然而CTEPH的发病机制仍未完全清楚，目前有研究显示炎症反应在其中发挥了重要作用。TNF-α、IL-6是两种重要的炎症因子，在其他类型的PH中已有学者对其进行研究，而在CTEPH中关于炎症因子的研究较少，本研究检测了CTEPH患者血清中炎症因子TNF-α、IL-6的水平，并进一步探讨其临床意义。
1. 资料与方法
1.1 临床资料
收集2015年1月至2020年1月于昆明医科大学第一附属医院就诊的59例急性肺栓塞后CTEPH患者的临床资料，并设为观察组。所纳入患者CTEPH的诊断符合2018年《肺血栓栓塞症诊治与预防指南》[3]推荐的诊断流程，对于临床疑诊或超声心动图检查提示PH的患者，可经过进一步检查明确CTEPH的诊断，主要包括肺V/Q显像、CTPA、MRPA、右心导管检查和肺动脉造影等。因右心导管检查为有创性检查且成本高昂，本研究采用超声心动图提示PH结合CTPA检查进行CTEPH的诊断。超声心动图PH的判断采用《中国肺高血压诊断和治疗指南2018》[4]中的相关标准。超声心动图右心功能不全的判断采用2018年《肺血栓栓塞症诊治与预防指南》[3]中的相关标准。排除标准：自身免疫性疾病、感染性疾病、恶性肿瘤、凝血功能异常、活动性出血、严重肝、肾疾病；原发性心肌病、心脏瓣膜病、左心功能不全、其他类型PH。
观察组根据超声心动图是否存在右心功能不全进一步分为右心功能正常组（观察组1）及右心功能不全组（观察组2）。观察组1共22例，其中男性15 例，女性 7例，年龄 41～77 岁，平均（65.86±9.17）岁。观察组2共37例，其中男性26例，女性11例，年龄 38～82岁，平均（60.62±10.24）岁。随机选取同期就诊的无PH体检人群30例为对照组。其中男性 21 例，女性 9 例，年龄35～83 岁，平均 （64.63±11.04）岁。3组基础情况的比较： 各组患者年龄、性别、基础疾病等比较，差异均无统计学意义 （P > 0.05），具有可比性，见表1。
表 1 3组基础情况的比较[n（%）]Table 1. Comparisons of basic conditions in different groups [n（%）]基础情况 对照组（n = 30） 观察组1（n = 22） 观察组2（n = 37） F/χ2 P 年龄（$\bar x \pm s $，岁） 64.63 ± 11.04 65.86 ± 9.17 60.62 ± 10.24 2.194 0.118 男性 21（70.00） 15（68.18） 26（70.27） 0.031 0.985 吸烟 12（40.00） 9（40.90） 15（40.54） 0.019 0.991 高血压 9（30.00） 7（31.82） 10（27.03） 0.167 0.924 糖尿病 8（26.67） 6（27.27） 9（24.32） 0.395 0.821 冠心病 7（23.33） 7（31.82） 8（21.62） 0.818 0.664 慢支炎 10（33.33） 9（40.91） 12（32.43） 0.481 0.786 1.2 方法
NT-proBNP 、TNF-α、IL-6的检测：对所有入选者静脉采血10mL，室温静置30 min后2 500 r/min离心10 min，分离血清，NT-proBNP水平即刻上机检测，另分装于-20℃ 冰箱保存用于TNF-α、IL-6的检测。NT-proBNP检测仪器为德国罗氏公司Cobas-6000全自动电化学发光免疫分析仪，采用配套试剂盒检测。TNF-α、IL-6的检测方法为多重微球流式免疫荧光发光法，检测仪器为美国Becton Dickinson公司FACS CantoⅡ分析型流式细胞仪，采用青岛瑞斯凯尔生物科技有限公司提供的细胞因子检测试剂盒检测。
PASP的测定：采用美国飞利浦Sparq心超机进行心脏彩超检查，根据三尖瓣返流程度估测肺动脉收缩压。
1.3 统计学处理
应用 SPSS 统计软件进行分析，正态分布计量资料以均数 （
$ \bar x \pm s$ ） 表示，多组间比较采用单因素方差分析，多重比较采用LSD-t检验。采用Pearson相关分析变量间的相关性。计数资料用构成比表示，采用χ2检验进行组间比较，P < 0.05 为差异有统计学意义。2. 结果
2.1 对照组与观察组血清TNF-α、IL-6 、NT-proBNP及PASP的比较
对照组、观察组1、观察组2 血清TNF-α、IL-6 、NT-proBNP及PASP的水平依次升高，单因素方差分析显示差异有统计学意义（P < 0.05），进一步多重比较结果显示各组间差异亦有统计学意义（P < 0.05），见表2。
2.2 TNF-α、IL-6与NT-proBNP、PASP的相关性分析
Pearson相关分析显示TNF-α与NT-proBNP、PASP存在极强相关性，r分别为0.852、0.814（P < 0.05）。IL-6与NT-proBNP、PASP存在强相关性，r分别为0.726、0.681（P < 0.05），见表3。
表 2 各组TNF-α、IL-6、NT-proBNP、PASP比较（$ \bar x \pm s$ ）Table 2. Comparisons of TNF-α，IL-6，NT-proBNP，PASP in different groups （$ \bar x \pm s$ ）分组 n TNF-α（pg/mL） IL-6（pg/mL） NT-proBNP（ng/L） PASP（mmHg） 对照组 30 13.54 ± 6.37 6.04 ± 2.89 265.07 ± 132.47 32.07 ± 6.15 观察组1 22 25.20 ± 11.87* 8.56 ± 4.25* 719.52 ± 345.23* 57.04 ± 11.26* 观察组2 37 40.75 ± 1.74*△ 14.95 ± 5.24*△ 1250.00 ± 421.22*△ 73.22 ± 11.79* △ F 59.099 34.169 68.382 126.399 P < 0.001 < 0.001 < 0.001 < 0.001 与对照组比较，*P < 0.05，与组1比较，△P < 0.05。 表 3 TNF-α、IL-6与NT-proBNP、PASP的相关性分析Table 3. Correlation analysis of TNF-α，IL-6 and NT-proBNP，PASP检测项目 NT-proBNP PASP r P r P TNF-α 0.852 < 0.001 0.814 < 0.001 IL-6 0.726 < 0.001 0.681 < 0.001 3. 讨论
CTEPH是急性肺血栓栓塞症的一种远期并发症，以肺动脉血栓机化、肺血管重塑致血管狭窄或闭塞，肺动脉压力进行性升高，最终导致右心功能衰竭为特征的一类疾病。CTEPH的病理生理过程复杂，发病机制目前尚未完全明确，其中炎症反应参与了CTEPH的发生发展。
TNF-α是一种多功能的炎症因子，具有促细胞生长和分化的促增殖作用，也具有炎症效应和调节免疫应答的作用，在细胞凋亡和坏死机制中也有重要作用。TNF-α与PH的发生密切相关，Fujita M等[5]的研究观察到TNF-α过表达转基因小鼠可发生PH。肺血管重塑是PH发生的重要原因，而内皮细胞间充质转化是肺血管重塑的重要内容。有研究[6-8]显示 TNF-α参与了CTEPH的血管重塑，并且TNF-α很可能促进了CTEPH肺血管重塑过程中的内皮细胞间充质转化。因而在CTEPH的炎症反应及血管重塑等病理生理过程中TNF-α都具有重要作用。
本研究结果显示CTEPH患者血清中存在TNF-α的高表达。近期Naito A等[9]的研究也证实CTEPH患者血清中存在TNF-α的高表达。在Langer F等[10]的研究中，CTEPH患者在行肺血栓动脉内膜切除术前血清中亦有着高浓度的的TNF-α，而术后24 h迅速下降。Wu D等[11]亦发现CTEPH大鼠模型血清中有着高水平的TNF-α。这些研究均提示了TNF-α在CTEPH的病理机制中有重要作用。
笔者进一步分析发现CTEPH患者中右心功能不全者血清TNF-α水平较右心功能正常者高，且TNF-α水平与PASP、NT-proBNP呈正相关，因此TNF-α的水平可以反应CTEPH患者的右心功能及肺动脉压水平。沈和平等[7]在CTEPH大鼠模型中亦发现肺动脉及血清中TNF-α的表达明显升高，且与平均肺动脉压呈显著正相关。因右心功能不全者往往有着更差的预后，推测血清TNF-α水平很可能与CTEPH患者的预后相关，这需要进一步的随访研究进行验证。
IL-6也是一种多功能的炎症因子，在免疫应答、炎症、造血及细胞存活、增殖、凋亡中均有重要作用。Tamura Y等[12]研究发现特发性PH患者存在肺血管平滑肌细胞IL-6受体水平上调。IL-6能促进肺动脉平滑肌细胞增殖[13]、能促进肺血管周细胞向平滑肌样细胞分化[14]。因而IL-6能对肺血管壁中的多种细胞产生影响从而参与PH的血管重塑。肺特异性IL-6过表达转基因小鼠的肺内病理改变与进展期PH的病理改变一致，包括远端小动脉肌化、从样动脉病变[15]。有研究[16]发现仅皮下注射IL-6就能引起小鼠发生PH，而IL-6基因敲除纯合子小鼠在低氧诱导下不出现肺动脉压升高[17]。
Humbert M等[18]的研究发现特发性PH患者血清和肺内IL-6水平显著升高 。近期Florentin J等的研究[19]发现动脉型PH的患者和低氧诱导的PH小鼠血清及肺内IL-6水平亦显著升高。而目前缺乏CTEPH患者IL-6的研究，笔者的研究显示与其它类型的PH类似，CTEPH患者血清IL-6水平显著升高。
笔者的研究还发现IL-6水平能反应CTEPH患者的右心功能，CTEPH患者中右心功能不全者血清IL-6水平较右心功能正常者显著升高，同时IL-6水平与NT-proBNP及PSAP呈显著正相关。Prins KW等[20]的研究显示动脉型PH患者的血清IL-6水平与右心功能呈显著负相关，这与笔者的研究结果类似，然而与笔者的研究结果不同的是Prins KW等[21]的研究却显示血清IL-6水平与平均肺动脉压无显著相关性。此外有研究发现血清IL-6水平是特发性、遗传性、结缔组织病及先心病相关PH不良预后的独立预测因子，推测血清高水平的IL-6也很可能与CTEPH患者的不良预后相关，这亦需要进一步研究。
CTEPH多发生于肺血栓栓塞后，而静脉血栓栓塞症患者血清有着显著升高的TNF-α、IL-6等炎症因子水平[22]，结合笔者的研究推测急性肺血栓栓塞后持续性高表达TNF-α、IL-6等炎症因子对CTEPH的发生可能有提示作用，笔者将进一步对此进行研究。
综上所述，笔者的研究显示在CTEPH患者血清中存在炎症因子TNF-α、IL-6的高表达，并可反应患者的右心功能及肺动脉压，但样本量尚小，需进一步扩大样本量来研究。同时TNF-α、IL-6在CTEPH血管重塑中的作用以及是否能预测急性肺血栓栓塞后CTEPH的发生仍需进一步行相关基础及临床研究探索。
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