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摘要:
口腔癌是一种常见的头颈部恶性肿瘤，其发病的分子机制复杂且尚需进一步探索。非编码RNA占人类转录本的95%以上，是口腔癌发生发展机制研究的重要切入点，非编码RNA中数量庞大的microRNA、lncRNA和circRNA通过不同的途径参与了生物体内绝大部分的生理病理进程，与mRNA和蛋白质共同构成了一个复杂的调控体系。本文总结了口腔癌相关非编码RNA的研究文献及最新进展，从microRNA、lncRNA和circRNA三个方面为口腔癌的研究及防治提供参考。
Abstract:Oral cancer is a common head and neck malignant tumor. Its molecular mechanism of pathogenesis is complex and needs further exploration. Non-coding RNAs account for more than 95% of human transcripts and include microRNAs, lncRNAs, and circRNAs. They are an important entry point for research on molecular mechanism of oral cancer. Non-coding RNAs and protein-coding genes constitute a complex regulatory system involved in the regulation of physiological and pathological processes. This review summarizes articles about oral cancer-related non-coding RNAs and presents valuable information from the perspectives of microRNA, lncRNA, and circRNA.
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Key words:
- OSCC /
- Non-coding RNA /
- MicroRNA /
- LncRNA /
- CircRNA
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0 引言
研究显示，中医药治疗恶性肿瘤药性温和，毒副作用小，具有“培元固本”“扶正祛邪”的特点[1-2]。现代药理研究证实，“扶正培元”方剂中很多核心药物除自身药理功效外，多药配合使用情况下还具有促进骨髓造血、提高免疫功能的效果，可起到较好抗癌的作用[3]。岐黄学者王平教授著有《元气论》，用调补元气法治疗恶性肿瘤，临床疗效满意。本研究以湖北省肿瘤医院运用中医药参与治疗肺癌的实证研究为基础，运用数据挖掘技术和网络药理学对中医药参与肺癌治疗用药规律进行分析，探索湖北省肿瘤医院治疗肺癌的中药用药规律。
1 资料与方法
1.1 患者一般情况
收集湖北省肿瘤医院2017年1月—2020年12月参与中医药治疗的3 234例肺癌住院患者的电子病案信息（门诊号、住院号、姓名、性别、年龄、疾病分期、发病时间、治疗方案、临床症状、体征、四诊信息、西医诊断、中药处方、剂型和剂量等）。3 234例肺癌患者中，男2 310例（71.43%），女924例（28.57%）；年龄范围：10~88岁，平均年龄（59.02±9.92）岁，发病最多的年龄段为55~65岁，占总人数的35.19%。
1.2 诊断和纳入标准
诊断和治疗参照《中国临床肿瘤学会（CSCO）肺癌诊疗指南（2017.V1）》要求，病理诊断参照国际癌症机构（IARC）于2021年5月出版的《WHO胸部肿瘤分类（第5版）》[4]，疾病分期诊断参照AJCC癌症分期手册。对湖北省肿瘤医院收治的诊断为肺癌患者的诊断和病例进行筛选。其中，处方纳入标准：入选方剂须是由3味以上中药组成；中药复方务必药味完全，药量准确，主治明确，疗效确实；因症状而作的加减用药，也纳入统计范畴内。排除精神病史或神经系统功能障碍，晚期危重症（含并发症）、预计生存期 < 6个月，患有心、肝、肾等严重器官损害，资料不全和拒绝配合治疗等患者。所有患者及家属均签署知情同意书。
1.3 统计学方法
采用IBM SPSS Modeler 18.0中的Apriori关联规则算法、FP-Growth算法、Label Propagation Algorithm（LPA）算法及岐黄数据AI工作站等软件对湖北省肿瘤医院运用中医药参与治疗肺癌的用药进行分析。
2 结果
2.1 药物频次统计
本研究共纳入有效病例3 234例，处方11 293付，169味中药，累计用药频次254 004次。按照药物使用频次从高到低进行排列筛选。为便于统计分析，我们主要收集使用频次前30位的药物数据进行分析。其中，茯苓使用频次最高，达7 975次，使用频率（频次/总处方数）为70.62%，见图 1。
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图 1 湖北省肿瘤医院肺癌患者药物使用频次Figure 1 Frequency of herbs of lung cancer patients in Hubei Cancer Hospital2.2 药物性味归经统计
2.2.1 药性统计
结果发现湖北省肿瘤医院中药治疗肺癌用药以温、平为主，频次为46 079、43 262；寒、凉为次，频次为36 198、17 742，见图 2。
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图 2 湖北省肿瘤医院中药治疗肺癌用药药性频次统计雷达图Figure 2 Radar chart of medicinal peculiarity of lung cancer in Hubei Cancer Hospital2.2.2 药味统计
湖北省肿瘤医院肺癌患者用药药味以甘味为主，苦、辛为次，频次分别为82 303次、76 966次和39 655次。淡味药物频次18 332次、涩味药物频次12 036次、酸味药物频次11 565次、咸味药物频次2 098次，见图 3。
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图 3 湖北省肿瘤医院中药治疗肺癌用药药味频次统计雷达图Figure 3 Radar chart of medicinal flavors of lung cancer in Hubei Cancer Hospital2.2.3 归经统计
用药分析结果显示，用药归经频次分布前三的分别为肺经、脾经和肝经，频次分别为81 184次、77 005次和72 764次。其次为胃经（48 951次）、肾经（36 900次）、心经（32 324次）、大肠经（14 286次）、胆经（12 515次）、膀胱经（4 567次）和心包经（2 020次），见图 4。
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图 4 湖北省肿瘤医院中药治疗肺癌用药归经频次统计雷达图Figure 4 Radar chart of medicinal channel affinity of lung cancer in Hubei Cancer Hospital2.3 药物关联和聚类分析
基于FP-Growth算法挖掘病案中中药间的关联规则，得到药物之间共现关系，设置最小支持度为20%（关联规则至少在20%的病例中出现），最小置信度为80%（在前置药物出现的前提下，后置药物出现的概率大于80%），得出如下48条强关联规则，见表 1。
表 1 肺癌患者用药药物关联分析Table 1 Drug association analysis of lung cancer patients
根据关联规则分析得到湖北省肿瘤医院中药参与治疗肺癌的核心方如下：黄芪、茯苓、麸炒白术、红景天、薏苡仁、麸炒枳壳、焦山楂。
2.4 药物聚类分析
以药品是否在某位肺癌患者身上使用为特征，使用层次聚类算法对超过1 000例的76种药品进行聚类分析，找出可能的药品聚类。结果发现以分组距离70为界，药品可以分为4类。第一类（黄色）为黄芪、茯苓、红景天；第二类（红色）为北柴胡、赤芍、麸炒白术、甘草、当归；第三类（绿色）为白英、女贞子、枸杞子等；第四类（蓝色包含的药物较多，可进一步以60为界，分类：（1）陈皮，（2）莪术、石见穿等，（3）南沙参、石上柏等，（4）炒王不留行等，（5）其他，见图 5。
2.5 复杂网络核心方分析
本研究采用Jaccard距离进行复杂网络构建，然后用复杂网络分析中的Label Propagation Algorithm（LPA）算法进行核心方分析，得到治疗肺癌的核心处方组成。
2.5.1 16味中药核心方
设置参数，边取0.1百分位数，节点取最大连接组，得到包含16味中药的备选核心方，见图 6。
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图 6 湖北省肿瘤医院肺癌治疗16味中药核心方Figure 6 Sixteen core prescriptions for lung cancer in Hubei Cancer Hospital2.5.2 23味中药核心方
设置参数，边取0.2百分位数，节点取最大连接组，得到包含23味中药的备选核心方，见图 7。
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图 7 湖北省肿瘤医院肺癌治疗23味中药核心方Figure 7 Twenty-three core prescriptions for lung cancer in Hubei Cancer Hospital3 讨论
WHO发布的《全球癌症负担》报告显示，2020年我国新发肺癌病例约82万例，死亡病例约71万例，死亡率近87%，占所有癌症死亡的23.8%，肺癌新发病例和死亡病例近20年一直位居全球第一[5-7]。本研究结果发现，湖北省肺癌发病年龄主要以中老年为主，主要为元气亏虚群体。在北欧和美国的研究中，肺癌男女患者比例约为1:0.58左右，患者主要以男性为主，这与导致肺癌的生活习惯有关[8-9]。
癌症发病，多因正虚邪恋。所谓“正虚”者，是机体不足以维系阴阳平衡，抵御外邪和自我修复能力减弱，是故“邪之所凑，其气必虚”；导致“邪恋”，致“久病多虚，久病必瘀”。姚舜宇等研究发现肺癌患者体质类型的比率及95%置信区间依次为气虚质28%（23%~32%)、阳虚质14%（10%~18%)、阴虚质14%（11%~17%）、气郁质11%（9%~12%)、痰湿质9%（7%~12%）、平和质8%（6%~11%)、血瘀质6%（4%~8%）、湿热质5%（3%~6%)、特禀质1%（1%~2%）[10]。肺癌规范化治疗手段通常为手术、放疗和内科治疗如化疗、靶向及免疫治疗等。手术为早期肿瘤的有效治疗手段，但手术及放疗等同外伤、火毒，耗损五脏精血。内科治疗随着化疗、靶向药物的摄入量和疗程增加, 治疗过程中极容易引起患者口腔溃疡、恶心、呕吐、食欲减退、腹泻等症状，严重影响患者进食，导致脾胃受损。高小月等[11]研究发现非小细胞肺癌患者化疗后偏颇体质增至87.92%，且化疗后无论是平和质还是偏颇体质，都更多地向气虚质、阳虚质、气郁质和血瘀质转变。
本研究结果发现，纳入分析的中药方药药性以温性为主，平、寒为次，药味以甘味为主，苦、辛为次，归经分布前三分别为肺经、脾经和肝经。从药性及药味分析结果可见，湖北省肿瘤医院肺癌用药皆以温补培元为主。归经分析可见肺脾同治，用药直达病位所在，兼顾后天之本，法从“培土生金”。
通过关联分析发现，本研究常用共现药物主要有黄芪、茯苓、白术、红景天、薏苡仁、枳壳、焦山楂。黄芪、白术主入脾、肺经，补中益气，健脾补肺；茯苓入心、肺、脾、肾经，健脾渗湿，宁心化痰；薏苡仁、麸炒枳壳、焦山楂主入脾经、胃经，健脾和胃，补后天之气；红景天主入肺、心经，益气活血，通脉平喘。常用共现药物体现了肺癌“元气亏虚”之病机贯穿始末，治法始终坚持“培元固本”，尤以补益肺脾药物即“培土生金”为主，祛邪攻瘤为辅的特点。
聚类药物组合中，第一类组合主要治则为补气健脾活血，通脉平喘，体现肺癌治疗调补元气为第一要义。第二类组合主要以调补肝肾为主，治则为疏肝理气，补气养血，肺为五脏之华盖，主气，司呼吸，下通膀胱，肾与膀胱气化不利必累及肺脏，故用药入肾经，而肝藏血，主疏泄，肺与肝共同维持人体的经络气血调达，肝又为少阳枢机，故用药入肝经，以调畅气机，和解少阳。第三类组合主要治则为消肿散结，滋养肝肾；而第四类药物多为临证加减，辩证施治，共奏培元固本，扶正祛邪之功。
通过复杂网络分析得出，湖北省肿瘤医院治疗肺癌的16味核心处方药物组成为黄芪、茯苓、白术、红景天、薏苡仁、枳壳、焦山楂、女贞子、枸杞子、香菇柄、白英、蜈蚣、天葵子、海藻、夏枯草、山慈菇。该药物组合其主要功效是补气健脾和胃，调补肝肾，软坚散结。芪苓术并用，益气以生血。黄芪之于人参，同为补气，人参为大补元气，而肿瘤患者多为表虚多汗，使用人参易加重汗出而伤阴。黄芪既补气亦固表。正如李东垣曰：“仲景以人参为补血者，盖血不自生，须得生阳气之药乃生，阳生则阴长，血乃旺矣。若阴虚单纯补血，血无由而生，无阳故也”。方中黄芪为补气药之首，《汤液本草》云：“黄芪补五脏诸虚不足，而泻阴火，去虚热”[12]。红景天，益气活血且具通脉平喘之效。薏苡仁与茯苓共奏健脾利湿之功，但薏苡仁亦主治肺痈、癌肿。枳壳、焦山楂，调和肝脾，理气和胃；女贞子、枸杞子，滋养肝肾；香菇柄为我院陈延昌老先生抗癌特色用药；白英、蜈蚣、天葵子、海藻、夏枯草抗癌消肿散结。
大量的肺癌临床研究和基础实验证实，中药通过调控固有免疫和适应性免疫发挥“培元固本”、“扶正祛邪”的作用，联合内科治疗能够减毒增效、提高晚期肺癌患者生存率、改善生活质量、延长生存期。中药复方使用多味中药组合，能够对肿瘤患者免疫系统产生多方面的立体调控作用。以上复方紧密契合肺癌“虚为本、实为标”的主要病机，均采用“培元固本”法，尤以“培土生金”法为主要治法，以“消痰散结化瘀”为辅，坚守了中医治疗“攻不宜过，补不宜滞”的基本原则。本文的研究主要是用药规律及和核心方的总结，在以后的进一步的研究中，还将对药物的临床疗效数据进行进一步的分析与探讨。
Competing interests: The authors declare that they have no competing interests.作者贡献：傅雨婷：文献查阅、文章撰写及修改杨汶峻：文献查阅蒋斌元：提供文章撰写思路及文章审阅 -
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