2. 南京医科大学附属泰州市人民医院胸外科,泰州 225300;
3. 复旦大学附属中山医院胸外科,上海 200032
2. Department of Thoracic Surgery, Taizhou People's Hospital, Nanjing Medical University, Taizhou 225300, Jiangsu, China;
3. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
生物节律也称昼夜节律、生物钟,英文表达“circadian rhythm”最早来源于拉丁语,意思为“大约1 d ”。在生物体内,生物节律是一种内源性、自主性,以地球自转时间为周期的“振荡器”,维持生物体1 d内的正常生理,包括睡眠-觉醒、活动行为、代谢、内分泌及细胞周期等,这是生物在进化过程中与地球环境相适应的结果[1]。在哺乳动物体内,生物节律由位于下丘脑前部的视交叉上核的中枢节律系统和位于全身组织细胞内的外周节律系统构成[2-3]。其中,中枢节律系统可接受由视网膜下丘脑束传递的感光信号,并受到光信号的调控,从而维持中枢生物节律系统的“振荡”;而外周生物节律系统,一方面受到中枢节律系统的同步“振荡”调控,一方面自主维持生物节律[4]。
在细胞水平,生物节律基因和相应表达产物调控生物节律,如时钟基因(CLOCK)、芳香烃受体核转位因子样蛋白1/2(aryl hydrocarbon receptor nuclear translocator-like 1/2, ARNTL1/2)。CLOCK与ARNTL1/2作为转录因子特异性直接驱动10%~15%基因转录,此外还同生物节律抑制因子昼夜节律(period, PER)基因和隐花色素(cryptochrome, CRY)基因等共同构成反馈回路,在动态变化的同时维持自我稳定,即重置“时钟相位”[5]。在该过程中,生物节律基因也同时将节律信息整合到机体和细胞的多种生理过程中,如细胞衰老、细胞代谢、DNA损伤修复和细胞周期进程等[6-7]。
生物节律的破坏会对机体的正常生理造成严重影响,包括细胞周期和细胞增殖能力的改变及恶性肿瘤的形成。流行病学调查[8]发现,工作导致生物节律紊乱的工人患乳腺癌的风险增加;动物研究[9]显示,对模型小鼠的中枢生物节律系统消融破坏后,小鼠体内的肿瘤会表现出明显的生长和进展;大量细胞研究[10-12]通过生物信息学分析发现,生物节律基因可能在肿瘤细胞的增殖、迁移、侵袭、肿瘤免疫逃逸等过程中发挥潜在作用;分子机制层面,目前已发现生物节律基因可通过促进肿瘤血管形成、重编程肿瘤细胞代谢等多种调控方式调控肿瘤的进展和转移,且在这个过程中具有一定的激素依赖性[13-14]。但是,目前生物节律在恶性肿瘤形成和发展中的作用及分子机制仍需进一步系统研究。
1 生物节律的基因调控基础生物节律以细胞为基本单位,其自主分子振荡器由中枢视交叉上核和外周组织细胞中相互作用的正转录/翻译反馈回路和负转录/翻译反馈回路共同组成[15-16]。PER1/2/3基因和CRY1/2基因为反馈回路中的重要分子,其表达产物可以特异结合于生物节律核心元件,具有抑制转录因子的作用[17]。生物节律的核心蛋白元件由CLOCK和ARNTL1/2构成,两种蛋白可以分别单独作为转录激活因子调控下游基因的表达,也可通过二者蛋白亚基中的螺旋-环-螺旋结构域相结合形成异二聚体转录激活因子,共同调控下游基因的表达[18-19]。生物节律核心输出基因表达产物和生物节律抑制基因表达产物间的相互作用,同时受到其他分子的间接调控,如CRY与PER结合后通过磷酸化降解[20],同时PER和CRY的表达又受到人分化型胚胎软骨发育基因1/2(differentiated embryonic chondrocyte expressed gene 1/2,DEC1/2)的调控[21]。这样既紧密联系又相互独立的调控网络构成了生物节律以固定时间相位稳定振荡的分子基础。
中枢节律系统还受到外界光信号的刺激和调节[22],因此其节律基因具有不同表达和调控模式。中枢节律系统中PER1和PER2基因的表达便会因光信号不同而出现差异。PER1受到光信号刺激后可迅速上调达到峰值,而PER2表达上调较慢[23]。光信号还会通过间接调控CRY1与ARNTL1的结合,抑制其形成二聚体,从而抑制由二聚体调控的下游基因的表达。此外,在接受同机体时间相位不同的光信号刺激时,中枢节律系统会表现出不同的调控结果。在正常情况下,光信号可以刺激中枢节律系统中的DEC1,但夜间光信号不导致DEC1表达增加,而刺激PER1/2表达[24],相关机制目前尚不完全清楚。
一些非编码RNA(如微小RNA、长链非编码RNA)也可在转录水平、翻译水平直接或间接调控生物节律基因或元件表达[25]。而另外一些分子通过与生物节律基因相互作用调控振荡过程,如:蛋白激酶C受体1(receptor for activated C kinase 1,RACK1)可介导PER1发挥作用[26],MAPK级联的激活能诱导和重置生物节律基因的表达和振荡[27]。
2 生物节律分子组蛋白修饰和甲基化调控基因组重编程和表观遗传变化在肿瘤发生发展过程中具有重要意义。一些关键的染色质重塑因子受到调控并通过影响组蛋白修饰而在该过程中发挥重要作用[28]。许多调节生物节律基因的组蛋白修饰酶与肿瘤进展有关。乙酰化是参与肿瘤发生和进展过程中主要的翻译后修饰,而参与生物节律系统调控的去乙酰化酶SIRT1/6与细胞衰老和肿瘤形成有关[29-30]。有研究[31]发现,SIRT1表达在白血病干细胞中异常上调,并且和原癌基因蛋白MYC之间存在串扰,而MYC在急性髓性白血病中驱动FLT3受体酪氨酸激酶抗性;SIRT6在肿瘤细胞有氧糖酵解过程中具有解控作用,而有氧糖酵解是肿瘤细胞赖以生长的关键产能机制。另外,组蛋白去乙酰化酶3(histone deacetylase 3, HDAC3)的表达受到生物节律元件的控制,其表达下调已被证实与肝细胞癌中肿瘤细胞的侵袭和转移过程相关[32]。这说明生物节律可调节组蛋白修饰酶,从而对肿瘤细胞的进展进行调控。
肿瘤细胞在肿瘤进展中的甲基化和去甲基化过程也受到生物节律的调控。DNA甲基化在肿瘤的发生和发展中同样具有关键性的作用[33],其中甲基转移酶MLL1/3(mixed lineage leukemia 1/3)作为关键调控因子在CLOCK: ARNTL1二聚体目的基因启动子区域募集的过程中具有重要作用[34]。MLL1/3在多种恶性肿瘤中发生突变,并可作为多种microRNA的靶向调控基因,调控肿瘤细胞的周期停滞和凋亡[35]。该过程便将甲基化调控及microRNA参与的生物节律调控串联起来。位于视交叉上核的中枢生物节律系统中存在与受到光信号刺激相关、与生物节律基因表达相适应的振荡动态DNA甲基化改变[36]。生物节律基因也直接受到甲基化的调控,CRY和PER的启动子区域在某些肿瘤细胞中被甲基化[37]。上述研究表明,甲基化过程与生物节律相互影响,生物节律对肿瘤细胞的表观遗传过程具有复杂的调控作用。
3 生物节律在肿瘤代谢中的重编程和缺氧微环境调控作用生物节律在细胞的正常生理和代谢过程中具有重要作用[38]。相比正常细胞生理和代谢过程,肿瘤细胞能量代谢出现明显的重编程和改变,其在增殖、迁移和侵袭等过程中对能量的需求和消耗增加;肿瘤细胞在缺氧环境中也会出现相应的改变[39]。肿瘤细胞这种生理代谢的改变伴随生物节律的改变甚至丧失。生物节律可通过调控糖酵解、糖异生、脂质生成和分解、氨基酸代谢和核苷酸形成等影响细胞代谢。代谢组学和脂质组学分析[40]已表明,细胞内将近一半的糖、脂质、氨基酸、核苷酸及辅酶因子均受到生物节律的调控。
在肝细胞癌中,P2驱动表达的肝细胞核因子4α(P2-HNF4α)通过抑制ARNTL1的转录,从而参与肿瘤细胞转移过程中一系列关键基因的表达,而在特定表达P2-HNF4α的肝癌细胞中过表达ARNTL2可再次抑制肿瘤细胞的生长[41]。MYC是多种恶性肿瘤进展过程中的关键基因,MYC在肿瘤细胞中的表达上调会破坏生物节律基因的表达,并扰乱肿瘤细胞的葡萄糖和谷氨酰胺代谢[42-43]。MYC的过表达则通过REV-ERBα抑制ARNTL1表达的负向作用,以及AMPK和己糖激酶1/2(HK1/2)对细胞代谢振荡的解除作用。
缺氧同样对肿瘤细胞代谢和肿瘤微血管生成具有重要作用[44],而生物节律对低氧诱导因子(hypoxia-inducible factor, HIF)的转录表达具有调控作用[45]。HIF是由HIF-1α和HIF-1β构成的二聚体,其中HIF-1α的表达受到生物节律元件ARNTL1和CLOCK及转录调节因子人叉头框K1(forkhead box K1, FOXK1)基因的共同调控。因此,生物节律也可调控缺氧依赖性基因的振荡表达[46]。在小鼠成肌细胞C2C12中,ARNTL1的敲除会改变FOXK1的质核定位,从而引起HIF-1α依赖的糖酵解过程减弱[47]。但是,耗氧增加的肿瘤微环境如何受到生物节律依赖性的转录调节目前仍不明确;肿瘤进展过程中的生物节律基因表达改变甚至丧失会对HIF依赖性的信号转导产生怎样的影响也不清楚。因此,生物节律破坏如何通过影响肿瘤代谢推动肿瘤进展,成为未来亟待解决的问题。
4 生物节律在肿瘤进展和转移中的作用肿瘤细胞与正常细胞具有不同的生物周期模式。肿瘤细胞生物节律的破坏与其增殖能力改变有关。PER1/2能抑制乳腺癌细胞增殖,而肿瘤细胞在1 d特定时间内通过下调PER1/2的表达促进肿瘤细胞增殖[48-49]。
正常生理情况下,生物节律元件可通过上调细胞周期抑制基因和降低存在驱动基因突变的细胞对增殖信号的反应能力,显著抑制细胞的异常生长和增殖。在生物节律元件被破坏后,PER2可通过下调β-catenin及其靶基因信号通路,抑制结肠肿瘤的发生和发展;而在结肠肿瘤细胞中,PER2的表达下调,从而导致β-catenin及cyclin D表达上调,促进结肠癌细胞的增殖[50]。而表达上调的β-catenin还会通过反馈性促进PER2的降解增强由PER2引起的促结肠癌肿瘤细胞增殖作用[51]。
转铁蛋白受体1(transferrin receptor 1, TFR1)是转铁蛋白向细胞运送铁过程所必须的细胞表面受体之一,在细胞铁死亡调控中具有重要作用[52]。目前已发现,TFR1的过表达与细胞的增殖加快有关,能促进结直肠癌进展[53]。在胰腺癌中,PER1表达能抑制肿瘤坏死因子α(TNF-α)对MIA PaCa-2细胞增殖和转移的抑制作用;而敲低PER1后,MIA PaCa-2细胞增殖和转移能力明显降低[54]。在前列腺癌细胞中,ARNTL1表达显著上调,同样具有促进肿瘤细胞增殖的作用[55]。褪黑激素可以通过上调CLOCK和PER2的表达、下调ARNTL1的表达,重置前列腺癌细胞的生物节律相位,从而抑制其生长和增殖。
此外,在肿瘤细胞中,DNA的合成可能受到血小板衍生生长因子(platelet derived growth factor, PDGF)等的调节[56]。PDGF在肿瘤发展过程中被异常激活,与肿瘤微血管生成、肿瘤细胞黏附和侵袭能力增强有关[57],而这一途径可能受到生物节律的调控[58]。DNA合成过程中具有抑制细胞凋亡作用的端粒酶在肝细胞癌的癌细胞中以生物节律模式异常表达[59]。
5 生物节律在肿瘤治疗中的时间动力学效应生物节律机制研究在对恶性肿瘤的干预或治疗中具有重要的临床转化价值。生物节律通过调控多个生理过程的节律振荡,影响药物治疗的效率和患者耐受度。目前,研究人员已考虑通过最佳时间疗法优化肿瘤患者的化疗给药方案,尽可能提高药物的抗肿瘤细胞作用,并尽可能减小药物对正常组织的毒性。
研究[60]表明,充分评估ARNTL1和REV-ERBα的转录谱有助于将化疗药物的毒性降至最低。ARNTL1的过表达可抑制结直肠癌细胞的增殖,并提高其对奥沙利铂的敏感性[61]。mTOR的表达受到节律基因的调控并振荡表达,在肾透明细胞癌的药物治疗中,在mTOR表达高峰期给药可改善患者预后[62]。一项Ⅱ期临床研究[63]显示,对局部晚期低位直肠腺癌患者采用与生物节律相适应的5-氟尿嘧啶联合亚叶酸钙计时化疗,可显著提高抗肿瘤效率,并降低不良事件发生率。肿瘤细胞的生物学参数(如生长动力学参数)在最佳治疗时机中起关键作用,这为个体化、精准化治疗方案的制定提供了重要参考。在肿瘤的靶向治疗过程中,肿瘤细胞周期和增殖速率是以细胞周期为靶点的特异性药物有效给药时间的重要参数[64]。有研究[65]表明,在接受伽马刀放射治疗的非小细胞肺癌脑转移患者中,相比于下午或夜间手术,早晨或上午手术后患者中枢神经系统相关死亡率更低、生存预后更好。
6 小结在过去的十余年间,从流行病学研究到基础研究,从转化研究到获得2017年诺贝尔生理或医学奖的研究,均表明生物节律几乎存在于人体的全部器官和组织细胞中,并与多个生理和病理过程相关。一方面,生物节律基因的表达产物多具有转录因子作用,可节律性地调控其他基因的表达,从而导致蛋白质在1 d内的振荡表达。因此,生物节律被破坏会引起这些基因和蛋白质的异常表达,从而导致细胞增殖失调和肿瘤发生。另一方面,生物节律基因还具有非节律性的调控功能,在细胞周期、DNA损伤反应和基因组稳定性方面发挥作用。
目前,生物节律对肿瘤进展的调控作用及调控机制仍未阐明,而深入研究生物节律基因与药物药效学、药代动力学参数之间的联系是目前亟待解决的问题。在个体化、精准化治疗时代,根据患者的生物节律节点和药物靶点的振荡来对治疗策略进行调整将是医学未来的重要发展方向之一。
利益冲突:所有作者声明不存在利益冲突。
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