维生素D与结直肠癌的相关性及作用机制
Correlations and Mechanisms between Vitamin D and Colorectal Cancer
DOI: 10.12677/acm.2024.1461794, PDF, HTML, XML, 下载: 24  浏览: 61  科研立项经费支持
作者: 赵 为, 刘 岚*:山东大学第二医院消化内科,山东 济南
关键词: 维生素D结直肠癌预防作用机制肠道微生态Vitamin D Colorectal Cancer Prevention Mechanism of Action Gut Microbiota
摘要: 维生素D传统上被认为对体内钙和磷平衡有影响,但最近的证据强调了它对结直肠癌(Colorectal Cancer, CRC)的保护作用。本文综述了维生素D在预防结直肠癌中的作用,并探讨了维生素D对结直肠癌的影响机制。我们从PubMed和Web of Science中检索了维生素D在结直肠癌预防和治疗中的作用和机制。维生素D在结直肠癌的防治中发挥着越来越重要的作用,然而,维生素D适当剂量的选择是其在预防结直肠癌作用中有争议的部分。1α,25-二羟基维生素D3 [1,25(OH)2D3]通过多种信号通路发挥抗CRC作用,包括抑制增殖、诱导分化和凋亡、抑制转移和血管生成。此外,在肿瘤微环境(Tumor Microenvironment, TME)中,维生素D可以作用于CRC相关的间质成纤维细胞和CRC干细胞,发挥抗肿瘤作用。它还可以通过调节肠道微生物群,促进肿瘤抑制。维生素D对CRC的有效预防作用可以指导维生素D的合理使用,并为未来临床试验的合理设计和潜在机制的研究提供信息。
Abstract: While vitamin D is traditionally acknowledged of effects on homeostasis and phosphorus, recent evidence has highlighted its protective effect against colorectal cancer (CRC). The review investigates vitamin D function in CRC preventing and discusses mechanisms by which it affects CRC. Vitamin D role and mechanism in CRC prevention and therapy were searched from PubMed and Web of Science. Vitamin D plays an increasingly significant role in CRC prevention and treatment. However, its controversial role in CRC prevention depends, in part, on the selection of appropriate doses. 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] exhibits anti-CRC effects through various signalling pathways, involving suppressing proliferation, inducting differentiation and apoptosis, and inhibiting metastasis and angiogenesis. Moreover, within the tumour microenvironment (TME), vitamin D can act on CRC-associated stromal fibroblasts and CRC stem cells to exert antitumour effects. It may also regulate the gut microbiota to promote tumour repression. Vitamin D has beneficial preventive effects against colorectal cancer. These findings can guide vitamin D using appropriately and inform rational design of future clinical trials and research on the underlying mechanisms.
文章引用:赵为, 刘岚. 维生素D与结直肠癌的相关性及作用机制[J]. 临床医学进展, 2024, 14(6): 443-452. https://doi.org/10.12677/acm.2024.1461794

1. 前言

结直肠癌(Colorectal Cancer, CRC)在全球的发病率很高,每年有近1000万人死于癌症,其中CRC排在第二位[1]。流行病学研究表明,通过改变饮食(如增加纤维摄入、低脂饮食、补充乳制品和钙、减少红肉和加工肉类摄入等)及生活方式,可在高达50%的病例中预防CRC的发生[2]。当CRC的病因和预后与生活方式和饮食因素相关联时,维生素D是一个值得注意的话题。维生素D是一种类固醇激素,主要功能是调节骨代谢,但具有许多其他生理功能,如抗炎、免疫调节和抗血管生成作用,可能作为癌症抑制剂发挥作用[3]。维生素D3是胆固醇的衍生物,因此,它也被称为胆钙化醇;25-羟基维生素D3 [25(OH)D]是维生素D3的主要形式;1α,25-二羟基维生素D3 [1,25(OH)2D3]是最活跃的维生素D代谢产物,参与了肠道器官的平衡[4]。维生素D缺乏症在世界范围内非常普遍,并与多种慢性疾病相关,包括恶性肿瘤[5]。在过去的几十年里,维生素D和CRC之间的关系得到了广泛的探索。目前的研究表明,维生素D与CRC的发病率呈负相关。此外,高维生素D水平有助于降低CRC和息肉的复发风险,并与CRC患者更好的生存率有关[6]。一项大规模的前瞻性研究也描述了血清维生素D浓度与CRC发病率之间的负相关关系,其中近端结肠癌的相关性最强[7]。这些结果表明维生素D在抑制CRC的发生发展中发挥着重要作用。

目前的观察性数据支持维生素D和CRC之间的关系,尽管在一些常见肿瘤的病因学中,维生素D不足的影响仍有争议。维生素D不仅能诱导CRC细胞凋亡和生长停滞,还能调节DNA修复、免疫和Wnt信号通路[6],支持了维生素D与CRC可能的因果关系。相关研究也显示,维生素D3的补充对结直肠腺瘤的影响可能与维生素D受体(Vitamin D Receptor, VDR)的基因型有关,有的基因型可能特别受益于维生素D3和/或钙补充剂,提示了两者之间可能的因果关系[8]-[10]。本文旨在系统分析维生素D与CRC的相关性,指导临床用药,并阐明其潜在机制。

2. 维生素D在预防结直肠癌中的作用

2.1. 预防作用

维生素D对CRC的发展有保护作用。来自病例对照和前瞻性队列研究的荟萃分析和系统回顾的定量结果支持维生素D补充与降低CRC风险之间的联系,描述了血清25(OH)D水平和维生素D摄入与CRC风险之间的负相关性[11] [12]以及血清25(OH)D浓度升高与死亡风险降低之间的联系[13],表明了维生素D对CRC预防的基本作用[14]。也有研究表明,维持足够的维生素D对预防CRC,特别是结肠肿瘤有潜在的好处[9]。一项涉及17个队列的研究表明,较高浓度的循环25(OH)D明显降低了女性的CRC风险[15]。另外Huang等人结合以往随机对照试验(Randomized Controlled Trials, RCTs)的数据,指出钙和维生素D对CRC发展的前瞻性益处,包括降低结直肠腺瘤发病率、抑制恶性转化和改善预后,对左侧CRC患者和女性具有额外的保护作用[16]。这些研究结果表明,维生素D缺乏可能是早期患CRC的一个危险因素,通过补充确保维生素D充足对于预防早发性CRC及结直肠腺瘤可能特别重要。

2.2. 推荐剂量

维生素D在预防CRC方面的争议部分归因于维生素D适当剂量的选择[14]。为了给所有年龄段的人提供最大的骨骼健康,大多数委员会认为,推荐的摄入量应确保血清25(OH)D浓度 ≥ 50 nmol/L。不同的委员会提出了不同的建议(表1) [17]。Bischoff等人认为,对于CRC来说,90~100 nmol/L的血清25(OH)D浓度是最有利的[18]。Gorham等人得出的结论是,每天摄入1000~2000 IU的维生素D可以明显降低CRC风险,而且没有毒性[19]。剂量反应分析表明,25(OH)D水平增加20 nmol/L与全因死亡率和CRC特异性死亡率分别降低7%和12%密切相关[20]。一项病例对照研究显示,100 IU/天的维生素D摄入可降低4%的CRC风险[21]。有研究表明,更高的总维生素D摄入量与早发性CRC风险降低有关[11] [22]。然而,还需要更大规模的前瞻性研究和临床试验来证实这种关联。此外,在维生素D的实际临床应用中,与高剂量相关的高钙血症限制了1,25(OH)2D3和维生素D的应用[23]。因此,高剂量的维生素D补充可能仍存在争议,但适当剂量的维生素D显然可以起到保护作用。

Table 1. The recommended vitamin D intake

1. 维生素D的推荐摄入量

机构

时间(年)

年龄

推荐摄入量

血清25(OH)D浓度

美国医学研究所

2011

1~70岁

600 IU/d

≥50 nmol/L

≥71岁

800 IU/d

加拿大卫生部

2010

≤1岁

400 IU/d

≥50 nmol/L

1~70岁

600 IU/d

≥71岁

800 IU/d

世界卫生组织

2016

1~70岁

200 IU/d

≥50 nmol/L

欧洲食品安全局

2016

1~70岁

600 IU/d

≥50 nmol/L

英国营养科学咨询委员会

2016

1~70岁

400 IU/d

≥50 nmol/L

美国内分泌学会

2011

≤1岁

400~1000 IU/d

≥75 nmol/L

1~18岁

600~1000 IU/d

≥18岁

1500~2000 IU/d

上述数据来自于发达国家在年龄各个阶段对维生素D的官方建议摄入量。

有几项研究评估了单独补充维生素D和与钙结合使用的差异。Grau等人进行了一项RCT研究,以确定CRC与维生素D或钙补充剂之间的联系,报告称只有同时接受钙和维生素D补充剂的人的CRC风险才会明显下降[24]。同样,Scragg等人证明,大剂量维生素D补充剂而没有钙剂对肿瘤预防无效[25]。虽然有研究表明维生素D和钙只有同时服用才能预防CRC,但相关研究相对较少,因此单独补充维生素D是否有利于预防CRC还有待进一步研究。

2.3. 未来应用

限制大剂量和长期服用维生素D的主要障碍是高钙血症和组织钙化[26] [27]。1,25(OH)2D3的功效由于化学不稳定性而受到限制,因为它很容易被CYP24A1转化为无活性形式[23]。因此,维生素D类似物逐渐受到关注。维生素D类似物EB1089保留了有效的抗增殖活性,降低了升高血钙的作用,具体而言,EB1089在10~20 μg/d的耐受性良好,明显比补充1,25(OH)2D3时的血钙含量低[28]。然而,对于CRC细胞,其生长抑制机制尚不清楚。此外,帕立骨化醇作为一种活性维生素D类似物,对VDR具有很高的结合亲和力,发挥了更好的抗增殖活性[29]。骨化三醇是一种活性维生素D,不仅能够促进人体对钙质的吸收,还能促进人体内的蛋白质合成。同时骨化三醇不需要经过肝肾转化就能吸收,为肝肾功能异常患者提供了更多的选择。研究表明骨化三醇在mRNA和蛋白质水平上增加了CRC肿瘤抑制基因CDH1的表达,从而发挥了抗肿瘤作用[30]。因此,进一步的临床试验应更多地关注预防CRC的维生素D的合适剂量、新的类似物及联合治疗方案,为患者提供更加个体化的治疗。

3. 维生素D在CRC中的作用机制

维生素D可以改变与CRC发生有关的基因和途径,为流行病学和临床试验数据提供了潜在的机制,表明维生素D与CRC之间可能的因果关系[30]。目前已经发现了维生素D预防CRC的一些特性,1,25(OH)2D3作为一种活性维生素D,可以通过多种信号通路发挥抗癌作用,包括抑制增殖、诱导细胞凋亡和分化、抑制血管生成和转移[31]。此外,在肿瘤微环境(Tumor Microenvironment, TME)中,维生素D可以作用于CRC相关的间质成纤维细胞和CRC干细胞;它还可以调节肠道微生物群,以促进肿瘤抑制。

3.1. CRC细胞

1,25(OH)2D3是一种主要的基因表达调节因子,通过与核受体超家族VDR结合发挥转录激活和抑制作用[32],它限制CRC细胞的增殖,诱导分化,促进凋亡,还通过调节与这些过程相关的基因和信号通路来抑制血管生成和转移[31]

3.1.1. 抑制细胞增殖

G1/G0期是维生素D最常抑制的细胞周期阶段。维生素D降低C-MYC的表达,抑制细胞周期蛋白D和E的活性,并通过上调p21和p27导致细胞周期阻滞[33]。此外,1,25(OH)2D3可通过抑制表皮生长因子(EGF)和胰岛素样生长因子II活化的细胞增殖途径[34] [35],进而促进转化生长因子(TGF)-β对结直肠癌细胞的抑制作用[36]

Wnt/β-catenin通路在胚胎发育和成体组织稳态中起关键作用,它的失调经常导致各类严重疾病发生,包括癌症和非癌症疾病[37]。Wnt/β-catenin通路的异常激活在CRC中发挥重要作用[38]。因此,Wnt/β-catenin通路是CRC预防和治疗中研究最多的通路之一。1,25(OH)2D3可结合VDR促进其进入细胞核,与维生素D反应元件(Vitamin D Response Elements, VDRE)结合,从而抑制Wnt下游靶点的转录,包括CYP24A1、CDH1、C-MYC和CDKN1A [23]。1,25(OH)2D3还能抑制β-catenin的转录活性[39],使其在胞浆内聚集,稳定入核,与TCF4/LEF-1等转录因子共同调控细胞增殖[40] [41]。此外,1,25(OH)2D3还可作用于p38MAPK-MSK1和RhoA-ROCK等非基因组激活剂影响CRC细胞增殖[42] [43]

长链非编码RNAs (Long Noncoding RNAs, lncRNAs)作为新型细胞信号调控因子,在CRC的发生和发展中起着至关重要的作用。1,25(OH)2D3可抑制lncTCF7的表达,并抑制IL-1b诱导的CRC细胞的生长和侵袭,因此,1,25(OH)2D3-VDR-lncTCF7信号轴可能是一个重要的CRC治疗靶点[44]。此外,1,25(OH)2D3可能与lncRNA母系表达基因3 (Maternally Expressed Gene 3, MEG3)的表达密切相关,MEG3是一种肿瘤抑制因子,可调节Clusterin蛋白活性。研究表明,MEG3敲除后可增强CRC细胞的增殖和迁移,MEG3的过表达可能抑制CRC细胞增殖。1,25(OH)2D3和VDR可与CRC细胞的启动子直接结合,提高MEG3的表达[45]。MEG3通过竞争性抑制miR-31与靶基因SFRP1的结合,抑制CRC细胞的增殖和迁移,从而在CRC的发生发展中起到抑制作用[46]。因此,我们推测:VDR/MEG3/Clusterin信号途径在结直肠癌治疗领域内具有显著潜力,它不仅有可能作为一个精确的治疗靶点,而且其作用机制的深入研究还可能揭示出一种潜在的生物标志物,用于评估疾病的预后和监测治疗效果。

3.1.2. 诱导细胞分化

除了抑制细胞增殖外,1,25(OH)2D3还能诱导CRC细胞分化。E-cadherin与肿瘤细胞的上皮表型密切相关,E-cadherin的缺乏会导致肿瘤细胞的侵袭性。1,25(OH)2D3可以诱导E-cadherin和其他分化的上皮标志物,如ZO-1,还可以抑制Wnt/β-catenin的下游靶点(如cyclin D和c-MYC),以诱导CRC细胞分化[23]。此外,1,25(OH)2D3还能提高DKK-1的表达来诱导细胞分化,DDK-1负责编码Wnt通路的细胞外抑制剂,影响细胞表面β-catenin-TCF复合物的转录功能[31] [47]

此外,1,25(OH)2D3调节多种细胞分化调节因子的表达[31]表2列出了这些细胞分化调节因子[48]-[51]

Table 2. Regulators of cell differentiation related to 1,25(OH)2D3

2. 与1,25(OH)2D3相关的细胞分化调节因子

细胞分化调节因子

功能

机制

CST5/cystatin D

一种编码抑制剂

1,25(OH)2D3启动了CST5/cystatin D的表达。Cystatin D的过量表
达可拮抗Wnt/β-catenin途径,并促使闭锁蛋白、E-cadherin和其他
粘附蛋白的表达,以抑制CRC细胞的增殖和迁移。

MicroRNA-22

一个短的非编码
RNA

MicroRNA-22是1,25(OH)2D3的一个作用靶点。1,25(OH)2D3诱
导MicroRNA-22抑制CRC细胞的增殖和迁移并介导其对CRC的
保护作用。

KDM6B/JMJD3

组蛋白H3赖氨酸
去甲基化酶

在CRC细胞中,1,25(OH)2D3通过刺激启动子而上调KDM6B,
以促进E-cadherin的诱导和细胞分化。

Sprouty-2

一种上皮表型的抑
癌因子

1,25(OH)2D3可抑制Sprouty-2的表达。Sprouty-2通过ZEB1上
调E-cadherin、紧密连接和上皮极性基因来促进EMT和增殖。

这些结论表明,1,25(OH)2D3调节与信号通路相关的基因和多种机制来阻止上皮–间质转化(Epithelial-Mesenchymal Transition, EMT),表明1,25(OH)2D3是一种有效的肠道上皮分化诱导剂。

3.1.3. 诱导细胞凋亡

1,25(OH)2D3通过下调生存基因(thymidylate synthase and survivin),上调促凋亡基因(G0S2、BAG1和BAK1),以及通过巨噬细胞以旁分泌方式干预IL-1β的分泌,使CRC细胞容易诱发凋亡[52] [53]。1,25(OH)2D3及其类似物EB1089诱导CRC细胞系分化标志物ALP诱导的p53非依赖性细胞凋亡,BAK水平的升高可能是EB1089或1,25(OH)2D3诱导细胞凋亡的分子基础[54]。此外,Boughanem等人指出,p62通过与VDR的相互作用抑制细胞凋亡并促进细胞生长,提示p62在CRC中发挥了致癌基因的作用[55]

3.1.4. 抑制转移和血管生成

DKK4由TCF/β-catenin诱导,在CRC中上调,促进肿瘤细胞侵袭和血管生成,而1,25(OH)2D3可以通过下调DKK4在CRC中发挥抗血管生成和抗侵袭作用[56]。1,25(OH)2D3减少血管内皮生长因子(Vascular Endothelial Growth Factor, VEGF)的合成,从而限制肿瘤间质成纤维细胞血管生成和迁移。此外,胰岛素样生长因子(Insulin-like Growth Factors, IGFs)也与CRC有关。IGF-1和IGF结合蛋白3 (IGFBP-3)通过提高VEGF转录促进血管生成,1,25(OH)2D3可作用于IGFBP-3的转录因子VDR,抑制血管生成[57]。因此,维生素D治疗可以通过减少IGF-1/IGFBP-3的合成来降低VEGF,从而抑制血管生成。

3.2. CRC相关间质成纤维细胞

1,25(OH)2D3还能调节间质成纤维细胞,并在CRC的发生发展中起到保护作用。细胞外基质成分、细胞因子和生长因子被归类为细胞外区域成分,约占癌症相关成纤维细胞(Cancer-Associated Fibroblasts, CAFs)中1,25(OH)2D3调控基因的15%。1,25(OH)2D3可作用于细胞因子、生长因子及与延长生存期有关的基因,并抑制了癌症相关成纤维细胞(Cancer-Associated Fibroblasts, CAFs)的原肿瘤特性。此外,由于1,25(OH)2D3干扰了CAFs中涉及免疫反应、缺氧、血管生成和细胞迁移基因的基因表达程序,这可能支持了1,25(OH)2D3对CRC间质成纤维细胞的抗肿瘤作用[58]。此外,肿瘤间质成纤维细胞中VDR的高表达与CRC患者更长的生存期相关[31]。因此,CRC的理想临床预后可能与间质成纤维细胞中1,25(OH)2D3相关基因和VDR的表达有关。

3.3. CRC干细胞

酸性微环境是促进肿瘤细胞生存与增殖的重要因素,通过影响耐药、克隆进化及免疫细胞功能等进而调控肿瘤侵袭。酸性微环境使维生素D-VDR信号通路敏感,促进CRC细胞的耐药性和干性。活性形式的维生素D抑制了酸性环境介导的自我更新和CRC干细胞中OCT4、SOX2和CD133的表达。诱导VDR的表达和酸性TME的正常化可以抑制CRC的发生和发展[59]

1,25(OH)2D3不仅能抑制酸性环境介导的CRC干细胞的自我更新,而且还能不同程度地抑制CRC干细胞的增殖。1,25(OH)2D3促进了肿瘤器官中一系列的分化特性,其促进肿瘤干细胞分化并抑制增殖,同时保持了正常结肠干细胞及其后代的未分化表型[60]

3.4. 肠道微生物群

肠道微生物群作为一个重要的代谢和免疫调节器,是结直肠癌发生发展的关键调节因子[61]。越来越多的数据表明,环境因素是肠道微生物组成和功能的重要决定因素,有助于改变局部和全身的免疫反应、调节代谢和宿主基因表达,从而影响癌症的进展[62]。肠道微生物群能通过释放多种代谢产物、蛋白质和大分子,与宿主的结肠上皮和免疫细胞相互作用,从而调节结直肠癌的发生发展[63]

最近的研究表明,肠道微生物群受到饮食摄入的严重影响和塑造,可能在改变CRC发生的风险中发挥作用[2]。1,25(OH)2D3通过控制抗氧化I期和II期酶的表达,参与类固醇、胆囊酸、异生素和其他化合物的分解代谢,从而促进肠道解毒、改善肠道微环境,影响CRC的发生和发展[64]。补充维生素D可能有助于塑造肠道微生物群,而微生物群可能部分介导补充维生素D对25(OH)D的影响[63]。目前相对一致的流行病学显示,CRC中核梭杆菌和脆弱拟杆菌富集,而产生丁酸的细菌数量减少。1,25(OH)2D3可通过作用于巨噬细胞,诱导抗菌肽合成,选择性杀灭致病菌,促进肠道内共生细菌的定植[64]。由于VDR转录的自噬调节剂和抗菌肽的作用,可以抑制或消除有害的肠道菌群,减少炎症反应[65]。维生素D调节肠道菌群,而肠道菌群调节肠道屏障的完整性并参与CRC的逆转。VDR还可通过JAK/STAT通路及其下游基因直接调节宿主与细菌之间的相互作用[66]。因此,我们也可以考虑使用VDR激活剂或益生菌来恢复肠道上皮VDR在CRC中的保护作用。未来如何更好地利用肠道微生物群,开发出有针对性的微生物疗法,作为结直肠肿瘤发生的化学预防剂,作为化疗和免疫疗法的辅助剂以提高药物疗效和安全性及作为用于CRC筛查和患者分层的生物标志物至关重要。

4. 结论

维生素D对结直肠癌有有益的预防作用,在结直肠癌的预防和治疗中起着越来越重要的作用。然而,维生素D补充的适当剂量尚未确定,口服维生素D和钙剂在预防结直肠癌中的相互作用也有待进一步研究。维生素D通过多种信号通路发挥抗癌作用,包括抑制增殖、诱导细胞凋亡和分化、抑制血管生成和转移。此外,维生素D可以作用于CRC相关的间质成纤维细胞和CRC干细胞;它还可以调节肠道微生物群,以促进肿瘤抑制。

基金项目

本研究得到山东省自然科学基金一般项目(ZR2020MH245)的资助。

NOTES

*通讯作者。

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