CYP19A1在消化道肿瘤中的研究进展
Research Progress of CYP19A1 in Digestive Tract Tumors
DOI: 10.12677/acm.2025.151005, PDF, HTML, XML,    科研立项经费支持
作者: 王佳琳:西安医学院研究生工作部,陕西 西安;冯 秀, 杨旭清:空军军医大学西京医院实验外科,陕西 西安;李纪鹏*:西安医学院研究生工作部,陕西 西安;空军军医大学西京医院实验外科,陕西 西安;空军军医大学西京医院消化外科,陕西 西安
关键词: CYP19A1雌激素消化道肿瘤CYP19A1 Estrogen Gastrointestinal Tumors
摘要: 消化道肿瘤是我国最常见的恶性肿瘤,发病率和死亡率均居高位,严重威胁人们的身体健康,亟需寻找有效的诊断方法和治疗靶点。CYP19A1属于细胞色素P450家族的成员,定位于内质网,是将雄激素构化为雌激素的关键限速酶,在不同组织中发挥不同的作用以维持重要的组织特异性功能。近年来的研究发现,CYP19A1在胃癌、结直肠癌等恶性消化道肿瘤中异常表达并促进肿瘤的进展。然而,CYP19A1在消化道肿瘤中的具体调控机制尚不明确。因此,本文对近年相关研究进行综述,以表明CYP19A1在消化道肿瘤生长过程中存在潜在的研究价值,对于靶向CYP19A1诠释消化道肿瘤的生长机制、预后预测以及靶向治疗等方面具有重要意义。
Abstract: Gastrointestinal tumors are the most prevalent malignant tumors in China, featuring high morbidity and mortality rates, seriously threatening people’s physical health. There is an urgent need to discover effective diagnostic approaches and therapeutic targets. Aromatase (CYP19A1), a member of the cytochrome P450 family, is located in the endoplasmic reticulum and serves as the key rate-limiting enzyme that converts androgens into estrogens, exerting diverse functions in different tissues to maintain crucial tissue-specific functions. Recent studies have revealed that CYP19A1 is aberrantly expressed in malignant gastrointestinal tumors such as gastric cancer and colorectal cancer and promotes tumor progression. Nevertheless, the specific mechanism underlying CYP19A1 in gastrointestinal tumors remains unclear. Thus, this article conducts a review of the relevant research in recent years to indicate the potential research value of CYP19A1 in the growth process of gastrointestinal tumors, which is of significant importance for interpreting the growth mechanism, prognosis prediction, and targeted therapy of gastrointestinal tumors by targeting CYP19A1.
文章引用:王佳琳, 冯秀, 杨旭清, 李纪鹏. CYP19A1在消化道肿瘤中的研究进展[J]. 临床医学进展, 2025, 15(1): 26-30. https://doi.org/10.12677/acm.2025.151005

1. 引言

根据全球癌症统计报告显示,结肠癌、胃癌、直肠癌、食管癌均位于世界新发与死亡癌症的前十位,占新发病例总数的18.5%、新增死亡例数的22.4% [1]。在我国,恶性肿瘤的发病率和死亡率亦逐年升高。根据国家癌症中心报告显示,结直肠癌、肝癌、胃癌、食管癌分别占新发和死亡癌症的33.2%和39.02% [2]。国内外数据均证实消化道肿瘤严重威胁人们的身体健康和生活质量。

目前,随着消化道肿瘤对各种放化疗治疗方案产生药物抵抗,亟需寻找更多的肿瘤治疗的新靶点。近几年研究表明,定位于内质网上的CYP19A1与肿瘤的增殖、侵袭和转移等密切相关,具有潜在的临床应用价值。因此,深入研究CYP19A1与胃癌、结直肠癌等消化道肿瘤的表达情况、作用机制及其临床意义对于探索消化道肿瘤的临床靶点治疗具有重要的指导意义。

2. CYP19A1及其生物学功能

CYP1 9A1基因全长约123 kb,位于15号染色体长臂的21.2区域,由一个93 kb的调控区和30 kb的编码区组成,编码的蛋白为芳香化酶,主要定位于细胞的内质网上,被广泛认为是从雄激素转化成雌激素的关键酶[3] [4]

CYP19A1具有重要的生物学功能,能够参与葡萄糖稳态、脂质稳态、大脑功能、卵泡生长、骨矿化、骨骺闭合和排卵过程协调等生理功能,它的表达和活性受不同启动子调控,在性腺、脂肪组织、皮肤、骨骼、脑、肾上腺、肝脏、胎盘、乳房、毛囊附近高度活跃[5]。除了调控激素合成外,近年来的研究显示,CYP19A1的异常表达与前列腺癌,肝癌及结直肠癌等消化道肿瘤的发生发展密切相关[6],然而具体的调控机制复杂多样。

3. CYP19A1在消化道肿瘤中的作用及机制

3.1. 前列腺癌

前列腺癌是老年男性中最常见的癌症之一,最终会发展为去势抵抗性前列腺癌。睾酮及雄激素受体信号转导通路与前列腺癌的发生密切相关,催化睾酮的芳香化酶会受到CYP19A1活性的影响,进而影响雄激素受体的表达。研究表明,在去势抵抗性前列腺癌中,CYP19A1通过代谢可受BRD4调节的睾酮来靶向雄激素受体减少细胞侵袭和增殖在前列腺癌的进展中发挥作用,同时CYP19A1的表达变化可影响细胞对BRD4抑制剂的敏感性。因此,CYP19A1可能是通过增强BRD4抑制剂的作用来治疗去势抵抗性前列腺癌的潜在靶点[7]。此外,骨转移作为前列腺癌死亡的关键原因之一,已有研究证实,在骨髓中,细胞周期蛋白A1和芳香化酶增强了包括雄激素受体、雌激素和基质金属蛋白酶MMP9等的水平进而促进前列腺癌细胞的转移[8]。此外,CYP19A1在前列腺癌转移组织比原发肿瘤高30倍,其等位基因的缺失会降低暴露于睾酮和雌激素处理后的小鼠前列腺癌的发病率[9]。Cintia Massillo等学者发现CTBP1和代谢综合征通过调节芳香酶的转录以及诱导白色脂肪组织炎症,导致促炎表型并增加血清雌二醇浓度,从而影响前列腺癌的生长[10]

3.2. 结直肠癌

结直肠癌是最常见的恶性肿瘤之一。据统计,2020年全球新发癌症病例19.3亿,死亡病例9.9亿,其中结直肠癌发病率和死亡率各占10%和9.4% [1]。近年来,我国结直肠癌发病率和死亡率逐年升高,根据国家癌症中心显示,我国结直肠癌新发病例和死亡病例分别位居第二位和第四位[2]

已有临床研究揭示内源性的雌激素水平与绝经后妇女结直肠癌风险呈负相关,暗示雌激素可能与结直肠癌的发展相关[11]。同时,雌激素通过抑制结肠中促炎因子的表达对急性诱导的结肠炎发挥保护作用,可能是降低炎症相关结肠癌风险的机制之一[12]。CYP19A1作为调控雄激素向雌激素转化的关键酶,在结直肠癌的发展过程中亦扮演着重要的角色。在最新研究中发现CYP19A1高表达与结直肠癌患者不良预后显著相关,并且可能与晚期病理分期有关,且CYP19A1会促进CRC的增殖和迁移[13]。已有研究揭示,基于脂质代谢相关基因的风险模型筛选出的CYP19A1,能够催化雌激素生物合成进而通过GPR30-AKT信号传导上调PD-L1、IL-6和TGF-β的表达,从而促进血管异常并抑制CD8+ T细胞功能,可以预测结肠癌的预后和免疫应答反应[14]。提示CYP19A1的抑制与PD-1阻断相结合有望成为结肠癌免疫治疗的一种有前途的治疗策略。此外,CYP19A1单核苷酸多态性可能会影响NFκB和IL-6基因的表达而影响结肠癌的进展[15]

3.3. 胃癌

胃癌是最常见的消化道恶性肿瘤,在全球范围内胃癌的发病率和死亡率分别位居第5位和第4位[1]。已有研究显示,与人类胃癌健康组织以及正常细胞系比较,CYP19A1在胃癌组织及胃癌细胞系中高表达,并与胃癌患者T、N分期及预后不良相关[16] [17]。在机制方面,CYP19A1主要通过调控脂代谢响应胃癌的免疫应答,同时也具有遗传多样性,特别是rs1004982、rs16964228、rs1902580可能参与改变雌激素水平并影响细胞凋亡、粘膜功能和致癌作用,与胃癌风险增加有关[18]-[20]。然而,更详细的机制仍有待进一步探索。

3.4. 食管癌

在消化道其他肿瘤中,已有研究采用Mass ARRAY技术,结合竞争性PCR和MALDI-TOF质谱分析,对食管鳞状细胞癌患者的12个SNP进行基因分型,发现CYP19A1基因的rs10046与食管癌的发病显著相关,并且环境和遗传因素亦可能共同作用于食管癌的易感性[21]。此外,研究者研究在研究凋亡途径上中的多态性发现,CYP19A1的rs445762与食管癌的早期发病息息相关[22]。这些研究为深入了解食管癌的发病机制和制定更有效的预防策略提供了新的见解。

4. 总结与展望

定位于内质网的CYP19A1能够通过不同启动子的调控作用于多种组织发挥重要功能,最新研究显示,CYP19A1在大部分消化道肿瘤中发挥促癌作用,其表达水平与消化道肿瘤的增殖、迁移和侵袭以及预后密切相关。尽管消化道肿瘤与CYP19A1的研究已有部分报道,主要通过其核酸多态性以及对激素的调控促进肿瘤的进展,然而CYP19A1对消化道肿瘤的调控仍存在其他机制,需要更多的研究去探索证实。总之,随着对CYP19A1相关研究的不断深化,开发靶向CYP19A1的药物,探索CYP19A1在消化道肿瘤中可以作为诊断标志物的前景有待进一步研究,未来对于消化道肿瘤的早期诊断与精准靶向治疗一定会有更好的指导意义。

基金项目

2023,陕西重点研发计划,2023-YSBF-676。

2023,肿瘤细胞生物学国家重点实验室项目,CBSKL2022ZZ44。

NOTES

*通讯作者。

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