miR-126-3p和SLC7A11在肺癌中的研究进展

2022年6月2日08:08:09miR-126-3p和SLC7A11在肺癌中的研究进展已关闭评论
摘要

党裔武 陆会平 陈罡【关键词】 miR-126-3p;SLC7A11;肺癌;铁死亡中图分类号:R734.2 ? 文献标志码:A ? DOI:10.3969/j.issn.1003-1383.202

    党裔武 陆会平 陈罡

    

    【关键词】 miR-126-3p;SLC7A11;肺癌;铁死亡

    中图分类号:R734.2 ? 文献标志码:A ? DOI:10.3969/j.issn.1003-1383.2021.05.014

    在我国乃至全世界常见癌症中肺癌是最常见且最致命的,在广西,其发病率和病死率也仅次于肝癌[1~3],严重危害人类健康。肺癌又可根据组织学分为非小细胞肺癌(non-small cell lung cancer,NSCLC)和小细胞肺癌,所有亚型均与吸烟有关[4],准确的组织学和分子分型对肺癌的治疗和预后判断至关重要。肺鳞癌(lung squamous cell carcinoma,LUSC)和肺腺癌是最常见的两种非小细胞肺癌。随着精准医疗的快速发展,人们通过分子病理学技术准确判断表面生长因子受体、程序性死亡配体1等基因的状态,针对性地指导肺癌患者进行酪氨酸激酶抑制剂及免疫检查点抑制剂治疗,从而有效延长患者寿命。然而,分子靶向药治疗的受益者十分有限,且不可避免的药物不良反应和耐药等问题也是接受靶向药物治疗患者所面临的巨大挑战。与此同时,迄今仍未发现明确的LUSC驱动基因和药物治疗靶点,针对LUSC的治疗方案较为局限。因此,寻找特异性LUSC诊疗分子靶标仍是当下肺癌防控的关键任务。近年众多文献报道微小RNA(microRNA,miRNA)与肺癌发生发展关系密切,本文将从miRNA的视角,以miR-126-3p及其潜在作用靶基因溶质载体家族成员7成员11(solute carrier family 7 member 11,SLC7A11,又称xCT)为例,对它们在肺癌中的作用及机理进行综述。

    1 miRNA的概况

    miRNA是一系列由18~22个核苷酸组成的内源性非编码RNA,参与人类多种恶性肿瘤的发生发展[5]。当前的研究认为miRNA可能因染色体异常、转录失调和表观修饰等原因在肺癌中表达失调,通过多分子、多途径、多步骤综合调节肺癌细胞增殖、迁移、侵袭和转移,故基于大量临床前和临床研究提出可将外周血和组织样本中检测到的miRNA作为肺癌早期诊断、疾病进展监测、治疗和预后预测的潜在生物标志物[6]。

    2 miR-126-3p与肺癌的关系

    miR-126-3p参与肺癌的发生发展。已有研究证实miR-126-3p在大多数肺癌组织中表达显著下调[7~12],表达上调后可经靶向SLC7A5延迟细胞周期G1期抑制小细胞肺癌细胞的增殖[7];低表达miR-126-3p的肺腺癌患者其病理分期更差、肿瘤直径更大、淋巴结转移更为常见[9,11],可通过靶向CCR1抑制NSCLC的生长、迁移和侵袭[13]。然而在外周血血清中,miR-126-3p的表达趋势尚存在争议,如法国和波兰的NSCLC患者血清中miR-126-3p表达显著下调[14~15],而中国肺癌患者血清及血清外泌体中的miR-126-3p明显上调[16~18]。由此可见,miR-126-3p在组织水平的表达趋势较为稳定,但其血清表达可能受人群遗传背景的影响,此现象还需要大样本检测进一步证實。总之,中外学者一致认为血清miR-126-3p表达水平可作为早期诊断、疾病进展和预后判断的潜在分子标志物[17,19~20]。同时miR-126-3p亦是肺癌治疗的潜在靶标。研究表明,放疗后肺癌患者血清中的miR-126-3p表达显著下调[21];隐丹参酮可显著上调非小细胞肺癌细胞的miR-126-3p表达水平,从而抑制细胞生长和侵袭能力[22]。然而,目前针对miR-126-3p在肺癌药物治疗中的作用及其下游靶标及调控信号途径的研究尚十分匮乏。为进一步探索miR-126-3p作用的分子机制,本课题组前期通过miRWalk预测发现SLC7A11是miR-126-3p的关键靶基因[11]。

    3 SLC7A11与肺癌的关系

    3.1 SLC7A11基因的作用机理

    SLC7A11蛋白与SLC3A2组成胱氨酸/谷氨酸反转运体(又称Xc-系统,以1∶1的比例为细胞摄取胱氨酸并交换胞内谷氨酸)。SLC7A11对胱氨酸和谷氨酸具有高度特异性,负责Xc-系统的基本转运活性,并通过调节内源性抗氧化剂-谷胱甘肽(glutathione,GSH)维持细胞的氧化还原平衡和调节细胞铁死亡(图1),对细胞的正常生长和发育至关重要。已有研究表明,SLC7A11在包括肺癌在内的多种人类恶性肿瘤中过表达,高表达的SLC7A11可通过抑制细胞铁死亡而导致患者不良预后,其机制研究表明肿瘤细胞通过上调SLC7A11表达维持高水平GSH以抵消自身代谢速率增加所导致的氧化应激,从而促进肿瘤细胞增殖侵袭和抑制细胞铁死亡[23~24],提示SLC7A11是驱动肿瘤发生发展的关键基因。

    3.2 SLC7A11基因在肺癌发生发展中的作用

    SLC7A11通过调节胞内胱氨酸/谷氨酸代谢、免疫细胞浸润,在肺癌发生、进展和治疗中发挥关键作用[25~30]。国内外学者对非小细胞肺癌患者的肺癌组织进行免疫组化检测发现SLC7A11主要定位于细胞膜[25]或细胞质[27],其mRNA和蛋白水平在肺腺癌和肺鳞癌中均显著上调,高表达的SLC7A11与患者总体生存期较差有关[25,27,31];肺腺癌A549细胞和LUSC H520、HCC15、HCC95细胞高表达SLC7A11,沉默这些细胞的SLC7A11基因表达可明显降低细胞生长速度、侵袭能力及谷氨酰胺依赖性,过表达SLC7A11基因不仅显著降低癌细胞内GSH/GSSG比率以提高细胞内微环境的氧化性,还可以诱导正常气道上皮细胞中的代谢重编程和氧化磷酸化,而这或许是吸烟促使正常细胞增殖和癌变的机制[25]。与此同时,一项有趣的研究将LUSC差异表达基因根据其表达水平和临床特征分为4个亚型:原始型(primitive)、经典型(classical)、分泌型(secretory)和基础型(basal),其中经典型基因在吸烟者中显著过表达,具有独特的异源生物代谢功能,与能量代谢(包括氧化磷酸化、柠檬酸循环、电子传递链等)、异源生物代谢(包括细胞色素p450、谷胱甘肽代谢)、细胞成分(线粒体内膜、呼吸链)等密切相关[32],而吸烟及吸烟最严重的患者均高度集中于经典型基因。在表达经典型基因的LUSC细胞系HCC15、NCI-H520和HCC95中SLC7A11的表达明显高于其他LUSC细胞系[25],提示SLC7A11可能通过调节细胞氧化还原平衡驱动吸烟所致LUSC的发生发展。

    3.3 SLC7A11基因在肺癌靶向治療中的前景

    SLC7A11亦可作为肺癌靶向治疗的潜在靶标。在肺癌分子靶向治疗和免疫治疗领域的研究表明,has-mir-373和has-mir-372通过竞争结合上调了SLC7A11的表达,从而调节肺腺癌的免疫浸润[26];但抑制SLC7A11会选择性杀死KRAS突变的肺腺癌细胞和抑制体内肿瘤生长[27];并且SLC7A11可作为PD-L1低表达且EGFR野生型NSCLC的潜在药物靶标[28];而人皮肤成纤维细胞SLC7A11的表达则有助于发现存在厄洛替尼治疗后皮疹风险的肺癌患者[33]。与此同时,SLC7A11也可作为中医药治疗肺癌的有效靶点,如萝卜硫素(sulforaphane)通过抑制SLC7A11表达和诱导铁死亡促进小细胞肺癌细胞死亡[30];双氢青蒿素通过对PRIM2/SLC7A11调控轴的抑制来阻止肺癌细胞增殖和克隆形成,并促进细胞发生铁死亡[29]。提示SLC7A11是LUSC极富潜力的治疗、疗效和预后预测靶点。

    4 小结

    在肺癌中表达下调的miR-126-3p和高表达的SC7A11往往提示患者预后不良,二者均可作为肺癌治疗的潜在靶标,并且SLC7A11是miR-126-3p的潜在靶基因,可能miR-126-3p通过靶向上调SLC7A11的表达而促进LUSC发生发展,但这一假设需要设计严谨的分子生物学实验进行验证。与此同时,鉴于SLC7A11对细胞铁死亡的调节作用,miR-126-3p/SLC7A11调控轴调控细胞铁死亡的机制尚未见相关的研究。总之,本综述全面阐述和分析了目前miR-126-3p和SLC7A11在肺癌中的研究进展,为肺癌尤其LUSC的诊疗提供新思路,有助于推动LUSC发生发展机制的研究。

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    (收稿日期:2021-02-18 修回日期:2021-03-12)

    (編辑:王琳葵 梁明佩)