STMN1在肿瘤中作用的研究进展

Research progress in the role of STMN1 in tumor

摘要

胞浆磷蛋白1(stathmin 1，STMN1)是一种微管结合蛋白，可促进微管解聚或抑制微管组装，调控细胞骨架形成、细胞周期进程等过程。STMN1在多种肿瘤中表达上调，主要通过核因子κB(nuclear factor-κB，NF-κB)、促分裂原活化的蛋白激酶(mitogen-activated protein kinase，MAPK)、铁死亡等经典途径促进肿瘤细胞的增殖、侵袭、转移，以及血管生成等恶性行为。STMN1还可通过影响机体免疫细胞功能，干预抗肿瘤免疫。临床数据显示STMN1高表达与肿瘤耐药和预后不良呈正相关，提示STMN1有作为肿瘤生物标志物和治疗分子靶点的潜能，具有重要的临床意义。

Abstract

Stathmin 1 (STMN1) is a microtubule-binding cytoplasmic phosphoprotein that promotes microtubule depolymerization or inhibits microtubule assembly, thereby regulating cytoskeletal organization and cell cycle progression. STMN1 is upregulated in a variety of malignant tumors, where it drives proliferation, invasion, metastasis, and angiogenesis through classic pathways such as nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and ferroptosis. STMN1 can also modulate the function of immune cells, thereby influencing antitumor immunity. Clinical data show that its high expression correlates positively with tumor drug resistance and poor prognosis, suggesting that STMN1 has potential as a tumor biomarker and therapeutic molecular target with important clinical significance.

关键词

胞浆磷蛋白1 / 微管 / 肿瘤 / 铁死亡 / 肿瘤免疫 / 肿瘤耐药

Key words

stathmin 1 / microtubule / tumor / ferroptosis / tumor immunity / tumor drug resistance

在2024年公布的世界卫生组织(World Health Organization，WHO)统计数据^[1]中，全球新发癌症约2 000万例，其中病死约970万例。近年来癌症的病死率一直居高不下，因此探索肿瘤发展的分子机制，寻找合适的治疗靶点和准确的早期诊断生物标志物，对于降低肿瘤患者病死率具有重要意义。

胞浆磷蛋白1(stathmin 1，STMN1)是一种微管结合蛋白，能调节微管的聚合和解聚，与有丝分裂、细胞凋亡等细胞活动有关，并在多种肿瘤细胞中表达量增加，参与肿瘤细胞的增殖、迁移和侵袭等恶性行为，对于促进肿瘤发展具有重要意义^[2]。本文从STMN1的发现和生物学功能、与肿瘤发生和发展的关系、在肿瘤中的调节机制和作为治疗靶点的价值方面进行文献总结，介绍STMN1在肿瘤中的研究进展，以期为实现肿瘤患者良好预后提供思路。

1 胞浆磷蛋白<bold>STMN1</bold>的发现和生物学功能

STMN1是一种致癌基因，也称Oncoprotein 18，编码高度保守的分子量约18 kD(1 D=1 u)的胞浆磷蛋白，属于Stathmin家族，最初从小鼠的胰岛素瘤和垂体细胞中提取获得^[3]。STMN1的功能主要通过磷酸化精确调控^[3]。在被发现的最初几年里，STMN1的功能一直不为人知，直到Belmont和Mitchson首次在实验中揭示它的微管不稳定活性后，STMN1的微管不稳定活性被不断证实^[4-5]。STMN1在调节细胞骨架形成、周期进程、有丝分裂、凋亡、迁移和侵袭等各种生物学过程中发挥重要作用^[6]。STMN1作为一种微管结合蛋白，具有微管蛋白结合结构域，可以直接结合微管的α/β-微管蛋白异二聚体，促进微管结构的解聚或抑制微管组装^[7]，以此维持细胞内微管聚合和解聚的平衡，调控微管的动态不稳定性。抑制STMN1可阻止纺锤体和微管解聚，将有丝分裂阻滞在G₂/M期，抑制细胞增殖。此外，STMN1通过自身磷酸化调节其微管解聚活性，STMN1的N-末端有4个丝氨酸磷酸化的位点，分别为Ser16、Ser25、Ser38和Ser63^[8]。在有丝分裂开始时，丝氨酸位点被磷酸化，STMN1与微管蛋白的亲和力降低。磷酸化的STMN1失去了解聚微管的能力，从而导致微管趋于稳定，保证纺锤体的正常形成^[9]。在有丝分裂的后期，STMN1被蛋白磷酸酶去磷酸化后发挥微管解聚功能，促进有丝分裂纺锤体解体，并退出有丝分裂。因此，STMN1的磷酸化状态影响了纺锤体的形成和细胞周期的进程，是保障细胞数目的重要因素^{[2, 6, 10]}。

2 <bold>STMN1</bold>与肿瘤的发生和发展

STMN1作为一个促癌因子，在多种恶性肿瘤中过度表达，参与癌症的发生和发展，促进肿瘤细胞的生长、转移和侵袭，并与作用于微管的肿瘤化疗药物的耐药性相关^[11]。STMN1在肝细胞肝癌(hepatocellular carcinoma，HCC)^[12]、前列腺癌^[13]、胆囊癌^[14]、结直肠癌^[15]、胰腺癌^[16]、乳腺癌^[8]和非小细胞肺癌(non-small cell lung cancer，NSCLC)^[17]中的表达水平升高常提示患者预后不良；不过在膀胱癌中，STMN1则发挥抑癌作用，STMN1表达水平升高常提示患者预后良好^[18]。

2.1 HCC

在HCC中，STMN1的高表达与甲胎蛋白(alpha fetoprotein，AFP)水平升高、肿瘤体积增大、血管浸润和肝内转移呈正相关，高表达STMN1患者的5年生存率较低，早期复发率较高，STMN1在HCC细胞中具有促癌功能^{[10, 19]}。生物信息学研究^[20]结果显示STMN1的mRNA和蛋白质表达水平在HCC细胞中升高，同时HCC肿瘤组织中DNA甲基化程度显著低于癌旁组织，提示HCC细胞中STMN1基因的转录活性增强。STMN1表达下调可降低HCC细胞的克隆形成能力和迁移能力。临床样本的组织微阵列测定结果表明STMN1的表达水平与肿瘤的分级呈正相关，STMN1的表达水平可用于评价肿瘤的分级^[20]。不仅如此，STMN1的高表达与HCC肿瘤免疫微环境和免疫检查点均有关，STMN1表达与程序性细胞死亡蛋白1(programmed cell death protein 1，PD-1)、淋巴细胞活化基因3(lymphocyte activation gene-3，LAG3)、细胞毒性T淋巴细胞相关蛋白4(cytotoxic T lymphocyte associate protein-4，CTLA-4)等免疫检查点表达呈显著正相关，与CD4⁺ T细胞、CD8⁺ T细胞、中性粒细胞、树突状细胞等免疫细胞浸润呈强负相关，提示STMN1在HCC中高表达可能与肿瘤免疫逃逸相关^[21]。

2.2 前列腺癌

STMN1是影响前列腺癌的独立风险因子，其表达上调提示患者预后生存不良^[22-23]。在前列腺癌细胞系中，敲低STMN1表达后，上皮标志物上皮钙黏素(E-cadherin)的表达量下调，同时间充质标志物波形蛋白(vimentin)的表达量上调，提示发生了上皮-间充质转化(epithelial-mesenchymal transition，EMT)，最终促进前列腺癌细胞的转移^[23-24]。

2.3 胆囊癌

人胆囊癌细胞中的STMN1的表达水平下调可抑制肿瘤生长、诱导细胞凋亡、影响有丝分裂的过程^[25-26]。此外，STMN1表达水平的高低还受肿瘤微环境的影响，如肿瘤微环境内的葡萄糖含量降低可上调STMN1的表达水平^[27]。

2.4 结直肠癌

STMN1的高表达也被认为是结直肠癌患者疾病进展和生存概率低的预测因子。STMN1的表达与结直肠癌患者的生存时间密切相关，过表达的STMN1可促进结直肠癌细胞的增殖和侵袭，降低患者的总生存率。敲低STMN1的表达可抑制结直肠癌细胞的黏附和转移，并可提升其对治疗药物如5-氟尿嘧啶的敏感性^{[15, 28]}。

2.5 胰腺癌

STMN1的表达水平下调可抑制胰腺癌细胞的增殖和侵袭^[29]。在胰腺导管癌中，STMN1的高表达与肿瘤的远处转移和分化不良等恶性行为有关^[30]。

2.6 乳腺癌

Cox回归分析结果^[31-32]显示：STMN1的高表达与乳腺癌复发时间呈负相关，且STMN1在不同丝氨酸位点的磷酸化对预后有不同的影响，如Ser16和Ser63的高水平磷酸化与较好的无病生存期相关，而Ser25和Ser38的高水平磷酸化则与较差的无病生存期相关。STMN1在Ser25/Ser38的磷酸化可促进乳腺癌细胞的迁移，同时也可能参与调节肿瘤细胞增殖、血管生成和免疫反应^[33]。在三阴性乳腺癌(triple negative breast cancer，TNBC)中，一方面，STMN1自身稳定性的增强和磷酸化水平的保持促进了TNBC的进展；另一方面，STMN1对微管不稳定性的促进降低了TNBC细胞对紫杉醇的敏感性^[34]。

2.7 NSCLC

相比癌旁组织，NSCLC细胞中的STMN1表达量显著上升^[35]，STMN1的高表达通过加速G₁/S期促进NSCLC细胞增殖，通过调控微管的稳定性促进迁移和侵袭，同时也与NSCLC预后不良有关^[17]。下调STMN1的表达和其Ser63，Ser25位点磷酸化水平可抑制NSCLC细胞的增殖、迁移和集落形成能力，最终抑制肿瘤细胞的恶性转化^[36]。其中，肺腺癌中STMN1的表达水平与肺腺癌的分化程度、淋巴结转移和TNM分期显著相关，抑制STMN1表达能显著延缓裸鼠皮下移植瘤的生长^[37]。

2.8 膀胱癌

在不同的癌症中，STMN1的作用也有所区别，在膀胱癌中敲除STMN1基因可促进癌细胞的体内外迁移、侵袭。Kaplan-Meier生存分析显示STMN1表达水平与膀胱癌患者的良好生存率呈正相关，在膀胱癌细胞中，STMN1抑制细胞EMT和转移过程^[18]。

3 <bold>STMN1</bold>在肿瘤细胞中的调节机制

STMN1在肿瘤细胞中的表达和活化受到核因子κB(nuclear factor-κB，NF-κB)、促分裂原活化的蛋白激酶(mitogen-activated protein kinase，MAPK)等信号通路的调控。STMN1不仅通过调控有丝分裂发挥作用，它通过影响肿瘤细胞的增殖、迁移和侵袭等多种关键的细胞生物学过程，成为驱动肿瘤恶性进展的核心分子之一。STMN1在不同类型肿瘤中的作用及其机制见表1。

3.1 <bold>NF-κB</bold>通路

NF-κB通路和STMN1相互作用。在人T细胞白血病病毒(human T cell leukemia virus，HTLV-1)诱导人类T细胞白血病/淋巴瘤的研究^[38]过程中发现，STMN1可作为转录共激活因子，通过与p65蛋白结合形成STMN1-p65复合物，从而显著增强NF-κB对下游靶基因的转录能力。此外，STMN1所具有的微管解聚功能与NF-κB通路共同作用，调节微管蛋白动力学，影响包括有丝分裂，细胞凋亡等在内的细胞生命过程。在NSCLC细胞中，抑制NF-κB可通过降低细胞周期蛋白依赖性激酶2(cyclin-dependent kinase 2，CDC2)和胞外信号调节激酶(extracellular signal-regulated kinase，ERK)的活性下调STMN1的表达水平^[36]。对肾透明细胞癌的研究^[39]也证实了NF-κB通路可在转录水平调控STMN1的表达，从而影响肿瘤细胞的增殖和侵袭。

3.2 <bold>MAPK</bold>通路

MAPK与肿瘤的发生和发展密切相关，MAPK是广泛表达的丝氨酸/酪氨酸激酶，MAPK包括3个重要的蛋白激酶家族：ERK、c-Jun NH2末端激酶和p38激酶家族^[40-42]。

早在20世纪末，科学家就已证明MAPK会直接影响STMN1丝氨酸位点的磷酸化，如MAPK可以磷酸化STMN1的Ser25和Ser38位点，且相对于Ser38位点，MAPK对于Ser25位点的亲和力更高^[43]。生物信息学分析^[44]显示：在HCC中，STMN1在MAPK通路介导的铁死亡过程中富集。提示STMN1可能在MAPK介导的铁死亡中发挥作用。细胞学研究^[45]证实：在TNBC细胞中，激活丝裂原活化胞外信号调节激酶(mitogen-activated extracellular signal-regulated kinase，MEK)可通过MEK/ERK/STMN1轴促进STMN1磷酸化。STMN1可能是MAPK的靶点。

3.3 铁死亡

铁死亡是一种依赖于铁离子的新型细胞程序性死亡方式，其特征包括细胞内谷胱甘肽(glutathione，GSH)水平下调，谷胱甘肽过氧化物酶(glutathione peroxidase，GSH-Px)失活，线粒体内的脂质过氧化物堆积等^[46]。一方面铁死亡本身可通过诱导肿瘤细胞死亡抑制肿瘤发生^[47]，另一方面铁死亡可通过激活免疫应答改变肿瘤微环境抑制肿瘤发展^[48]。

STMN1与铁死亡相关。在HCC细胞中，激活铁死亡可下调STMN1的mRNA和蛋白质表达水平^[44]。进一步研究^[49]表明：HCC中高表达的STMN1能够以GSH依赖的方式抑制细胞铁死亡，从而促进HCC的生长。STMN1在调控HCC铁死亡过程中发挥重要作用，其表达上调可显著抑制铁死亡，有利于肿瘤细胞的存活与增殖。此外，STMN1可通过调控与铁死亡相关基因表达的转录因子，参与对HCC细胞铁死亡过程的精细调节^[50]。

3.4 EMT

EMT是上皮细胞获得间充质特征的过程，获得该特征的肿瘤细胞可以通过血液、淋巴等途径向其他部位转移^[51]。在此过程中，上皮标志物如E-cadherin的表达下降，间充质标志物如N-钙黏蛋白和vimentin蛋白的表达上升^[52]。

在HCC中，STMN1基因表达水平与间充质标志物呈正相关，STMN1可能通过调节微管稳定性来促进EMT。体外研究^[19]证明，敲低STMN1表达可增加微管稳定性，从而阻止EMT的发生，抑制HCC细胞的侵袭和转移。在下咽鳞状细胞癌中，敲低STMN1表达将导致上皮标志物E-cadherin的表达上调及间充质标志物vimentin表达下调，表明高表达的STMN1可通过促进EMT增强下咽鳞状细胞癌的转移和侵袭^[53]。然而，在膀胱癌中敲除STMN1基因可下调E-cadherin的表达水平，促进膀胱癌细胞的EMT进程^[18]。

4 <bold>STMN1</bold>作为治疗靶点的价值

STMN1与肿瘤的恶性进展和预后相关，能影响化疗药物耐药性产生，且与肿瘤细胞免疫检查点和肿瘤微环境免疫细胞活化密切相关。“抗STMN1”靶向治疗可能有助于提高肿瘤患者治疗后的生存质量，可能成为治疗恶性肿瘤的潜在策略^[56]。

4.1 <bold>STMN1</bold>与肿瘤预后标志物

STMN1是多种肿瘤的预后标志物，也可用于预测治疗后患者的预后^[32]。在HCC中，STMN1可用于评价药物的治疗效果^[10]；在靶向BRCA1阳性乳腺癌治疗中，STMN1可作为潜在的生物标志物^[33]。此外，磷酸化的STMN1(Ser38)表达水平的升高与肿瘤细胞增殖有关，能提供重要的子宫内膜癌患者预后信息^[57]。

4.2 <bold>STMN1</bold>与肿瘤细胞耐药性

STMN1与多种肿瘤细胞耐药性的产生密切相关。在乳腺癌、肺癌、胃癌、肝内胆管癌细胞中，STMN1的高表达与紫杉醇的耐药性相关，敲低STMN1则可促进紫杉醇诱导的细胞凋亡，增加肿瘤细胞对紫杉醇的敏感性^{[55, 58]}。在小鼠体内实验中进一步证实，敲低STMN1联合紫杉醇协同治疗可抑制NSCLC细胞的生长，促进移植肿瘤的分化^[54]。根据STMN1作用于微管蛋白的功能推测，STMN1可作为其余常规靶向微管蛋白的抗癌药物敏感性的潜在标志物^[34]。

4.3 <bold>STMN1</bold>与肿瘤免疫治疗

在HCC中，STMN1表达水平升高与程序性死亡受体配体1(programmed death-ligand 1，PD-L1)、CTLA-4等免疫检查点表达水平上调呈正相关，并且STMN1的表达水平与肿瘤微环境中免疫细胞的浸润密切相关，揭示了STMN1作为免疫治疗潜在靶点的可能性^[21]。在乳腺癌细胞中，STMN1的高表达与免疫检查点转录调控因子叉头框蛋白P3(forkhead box P3，FOXP3)、CTLA-4、PD-L1和PD-1的高表达呈正相关^[33]。在软组织肉瘤的免疫微环境中，免疫细胞的浸润与肿瘤内STMN1表达相关，最终影响患者的生存率，提示STMN1可作为软组织肉瘤免疫治疗的新靶点。在口腔鳞状细胞癌微环境中，癌细胞与高表达STMN1的毛细血管内皮细胞发生相互作用，共同促进肿瘤的免疫逃逸^[59]。

同时，STMN1的表达水平可以影响免疫细胞的功能。在自然杀伤细胞中，STMN1的表达水平与自然杀伤细胞基因特征的表达间接相关^[60]。在巨噬细胞中，STMN1的表达水平升高会抑制由补体C3介导的细胞活化过程和吞噬作用；在经典活化的巨噬细胞中，STMN1的表达水平显著降低。STMN1可通过破坏微管的稳定性，阻止巨噬细胞发挥正常功能，下调其表达对于激活巨噬细胞的经典途径至关重要^[61]。在T细胞中，STMN1的表达对其活化过程起重要的调控作用。磷酸化的STMN1定位于T细胞极化过程中的免疫突触区域，可显著加快活化后T细胞内的微管聚合速率。当STMN1表达水平降低时，微管生长速率减缓，导致CD8⁺ T细胞微管组织中心结构及功能异常，进而损害其对靶细胞的溶解能力，最终削弱CD8⁺ T细胞的细胞毒性效应^[62]。

5 结 语

STMN1在诸多肿瘤中表达上调，普遍认为它是一种促癌因子，但在膀胱癌中则作用相反。STMN1可以通过微管结合作用影响细胞骨架相关功能，对于肿瘤细胞的增殖、迁移、侵袭、凋亡以及有丝分裂都具有重大影响。本文总结了STMN1在肿瘤中的调节通路和机制，并揭示了STMN1作为潜在生物标志物、抗耐药性关键蛋白质和免疫治疗靶点的价值，希望关于STMN1的相关研究可以对日后临床肿瘤诊断和治疗提供新的思路，改善患者的预后。

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基金资助

安徽省自然科学基金(2308085QH276)

安徽医科大学大学生创新创业计划(AYDDCxj2022011)

安徽医科大学“早期接触科研”训练计划(2021-ZQKY-110)

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