兰州理工大学学报稿件信息
S100P在肿瘤发生发展中的作用机制及临床价值
李伟沣1，谢菲岚2，梅晓月3，刘璐 4，刘锦涛#
(1．广东医科大学 研究生学院，广东 湛江524000；2，3，4，# 宝安区人民医院 消化内科，广东 深圳 518100)
摘要：S100P属于钙结合蛋白S100家族，在多种肿瘤异常表达。研究发现，S100P与肿瘤细胞的增殖、侵润转移密切相关，是驱动肿瘤发生发展的重要基因。本文从S100P结构与功能出发，分析S100P在不同恶性肿瘤中的表达特点及临床意义，为肿瘤临床诊断和靶向治疗提供新的参考与选择。
关键词：S100P；肿瘤；作用机制；临床价值
The role of S100P in tumorigenesis and its potential clinical applications LI Weifeng1, XIE Feilan2, MEI Xiaoyue3, LIU Lu 4, LIU Jintao #.（1.Department of Guangdong Medical University，Guangdong Zhanjiang 524000，China; 2，3，4，#. Digestive System Department，Baoan People＇s Hospital of Shenzhen，Guangdong Shenzhen 518100，China．）
Abstract:
S100P is a member of the S100 family of calcium-binding proteins, and is expressed at high level in a variety of different tumor types. S100P has been shown to mediate tumor growth, metastasis and invasion. In addition, its expression is associated with drug resistance and poor clinic outcome. Therefore, the S100P could potentially serve as diagnostic marker, prognostic/predictive indicator and therapy target for different carcinomas. This review summarizes the role and potential clinical applications of S100P in cancer.
Key words: S100P; Tumor; Mechanism; Clinical applications
肿瘤是危害人类健康的重大疾病，但其早期通常缺乏特异性症状，多数患者在确诊时已处于中晚期，使得临床治愈率较低。早发现、早诊断、早治疗是治愈癌症，提高患者生存率的关键。寻找肿瘤相关特异性标志物，研究其作用机制，探索其临床价值是当下的研究热点。S100P是S100家族的成员，广泛存在于人体组织中，其中在胎盘和胃中的表达量最高[1,2]。随着研究的不断深入，发现S100P在乳腺癌、前列腺癌、肺癌等多种恶性肿瘤组织中表达水平显著提高，其表达水平与肿瘤增殖、侵袭等密切相关，因此，S100P被认为是驱动肿瘤发生发展的重要基因。
1. S100P
S100家族是EF-手型钙结合蛋白家族中最大的亚族，包括S100A1～S100A16、S100B、S100G、S100P及S100Z等20多个成员[3]。S100家族蛋白具有调控胞内钙稳态、细胞周期、细胞生长和迁移、转录因子等重要功能，因此，S100蛋白的表达异常和失调常伴随多种肿瘤发生发展的过程[4]。
人S100P基因位于染色体4p16，其序列全长为510bp，具有1个内含子和2 个外显子，共编码 95个氨基酸。与其它S100蛋白一样，S100P具有两个呈“螺旋-环-螺旋”的EF-手型结构域，可各自结合一个二价金属离子，其中C端的EF-手型结构域更为保守，与Ca2+亲和力也更高。结构生物学研究证明，S100P结合Ca2+/Mg2+后，其构象发生大的改变，暴露出配体结合位点，通过与配体的相互作用发挥其生物学功能[5]。S100P一般以同源二聚体(S100P/S100P)的形式存在和发挥功能，也可以与S100A1结合形成不稳定的异源二聚体（S100P/S100A1）[6]。
2. S100P调控肿瘤发生发展的分子机制
研究发现，S100家族蛋白广泛地参与细胞内和细胞外功能的调节。细胞内，通过介导Ca2+依赖的信号传导途径，S100调节细胞增殖分化、细胞凋亡、黏附运动、细胞骨架的构成和蛋白质磷酸化等过程；细胞外，S100以旁分泌或自分泌等方式激活相应的靶蛋白，参与炎症反应、肿瘤疾病等病理过程[4]。
S100P属于S100蛋白家族，其异常表达具有促进细胞异常增生、提高肿瘤细胞浸润能力等作用。目前，已发现的S100P配体包括晚期糖基化终末产物受体（Receptor forAdvanced Glycation End products，RAGE）、IQ结构域GTP酶激活蛋白1（IQ-domain GTPase-activating protein 1，IQGAP1）、钙周期素结合蛋白（Calcyclin-binding-protein，又称Siah-interaction-protein，Cacy BP/SIP）、S100P结合蛋白配体、埃兹蛋白、蛋白酶体D等，通过与这些配体的结合而发挥不同的生物学功能。
2.1 RAGE
RAGE是免疫球蛋白超家族成员，能结合多种配体而启动不同的信号通路，可激活细胞内氧化应激和炎症反应，导致细胞或组织功能紊乱。目前，RAGE-配体相互作用调控肿瘤细胞存活和增殖的分子机制已相对明确：RAGE与配体结合后，激活MAPK、PI3K/ AKT、JAK/STAT等信号通路，促进转录因子NF-κB、AP-1、STAT1/3活性，调控多种生长因子、纤维连接蛋白等基因的表达，从而促进肿瘤的发生发展[7]。Fuentes[8]等应用Western blot、RT-PCR等方法检测到，阻断RAGE可抑制 S100P过表达介导的直肠癌细胞增殖。进一步研究发现，经S100P 与RAGE 结合后，激活了ERK1/2（external-signal regulated kinase 1/2）信号传导通路，通过活化NF-kB，促进结直肠癌的生长和迁移。Shen[9]等研究发现，异常表达的S100P能通过激活RAGE/ERK信号通路，促进上皮-间质转化，从而增强了结直肠癌的侵袭和转移能力。通过阻断S100P与RAGE相互作用来抑制肿瘤细胞生长已成为目前肿瘤治疗研究的热点。
2.2 IQGAP1
Heil[10]等利用S100P/S100P作为固定相，通过亲和层析的方法筛选到一个新的配体蛋白（分子量～190kDa），并采用蛋白质串联质谱MALDI-MS技术，鉴定该配体为IQGAP1。IQGAP1是人体组织中广泛存在的支架蛋白，作为细胞定向运动的重要调控分子，在细胞黏附、运动、骨架改变及增殖等方面发挥重要作用。越来越多的研究证明，IQGAP1通过多种途径在肿瘤细胞的增殖和迁移侵袭中扮演重要角色。Heil等也发现，S100P能够抑制表皮生长因子（EGF）诱导的IQGAP1磷酸化，影响B-raf的结合和MEK1/2的激活，因此，S100P对EGF诱导的细胞增殖具有抑制效果。
埃兹蛋白是一种位于细胞内的桥接蛋白，主要参与上皮细胞中细胞骨架与膜蛋白的连接，具有维持细胞形态和运动、连接黏附分子及调节信号传导等功能。近来研究发现，埃兹蛋白在肿瘤细胞中异常表达，在肿瘤浸润转移过程中发挥重要作用[11]。静息状态下，胞浆内埃兹蛋白N端和C端结构域折叠在一起，掩盖了与其他分子结合的点位。Gerke[12] 课题组研究发现，与磷脂酰肌醇（Phosphatidylinositol 4,5-bisphosphate，PIP2）活化埃兹蛋白方式类似，S100P能直接结合到埃兹蛋白N端结构域，使得埃兹蛋白暴露出配体的结合位点，提高了肿瘤细胞的迁移能力。
2.4 Cacy BP/SIP
钙周期素结合蛋白Cacy BP/SIP是最早发现的S100P配体之一，与Siah-1、Skp1 和TBL1 组成泛素化连接酶复合物，参与致癌基因β-catenin的降解[13]。目前，S100P与Cacy BP/SIP对β-catenin泛素化降解的影响尚未明确，有待进一步研究。
2.5 S100PBR
Dowen[14]等以S35标记的S100P为探针，利用Far Western技术从胎盘cDNA噬菌体表达库中筛选出一株编码S100P结合蛋白的cDNA克隆。测序结果显示，该cDNA为RIKEN基因的N端片段，因此该蛋白被命名为S100PBPR（S100P binding protein Riken）。进一步研究发现，在胰腺导管上皮内瘤变和胰腺导管腺癌均可检测到S100PBPR和S100P的转录本，而正常的胰腺导管细胞未发现S100PBPR。该结果提示，S100P与S100PBPR相互作用参与了早期胰腺肿瘤发展的调控。Lines[15]等发现，在早期胰腺癌组织中，S100PBPR细胞内的定位发生改变，而在恶性胰腺肿瘤及转移性淋巴结组织，S100PBPR表达量显著减少。细胞黏附性的丧失是肿瘤转移过程中的关键步骤。S100PBPR能负向调控蛋白酶cathepsin Z的转录，而cathepsin Z与整合素αvβ5相互作用，可介导恶性胰腺肿瘤细胞黏附性的改变。目前，S100P与S100PBPR相互作用影响胰腺肿瘤发生发展机制尚未报道。
此外，S100P可通过影响β-连环蛋白，刺激其核内转位，使β-连环蛋白与T细胞因子/淋巴增强因子（TCF / LEF）相互作用，从而增加Cyclin D1和c-myc的表达，从而调控肿瘤细胞的分化和增殖[16]。
3. S100P在肿瘤诊断中的价值
S100P在大多数的正常组织中不表达或低表达，但在乳腺癌、前列腺癌、胰腺癌、肺癌、结直肠癌等多种肿瘤组织中呈高表达，而且其表达水平与肿瘤分期、生存期及复发转移等密切相关，因此，S100P有望成为重要的肿瘤早期诊断、预测进展、复发等的标志物（见表一）。
4. S100P在肿瘤治疗中的价值
越来越多的研究证明，异常表达的S100P是驱动乳腺癌、结直肠癌、肝癌、胆管癌、胰腺癌等多种肿瘤发生发展的重要基因，而且S100P表达水平对化疗药物的敏感性也有重要影响，因此，S100P成为了肿瘤靶向治疗的热门靶点。目前，有3类药物或方法可抑制S100P的作用。一类为小分子抑制剂，可与配体竞争结合位点，从而抑制S100P与配体相互作用，阻断下游信号的激活。这类药物有色甘酸及类似物，它们能干扰S100P与RAGE相互作用，抑制NF-kB信号通路的激活，控制胰腺肿瘤的增殖和转移[40,41]。另一类为单克隆抗体，可在胞外阻断S100P与配体的相互作用。Dakhel[42]等发现抗S100P抗体能有效抑制胰腺癌细胞增殖和肝转移。还有一类为反义RNA，与S100P mRNA结合后，导致其降解，从而降低S100P的表达水平[43,44,45]。
此外，多个研究发现，S100P的表达水平与胰腺癌[30]、结直肠癌[30]、前列腺癌[22]对化疗药物的敏感性密切相关，因此，对于S100P异常表达的患者，化疗联合S100P靶向治疗策略，有望增强对化疗药物的敏感性，改善疗效。
5 结语与展望
综上所述， S100P与肿瘤细胞的增殖、侵润转移密切相关，是驱动肿瘤发生发展的重要基因。异常表达的S100P可以作为乳腺癌、胰腺癌、肺癌等早期诊断的标志物，其表达水平与多种肿瘤恶性程度、临床分期、淋巴转移情况等密切相关，可作为预测进展及生存期等的指标。S100P靶向治疗是目前研究的热点，而且联合化疗有望为S100P阳性肿瘤患者提供新的治疗思路。
表一 S100P在不同肿瘤中的表达情况
|
肿瘤 乳腺癌 |
S100P在不同肿瘤中表达的相关价值 S100P过表达参与乳腺肿瘤早期启动生长的调控，使细胞获得无限增殖能力，可作为乳腺癌早前诊断标志物[17,18] S100P表达水平与乳腺癌发生风险、患者存活时间、乳腺癌恶性程度等成正相关[19,20] |
|
前列腺癌 |
S100P与前列腺癌恶性程度正相关，可作为前列腺癌进展情况的标志物[21] 过表达S100P抑制喜树碱诱导的细胞凋亡，因此S100P可作为化疗药物喜树碱敏感性的标志物[22] |
|
胰腺癌 |
S100P在胰腺肿瘤及肿瘤样病变组织表达显著升高，可作为区分慢性胰腺炎和肿瘤病变的标志物[23,24] S100P表达水平与胰腺上皮内瘤变级别成正相关[14] S100P表达水平与胰腺癌分化程度、临床分期及淋巴转移情况相关[25,26,27] |
|
肺癌 |
S100P在早期非小细胞肺癌和肺腺癌表达升高，可作为早期诊断标志物[28] S100P联合S100A2、trypsinogenIVb可预测肺癌转移和生存期[29] |
|
结直肠癌 |
S100P过表达促进结直肠癌细胞的侵袭和转移，可作为预测结肠癌进展的标志物[30] |
|
|
用于区别扁平腺瘤与正常粘膜[31] S100P与溃疡性肠炎临床分级呈正相关[32] |
|
肝癌 |
S100P可作为预测晚期肝癌生存期和早期复发的标志物[33] |
|
胆管癌 |
S100P可作为胆管癌早期诊断的标志物，其灵敏性优于经典的细胞学检测[34] S100P表达水平与胆管癌恶性程度、血管和淋巴侵犯以及转移相关[35] |
|
卵巢癌 |
S100P表达水平与卵巢癌临床分期、血清CA125水平、淋巴结转移等相关，可作为卵巢癌生存期的独立预后指标[36] |
|
食管癌 |
与癌旁组织相比，S100P在食管鳞状细胞癌组织中的表达下调[37,38] |
|
子宫内膜癌 |
S100P在子宫内膜癌组织中的表达上调，并与肿瘤分期呈正相关[16] |
|
黑色素瘤 |
S100P在黑色素瘤组织中的表达水平远高于良性色素痣，尤其在转移性黑色素瘤的表达水平更高[39] |
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