Application of 68Ga-PSMA-617 Molecular Probe for Micro-PET Imaging of Gliomas Model
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摘要:目的
探讨68Ga-PSMA-617在神经胶质瘤U87MG荷瘤鼠的显像情况。
方法将靶向前列腺特异性膜抗原（prostate specific membrane antigen, PSMA）的新型探针DKFZ-PSMA-617进行68Ga核素标记，利用Radio-TLC对68Ga-PSMA-617的放射化学纯度进行快速质控，然后进行细胞水平实验，尾静脉注射5和40 min后对U87MG荷瘤鼠进行micro-PET显像，同时对PSMA阻滞剂ZJ-43（25 mg/kg）共注射组进行注射后40 min的图像采集。
结果Radio-TLC对68Ga-PSMA-617的标记率及放化纯测定可在10 min内完成，放化纯高达（99.0±1.9）%，细胞水平实验显示68Ga-PSMA-617分子探针的特异性，同时也显示U87MG细胞表面仅有较少量PSMA表达，而U87MG荷瘤鼠的micro-PET显像可见随时间延长肿瘤对PSMA靶向分子探针的放射性摄取的逐渐增高，靶与非靶比值从1.85±0.02（5 min）增长至3.62±0.175（40 min），且肿瘤对该探针的摄取可被PSMA阻滞剂ZJ-43所抑制。
结论68Ga-PSMA-617不仅可应用于前列腺癌的诊断，也有望应用于新生血管丰富的神经胶质瘤的诊断。
Abstract:ObjectiveTo investigate the application of 68Ga-PSMA-617 molecular probe for micro-PET imaging of gliomas tumor model.
MethodsDKFZ-PSMA-617, an effective prostate specific membrane antigen (PSMA) targeted probes, was chosen to be the precursor to be radiolabelled with 68Ga. The radio-chemical yield of 68Ga-PSMA-617 was analyzed by Radio-TLC. Cell uptake experiments were performed on PSMA (+) LNCaP, PSMA (-) PC-3 and U87MG cells. Nude mice bearing U87MG were injected with 68Ga-PSMA-617(7.4 MBq) via the tail vein. Micro-PET imaging was performed 5 and 40 min after the injection. Blocking studies were also performed in U87MG tumor-bearing mice after 40 min of co-injection of 68Ga-PSMA-617 with the PSMA inhibitor (S)-2-(3-((S)-1-carboxy-3-methylbutyl)ureido) pentanedioic acid (ZJ-43) (25 mg/kg).
ResultsThe radiotracer had a good radio-chemical yield of (99.0±1.9)% quickly tested by Radio-TLC. In cell uptake experiments, the specificity of 68Ga-PSMA-617 was confirmed in PSMA (+) LNCaP cells and PSMA (-) PC-3 cells; meanwhile, it proved the low expression level of PSMA in gliomas U87MG cell line. From micro-PET imaging, U87MG xenografts tumors were visualized and it showed good tumor-to-background value from 1.85±0.02 (5 min) to 3.62±0.175 (40 min) which could be blocked by ZJ-43.
Conclusion68Ga-PSMA-617 has the potential to be used not only in prostate cancer but also in gliomas tumor model.
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Key words:
- Prostate specific membrane antigen /
- Neo-vasculature /
- PET /
- Glioma /
- Gallium-68
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0 引言
卵巢癌是最常见的女性恶性肿瘤之一，据统计，2020年中国有约55 300例卵巢癌新发病例和37 500例死亡病例[1]。卵巢癌转移能力较强，多数于诊断时已出现疾病进展或广泛转移，患者5年生存率不足30%[2]，因此，研究卵巢癌侵袭转移的机制对于该疾病的治疗具有重要意义。
近年来大量研究揭示了线粒体代谢相关基因与肿瘤转移、发展密切相关[3-5]。醛脱氢酶5家族A1（ALDH5A1）编码产物为琥珀酸半醛脱氢酶（SSADH），在线粒体代谢中通过催化琥珀酸半醛的氧化反应来降解γ-氨基丁酸（GABA）。ALDH5A1表达下调，SSADH功能缺陷会导致GABA正常降解途径受阻，转而生成γ-羟基丁酸（GHB），Hilvo等[6]报道了GHB可作为高级别卵巢浆液性癌生物标志，其蓄积提示卵巢癌的进展以及预后不良。
Deng等[7]发现ALDH5A1表达下调可通过抑制甲状腺癌细胞增殖、转移、侵袭、上皮间质转化等途径进而抑制肿瘤发生发展；Kaur等[8]采用Gene Sapiens微阵列数据库进行Meta分析发现，在特定类型肿瘤如胶质瘤、白血病、淋巴瘤中发现ALDH5A1表达上调，而在乳腺癌中ALDH5A1则较正常组织表达下调。
本课题组前期研究也表明，卵巢癌患者肿瘤组织ALDH5A1较正常卵巢组织表达下调，且ALDH5A1低表达与卵巢癌患者临床预后不良相关[9]，然而具体分子机制尚不清楚。本研究将进一步探讨ALDH5A1在卵巢癌发生发展中的作用。
1 资料与方法
1.1 细胞
人卵巢癌上皮SKOV3细胞系来自美国ATCC细胞库。该细胞系在添加10%胎牛血清（FBS，购于美国Gibco公司）和1%青霉素/链霉素（购于美国Gibco公司）的McCoy’s 5A培养基（购于瑞士Lonza公司）中培养，置于37℃、5%CO2的加湿培养箱中。
1.2 生物信息数据库
GEO数据库[9]下载GSE20565卵巢癌转录组数据，分析ALDH5A1 mRNA表达水平。为进一步证实ALDH5A1和共表达基因的蛋白质组学表达，分析从人类蛋白图谱数据库（https://www.proteinatlas.org/）中获得的卵巢癌组织芯片（TMA）队列。
基于网络工具PROGgeneV2[10]评估卵巢癌中ALDH5A1表达水平与患者预后的相关性。运用TCGA数据库中ALDH5A1 mRNA表达数据和578例卵巢癌患者的总生存率信息建立Kaplan-Meier生存曲线图。Kaplan-Meier plotter在线平台芯片数据分析不同TP53突变型别与卵巢癌患者总生存率的关系。
1.3 实验方法
1.3.1 小干扰RNA
下调目的基因ALDH5A1 ALDH5A1 siRNA购自上海生工生物技术有限公司。靶标序列如下：siRNA1: 5’-CGGAAGTGGTACAATTTAATG-3’；siRNA2: 5’-GGTTCAACAACTACAGGAAAG-3’。LipofectamineTM3000（Thermo Fisher）将siRNA和阴性对照按说明书转染到SKOV3细胞中。转染48 h后测定敲减效率。
1.3.2 细胞划痕实验
SKOV3野生型细胞和转染siRNA的细胞按1×106个细胞/孔的密度接种于六孔板中，在5%CO2、37℃下孵育。过夜培养，细胞生长到100%密度。用移液器无菌100 μl枪头尖端在单层细胞上划出划痕。PBS冲洗细胞1次，去除细胞碎片，抚平划痕边缘，再用2.5 ml McCoy's 5A培养基进行细胞培养。倒置显微镜摄取划痕边缘的图像。
1.3.3 细胞侵袭实验
依据试剂盒说明书，用包被人工基质层（Matrigel）的Transwell小室评估SKOV3细胞侵袭能力。将基质在冰上融化，然后将30 μl的基质添加到24孔的Transwell小室中并凝固，野生或转染siRNA的细胞按1×105个细胞/孔的密度置于基质凝胶涂层顶部，在37℃、5%CO2下孵育10 min，使细胞下沉。下室为含有McCoy's 5A培养基，10%胎牛血清作为化学引诱剂。在5%CO2、37℃下孵育24 h后，用棉签去除未穿透膜的细胞。成功迁移至膜底面的细胞，4%聚甲醛固定，0.2%结晶紫染色10 min。倒置显微镜下计数细胞数量。
1.3.4 ALDH5A1共表达基因数据库检索与分析
来自Cancer Cell Line Encyclopedia（CCLE）中的卵巢癌细胞系（n=47）和TCGA中的卵巢浆液性囊腺癌（n=489）患者数据用cBioPortal[11]在线平台进行分析。当Spearman相关性 > 0.2和P < 0.05时，认为该基因为ALDH5A1共表达基因。采用g: Profiler[12]和Metascape[13]两个在线平台数据库中ALDH5A1的共同共表达基因进行通路富集分析。Metascape在线平台将具有相似功能的重要GO关键词可视化为交互网络，进一步确定关键词之间的关系，其中P < 0.01、相关度评分 > 0.3的项位于网状图边缘。此外，运用cBioPortal对ALDH5A1与细胞外基质（ECM）组织通路关键基因进行共表达分析。
1.3.5 实时荧光定量RT-PCR（qRT-PCR）
试剂盒（Invitrogen）提取细胞总RNA，用反转录酶（TransGen Biotech）以1 μg总RNA合成cDNA。SYBR Green PCR Master Mix（Takara Bio）和Light Cycler（Roche）行qRT-PCR分析。结果用2-∆∆ct计算。
1.4 统计学方法
所有数据使用GraphPad Prism 8.0进行分析，以三次重复的（x±s）表示。两组间定量资料用Student's t检验。P < 0.05为差异有统计学意义。
2 结果
2.1 ALDH5A1下调促进卵巢癌细胞侵袭与转移
结果显示，转移灶组织（n=35）与原发灶（n=90）相比，转移灶的ALDH5A1表达水平显著下调（P=1.6×10-5），见图 1A。
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图 1 ALDH5A1下调促进卵巢癌细胞侵袭与转移Figure 1 ALDH5A1 downregulation promoted metastasis and invasion of ovarian cancerA: transcription level of ALDH5A1 in the metastatic site of ovarian cancer (OC) (n=35) was markedly downregulated compared with that in the primary site (n=90), P=1.6×10-5; B: qRT-PCR analysis confirmed that ALDH5A1 expression was successfully downregulated in SKOV3-siRNA cells; C: Transwell assay showed that the invasion ability of OC cells dramatically increased; D: scratch-wound healing assay showed that the migratory ability of SKOV3 cells dramatically increased.siRNA技术建立ALDH5A1表达下调的SKOV3卵巢癌细胞系，并用qRT-PCR验证：相比于SKOV3-NC组，SKOV3-siRNA1及SKOV3-siRNA2组中ALDH5A1mRNA表达水平下调，见图 1B。Transwell实验表明，随着ALDH5A1表达水平下调，卵巢癌细胞的迁移能力显著增强（P < 0.0001），见图 1C。划痕实验表明，卵巢癌细胞的迁移能力与ALDH5A1表达水平呈负相关（P < 0.01），见图 1D。
2.2 ALDH5A1与卵巢癌中ECM信号通路的关系
运用cBioPortal在线平台从CCLE数据库中提取了47个卵巢癌细胞株中1 575个ALDH5A1共表达基因，见附表 1，从TCGA数据库中的489个卵巢癌患者中提取了1 220个ALDH5A1共表达基因，见附表 2。通过取这两个共表达基因集的交集，发现有128个共同的共表达基因重叠，见图 2A、附表 3（附表 1~3请扫描本文OSID码）。对上述128个ALDH5A1的共表达基因进行功能富集分析，以识别共表达基因列表中可能存在的信号通路。首先，运用g: Profiler鉴定ALDH5A1与128个共表达基因的功能信息和富集途径及过程。如图 2B所示，生物进程（biological processes: BPs）方面，这些基因主要富集在ECM组织（GO: 0030198）和细胞外结构组织（GO: 0043062）；细胞组成（cellular components: CCs）方面，这些基因主要富集在ECM通路中（GO: 0031012）；分子功能（molecular functions: MFs）分析和Reactome（REAC）分析也显示这些基因在ECM结构成分（GO: 0005201）和ECM组织（REAC: R-HSA-1474244）中显著富集。同时用Metascape平台再次进行了GO分析。推测结果中与ALDH5A1关联密切的20种生命活动，其中富集最显著的基因集是ECM组织通路（GO: 0030198），见图 2C。Metascape绘制的共表达通路富集网路显示此20种生命活动彼此密切相关，见图 2D。
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图 2 ALDH5A1基因功能富集分析以及其与卵巢癌中的共表达基因Figure 2 Gene-Ontology analysis of ALDH5A1 and coexpressed genes revealing the relationship between ALDH5A1 and ECM signaling pathways in OCA: Venn diagram showing the common coexpression genes that were found to overlap with ovarian cancer data derived from the CCLE database and TCGA database; B: g: Profiler was used to identify the functional information and enriched pathways and processes of ALDH5A1 and the 128 common co-expression genes; C: Metascape platform showing the top 20 putative biological processes; D: biological processes as revealed by Metascape in a network diagram.2.3 卵巢癌患者TP53突变型别影响ALDH5A1与ECM途径中分子的相关性
运用g: Profiler平台找到ECM通路中与ALDH5A1密切相关的基因MMP2、MMP3和MMP14。借助cBioportal平台中的卵巢癌数据库（TCGA, Firehouse Legacy数据集中卵巢浆液性囊腺癌临床资料）转录组数据“RNA Seq V2 RSEM” mRNA表达谱，对ALDH5A1与MMP2、MMP3、MMP14等基因的mRNA表达水平进行Sperman相关性分析。结果提示ALDH5A1与MMP2表达呈负相关（R=-0.34），ALDH5A1与MMP3表达呈负相关（R=-0.27），ALDH5A1与MMP14表达呈负相关（R=-0.30），见图 3A。通过分析GEO数据库中卵巢癌转录组芯片数据GSE63885，验证ALDH5A1与MMP2、MMP3、MMP14表达水平的相关性。发现ALDH5A1与MMPs表达水平的相关性与卵巢癌患者是否存在TP53突变有关：在所有卵巢癌患者（n=101）中，ALDH5A1仅与MMP14表达水平显著性负相关（R=-0.26, P=0.009）；而存在TP53突变（n=75）的卵巢癌患者中，ALDH5A1与MMP14表达水平负相关更加显著（R=-0.36, P=0.0014）；在TP53野生型（n=15）卵巢癌患者中，ALDH5A1与MMP2、MMP3、MMP14表达均无显著相关性，见图 3B。
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图 3 ALDH5A1与ECM组织通路的共表达分析Figure 3 Coexpression analysis of ALDH5A1 and correlated genes among ECM pathwaysA: A negative correlation of mRNA expression was found between ALDH5A1 and MMP2, MMP3, MMP14. mRNA expression data was from "RNA Seq V2 RSEM" profile; B: Analysis of the GEO transcriptome chip data GSE63885 shows the correlation between ALDH5A1 and MMPs in relation to TP53 mutation type. The mRNA level is quantified by log2 (normalized counts + 1); P value was calculated by Person's correlation test.一方面，我们从HPA数据库中获取卵巢癌TMA队列，临床样本免疫组织化学染色结果从蛋白水平验证卵巢癌患者ALDH5A1和MMPs表达水平呈负相关：ALDH5A1低表达组（Stain: Not detected/Intensity: Negative）中MMP14表达水平（Stain: low/Intensity: Weak）相较于高表达组（Stain: Medium/Intensity: Moderate）MMP14表达水平（Stain: Not detected/Intensity: Negative）有所提升，与转录组数据分析结果一致，见图 4。
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图 4 HPA数据库中两例代表性卵巢癌患者免疫组织化学提示ALDH5A1和MMP14表达负相关Figure 4 Immunohistochemical staining results from HPA database demonstrating the negative correlation between ALDH5A1 and MMP142.4 ALDH5A1低表达的卵巢癌患者预后
在卵巢癌患者中ALDH5A1表达较低者预后较差。ALDH5A1高水平卵巢癌患者的总生存率明显高于ALDH5A1低水平卵巢癌患者（HR=0.75（0.64~0.88）, P=0.0005），见图 5A。病理Ⅱ级和Ⅲ级患者ALDH5A1高表达与OS改善相关（HR=0.54（0.34~0.88）, P=0.0127; HR=0.79（0.66~0.94）, P=0.0077），见图 5B~C。
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图 5 ALDH5A1 mRNA表达水平与卵巢癌患者预后相关分析Figure 5 Relative analysis between ALDH5A1 mRNA expression and the prognosis of OC patientsA-C: data from TCGA database. A: all OC patients (n=578); B: gradeⅡ OC patients (n=78); C: gradeⅢ OC patients (n=481); D-F: data from Kaplan-Meier plotter online trancriptome chip data; D: all OC patients (n=1656); E: TP53-mutated OC patients (n=506); F: TP53-wild OC patients (n=94).TP53突变型患者的ALDH5A1表达与总生存时间相关性更为显著（HR=0.71（0.56~0.89）, P=0.0026），见图 5E，而TP53野生型卵巢癌患者的ALDH5A1表达则与总生存时间无显著相关（HR=1.07（0.62~1.85）, P=0.82），见图 5F。
3 讨论
真核细胞的线粒体是一种重要的细胞器，在调节细胞增殖、分化、凋亡过程中发挥关键作用[6]。ALDH5A1属于ALDHs家族，编码产物为SSADH，后者对于线粒体代谢中GABA的降解起着非常重要的作用，功能缺陷或降低可导致GABA和GHB在体内蓄积。早在2001年即有研究报道，卵巢癌患者尿液中可观察到GABA浓度升高[14]。Hilvo等[6]发现高级别浆液性卵巢癌患者中GHB有异常蓄积现象，并证明这种蓄积现象是由ALDH5A1基因突变和活性降低引起的。尽管多项研究一致认为ALDH5A1与卵巢癌的发生发展相关，但卵巢癌中ALDH5A1作用的具体分子机制尚不清楚。
本研究发现与原发灶相比，卵巢癌患者转移组织中ALDH5A1的表达水平降低，提示细胞中ALDH5A1表达下调可能促进卵巢癌的侵袭和迁移。为深入了解ALDH5A1的功能，我们进行了功能富集分析，结果显示ALDH5A1共表达基因主要与ECM通路相关。ECM是由细胞合成并分泌到细胞外，分布在细胞表面或细胞之间的大分子物质，由基底膜（basement membrane, BM）和细胞间基质组成，是阻止肿瘤细胞转移的重要组织屏障。肿瘤细胞侵袭转移的首要条件是降解ECM和破坏BM，而MMPs是降解ECM最重要的蛋白酶类[15]。
近年来许多研究表明MMPs和肿瘤的发生发展密切相关，MMP2蛋白在卵巢癌转移中起早期应答蛋白的作用[16-18]。MMP14在基底膜和间质组织迁移过程中细胞外基质降解中发挥着核心作用[19]，它刺激肿瘤-间质信号通路并促进卵巢癌细胞上的血管生成和肿瘤生长[20]。本研究从转录组表达数据、HPA免疫组织化学样本、生存分析数据发现，ALDH5A1下调促进卵巢癌细胞的侵袭和迁移与ECM通路中的关键基因MMP14相关，且这种影响可能与卵巢癌患者TP53突变有关。
综上所述，本研究发现ALDH5A1表达下调与卵巢癌转移密切相关，并初步探讨了ALDH5A1下调可能通过ECM通路影响卵巢癌细胞的侵袭转移能力，提示卵巢癌患者预后不良，具体分子机制尚需进一步研究。本研究提示ALDH5A1可能作为卵巢癌转移标志物以及潜在的治疗靶点。
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图 1 68GaCl3以及68Ga-PSMA-617标记产物纯化前后的radio-TLC分析
Figure 1 Radio-TLC analysis of 68GaCl3 and 68Ga-PSMA-617 before and after purification
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图 2 natGa-PSMA-617的质谱分析及68Ga-PSMA-617的HPLC分析
Figure 2 MALDI-TOF-MS analysis of natGa-PSMA-617 and HPLC analysis of 68Ga-PSMA-617 compound
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图 3 68Ga-PSMA-617在LNCaP、PC-3和U87MG的细胞摄取分析(n=4)
Figure 3 Cell uptake of 68Ga-PSMA-617 in LNCaP, PC-3 and U87MG cell lines (n=4)
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图 4 68Ga-PSMA-617在U87MG的micro-PET显像
Figure 4 Micro-PET images of 68Ga-PSMA-617 in U87MG bearing mice
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