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. 2020 Dec 20;40(12):1732–1739. [Article in Chinese] doi: 10.12122/j.issn.1673-4254.2020.12.06

锌指蛋白ZNF652在乳腺癌组织和细胞中的高表达可促进乳腺癌的发生发展

High expression of ZNF652 promotes carcinogenesis and progression of breast cancer

Ting LEI 1,2, Bin XIAO 2, Yongyin HE 1,2, Zhaohui SUN 2, Linhai LI 2,*
PMCID: PMC7835683  PMID: 33380394

Abstract

Objective

To investigate the expression of ZNF652 in breast cancer tissues and cells and explore its role in breast cancer cell proliferation, invasion and migration.

Methods

We exploited the data from the TCGA database to analyze the differential expression of ZNF652 in breast cancer tissues and adjacent tissues and the correlations of ZNF652 expression with the clinicopathological characteristics of breast cancer patients including molecular subtypes, pathological types, TNM stages and clinical stages. RT-qPCR and Western blotting were used to detect the expression of ZNF652 in 5 breast cancer cell lines including MCF-7, MDA-MB-231, SK-BR-3, UACC-812 and BT-474. Using a lentivirus system and siRNA technique, we assessed the effects of ZNF652 over-expression and knockdown on proliferation, colony forming ability, migration and invasion of breast cancer cells with CCK-8 assay, clonogenic assay, Transwell assay and wound healing assay. The subcellular localization of ZNF652 in 293T cells was determined using immunofluorescence assay.

Results

ZNF652 was significantly up-regulated in breast cancer tissues (P < 0.001). In breast cancer tissues of different molecular types, ZNF652 was down-regulated in TNBC breast cancer tissues but increased in HER2+, Luminal A and Luminal B breast cancer tissues (P < 0.01 or 0.001). The expression of ZNF652 was significantly higher in breast cancer tissues of all pathological types except for mucinous carcinoma than in the adjacent tissues (P < 0.05). The high expression of ZNF652 was closely related to distant metastasis and malignancy of breast cancer (P < 0.01 or 0.001). The mRNA and protein expression levels of ZNF652 was significantly higher in the 5 breast cancer cell lines than in normal breast cells (P < 0.05 or 0.001). Overexpression of ZNF652 promoted the proliferation, invasion and migration of breast cancer cells, while ZNF652 knockdown produced the opposite effects (P < 0.05). Immunofluorescence assay identified subcellular localization of ZNF652 in the nuclei of 293T cells.

Conclusion

ZNF652 is highly expressed in breast cancer tissues and cells to promote the development and progression of breast cancer and may serve as a potential molecular target for diagnosis and treatment of the malignancy.

Keywords: breast cancer, ZNF652, zinc finger protein, oncogene

乳腺癌是起源于乳腺上皮组织的恶性肿瘤，是女性癌症死亡的主要原因[1-3]。尽管目前乳腺肿瘤治疗手段日益完善[4]，但耐药、复发和转移现象依然常见。因此深入研究乳腺癌发生发展的分子机制，寻找潜在的诊断标志物和治疗靶点，对提高乳腺癌患者疗效具有重要意义。

锌指蛋白是人类基因组中最大的转录因子家族，通过与特定的DNA序列结合实现转录调控，相关研究已证实其广泛参与乳腺癌增殖、侵袭和转移等生物学进程[5-8]。ZNF652属于C2H2型锌指蛋白，位于17q21.32，蛋白中心区域含7个锌指基序（CX2CX12HX3H），其中3个由TGEKP连接子序列连接，表明ZNF652是一种DNA结合蛋白[9-10]。因17号染色体常参与乳腺肿瘤杂合性缺失，有研究者推测ZNF652可能在乳腺肿瘤发生发展中发挥作用[11-12]，但其具体生物学机制仍有待探索。本研究拟通过分析ZNF652在乳腺癌组织和细胞中的表达及其对乳腺癌细胞增殖、侵袭和迁移的影响，阐明其在乳腺癌发生发展中的生物学作用，为乳腺癌诊断及靶向治疗提供新的靶点及实验依据。

1. 材料和方法

1.1. 数据

数据下载自USCS Xena（<a href="https://xenabrowser.net" target="_blank">https://xenabrowser.net</a>，含1104例乳腺癌组织和113例癌旁组织样本）和UALCAN（<a href="http://ualcan.path.uab.edu/" target="_blank">http://ualcan.path.uab.edu/</a>，含1097例乳腺癌组织和114例癌旁组织样本），其中包括ZNF652基因表达谱矩阵和样本临床信息。

1.2. 材料

细胞：人肾上皮细胞株（HEK293T）、人乳腺癌细胞株（MCF-7、MDA-MB-231、SK-BR-3、BT-474、UACC-812）及正常人乳腺上皮细胞株（MCF-10A）由中国科学院典型培养物保藏委员会细胞库提供。

主要试剂：DMEM（Cat：C11995500BT）、RPMI 1640培养基（Cat：C11875500BT）和胎牛血清（fatal bovine serum，FBS）（Cat：16000-044）（Gibco）；乳腺上皮细胞培养基MEBM（Cat：CC-3151）（Lonza）；CCK-8试剂（Cat：CK04）（同仁化学）；Lipofectamine 2000转染试剂（Cat：11668019）和ZNF652多克隆抗体（Cat：PA5- 40418）（Invitrogen）；DYKDDDDK Tag兔抗（Cat：14793）（CST）；GAPDH多克隆抗体（Cat：CSB-MA000071M0m）（华美生物）；PrimeScript RT试剂盒（Cat：RR037A）和SYBR® Premix Ex Taq TM Ⅱ试剂盒（Cat：RR820A）（Takara）；带Flag标签的ZNF652慢病毒及GFP荧光质粒由南昌聚焦生物科技有限公司构建；ZNF652引物由艾基生物有限公司合成；ZNF652 siRNA（小干扰RNA）试剂盒（锐博生物）。

1.3. 方法

1.3.1. 细胞培养及转染

HEK293T、MCF-7、MDA-MB-231、SK-BR-3和UACC-812细胞系用DMEM+10% FBS培养，BT-474用RPMI 1640+10% FBS培养，MCF10A用MEBM培养；所有细胞培养条件为37 ℃、5% CO2；瞬转：细胞融合度达到70%~80%时，使用胰酶消化后收集细胞并铺至6孔板中，待完全贴壁后按照转染试剂说明书转染ZNF652及对照siRNA的序列进行敲低。稳转：铺2×105/孔的MDA-MB-231细胞至24孔板中，待贴壁后转染含有ZNF652基因片段的慢病毒载体，空载体慢病毒作为对照，48 h后加入0.5 μg/mL的嘌呤霉素筛选2 d左右。

1.3.2. RT-qPCR

收集细胞并采用TRIzol裂解法提取总RNA，紫外分光光度计检测浓度和纯度。设计合成ZNF652引物F：5'-GATGCGAGAACTGTGACGAA-3'，R：5'-GAAATCCTTGCCACACCACT-3'，内参GAPDH引物F：5'-GGTATGACAACGAATTTGGC-3'，R：5'-GAGCACAGGGTACTTTATTG-3'。将提取的总RNA反转录为cDNA，以cDNA作为模板进行RT-qPCR，每个样品设置3个重复，获得各样品的循环阈值（Ct）。反应条件：95 ℃ 30 s；95 ℃ 5 s、60 ℃ 30 s，共40个循环。采用2-△△Ct法对样本基因进行差异表达相对定量分析。

1.3.3. Western blot

收集细胞并提取总蛋白，加入上样缓冲液后沸水煮10 min变性，待冰上冷却，每个蛋白样品取20 μL进行SDS-PAGE电泳和转膜。5%脱脂奶粉中室温封闭2 h，TBST缓冲液洗膜后，加入抗ZNF652或抗Flag兔一抗（1:1000），4 ℃孵育过夜。次日洗膜后，加入山羊抗兔二抗（1:5000），置于摇床上室温孵育2 h。再次洗膜后，加入ECL化学发光液，使用Bio-Rad化学发光仪进行曝光、显影。

1.3.4. CCK-8法

将5×103/孔的细胞接种于96孔板，待完全贴壁后进行转染。分别在转染的第0、1、2、3、4、5天每孔各加入10 μL CCK-8试剂，培养箱中常规孵育2 h。酶标仪检测A450 nm处的光密度值。

1.3.5. 软琼脂克隆形成实验

收集对数生长期细胞，用含20% FBS的DMEM培养液制备1×106个细胞/L的单细胞悬液。用蒸馏水分别制备出1.2%和0.7%两个浓度的低溶点琼脂糖液，高压灭菌后维持40 ℃不凝固。按1:1比例混合1.2%的琼脂糖和2×DMEM培养基（含2×抗生素和20% FBS），取3 mL混合液注入直径6 cm的平皿中，冷却凝固后作底层琼脂置CO2温箱中备用。按1:1比例混合0.7%的琼脂糖和2×DMEM培养基，加入0.2 mL的细胞悬液并充分混匀，注入铺有1.2%琼脂糖底层平皿中，形成双琼脂层。待上层琼脂凝固后，置入培养箱中培养10~14 d。倒置显微镜下观察细胞克隆数，计算形成率。

1.3.6. Transwell

Transwell迁移实验上室加入用200 μL无血清培养基配制的2×105/mL的细胞悬液，下室加入500 μL含10% FBS的DMEM培养基。常规培养48 h后取出小室，PBS洗去培养基，用湿棉棒擦去上室底部膜表面的细胞，0.1%结晶紫染色10 min，PBS冲洗并干燥后镜下随机选3个视野拍照及计数。Transwell侵袭实验：实验前在transwell小室的上室中加入50 μL稀释后的基质胶（基质胶：无血清培养基=1:3，根据细胞穿透能力选择稀释倍数），放入培养箱中孵育，待基质胶凝固后进行实验，步骤同迁移实验。

1.3.7. 伤口愈合实验

消化离心收集ZNF652过表达细胞，按6×105/孔的比例接种于6孔板，6孔板背面画5条平行线作为标记，待完全贴壁后用无菌移液枪头在细胞中划2条垂直于背面平行线的直线，PBS润洗3次后加入2 mL无血清DMEM培养基，放入培养箱进行培养，分别于0、24、48 h在倒置显微镜下观察并拍照，Image J测量细胞向划痕区域的迁移距离。

1.3.8. 免疫荧光实验

收集2×105/孔的HEK293T细胞，铺至放有盖玻片的六孔板中，待完全贴壁后，分实验组和对照组转染ZNF652荧光质粒及空载体质粒，置入培养箱中培养48 h。弃培养基，PBS润洗3次，4%甲醛固定15 min后，再用PBS洗3次，3 min/次。加入500 μL 0.25%的Triton X-100室温透化10 min，PBS洗4次，5 min/次。在玻片上滴加100 μL DAPI工作液（原液以1:100比例用PBS稀释），室温避光孵育10 min，PBS洗涤1次后封片，荧光共聚焦显微镜下观察并拍照。

1.3.9. 统计学方法

采用SPSS20.0软件对实验结果进行分析。定量资料采用均数±标准差表示，组间均值比较采用t检验，多组均值比较采用方差分析，两两比较采用LSD，以P < 0.05为差异有统计学意义。

2. 结果

2.1. ZNF652在乳腺癌组织中的表达

TCGA（The Cancer Genome Atlas）数据库分析表明，ZNF652在乳腺癌组织中表达（3.37±0.76）较癌旁组织（3.12±0.62）显著上调（P=1.03E-04，图 1A）。在不同分子分型的乳腺癌中，ZNF652在三阴性（TNBC）型（2.78±0.63）乳腺癌组织中表达下调（P=7.09E-05），而在HER2 +型（3.68 ± 1.27）、Luminal A型（3.36 ± 0.63）及Luminal B型（3.47±0.85）乳腺癌组织中表达上调（依次为P=0.014、P=0.0003和P=0.0003，图 1B）。除粘液癌外，ZNF652在不同病理类型的乳腺癌组织中的表达水平均升高，其中以浸润性导管癌差异最为显著（P=1.46E-06，图 1C）。ZNF652在乳腺癌T1-T5及N0-NX期之间的表达差异无统计学意义（P > 0.05，图 1D、E）；ZNF652在M0-MX期间的表达量逐渐降低（P=0.005，图 1F）；ZNF652在乳腺癌不同临床分级中的表达量逐渐降低，但均高于癌旁组织（Ⅰ~Ⅲ级依次为P=0.004，P=3.87E-05和P=0.006，图 1G）。

1.

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基于TCGA数据库分析ZNF652在乳腺癌组织中的mRNA表达水平

Expressions of ZNF652 mRNA in breast cancer tissues based on TCGA dataset. A: Breast cancer and adjacent tissues. B: Molecular subtypes; C: Pathological types (IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma). D-F: TNM grades. G: Clinical stages. Data in A, B, D, E, and F are from USCS Xena, and data in C and G are from UALCAN. *P < 0.05, **P < 0.01, ***P < 0.001 vs Normal.

2.2. ZNF652在5种乳腺癌细胞系中的表达水平

利用RT-qPCR和Western blot鉴定ZNF652在MDA-MB-231、BT474、MCF-7、SK-BR-3和UACC-812乳腺癌细胞系中的表达水平，结果显示，与正常乳腺细胞MCF-10A相比，ZNF652基因在5种乳腺癌细胞系中的mRNA和蛋白表达水平较高，差异有统计学意义（P < 0.05及P < 0.001，图 2）。

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ZNF652在5种乳腺癌细胞中的mRNA和蛋白表达水平

ZNF652 mRNA and protein expressions in 5 breast cancer cells. A: mRNA expression identified by RTqPCR; B: Protein expression identified by Western blotting. *P < 0.05, ***P < 0.001 vs MCF-10A.

2.3. 过表达ZNF652对乳腺癌细胞体外增殖、侵袭和迁移的影响

RT-qPCR和Western blot实验表明，稳定表达细胞株中ZNF652的mRNA和蛋白表达水平明显升高（图 3A、B）；CCK-8及软琼脂克隆形成实验证实，过表达ZNF652促进乳腺癌细胞增殖并增强其集落形成能力（图 3C、G）；Transwell迁移和侵袭实验发现，过表达ZNF652促进乳腺癌细胞的迁移和侵袭能力（图 3D、E）；伤口愈合实验表明，划痕48 h后过表达ZNF652细胞的伤口愈合能力更强（图 3F）。

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过表达ZNF652对乳腺癌细胞增殖、侵袭和迁移的影响

Effects of ZNF652 overexpression on breast cancer cell proliferation, invasion and migration. A, B: Western blotting and RT-qPCR verification of ZNF652 overexpression; C: CCK-8 assay; D, E: Transwell invasion and migration assay (Original magnification: ×100); F: Wound healing assay (×100); G: Clonogenic assay (0.1% crystal violet staining, ×1). *P < 0.05, **P < 0.01, ***P < 0.001.

2.4. 敲低ZNF652对乳腺癌细胞体外增殖、侵袭和迁移的影响

qPCR和Western blot表明，敲除细胞株中ZNF652450 mRNA和蛋白表达水平降低，其中敲除效率较高的si-ZNF652-1用于后续实验（图 4A、B）。CCK-8实验表明，敲低ZNF652抑制乳腺癌细胞增殖（图 4C）；Transwell迁移和侵袭实验表明，敲低ZNF652抑制乳腺癌细胞的迁移和侵袭能力（图 3D、E）。

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敲低ZNF652对乳腺癌细胞增殖、侵袭和迁移的影响

Effects of knocking down ZNF652 on breast cancer cell proliferation, invasion and migration. A, B: Western blotting and RT-qPCR verification of ZNF652 knockdown efficiency; C: CCK-8 assay; D, E: Transwell invasion and migration assay (0.1% crystal violet staining, ×100). *P < 0.05, **P < 0.01, ***P < 0.001 vs si-NC.

2.5. ZNF652的亚细胞定位

免疫荧光实验结果显示，绿色荧光GFP-ZNF652与蓝色荧光DAPI在细胞核内重合（图 5）。

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ZNF652在293T细胞中的定位

Localization of ZNF652 in 293T cells. The cells transfected with GFP-ZNF652/Vector plasmid were stained with DAPI.

3. 讨论

作为人体内重要的转录因子，锌指蛋白参与多种癌症的生物学进程。ZNF703是常见乳腺癌致癌基因，其表达上调和细胞凋亡耐药、化疗耐药之间存在直接联系[13]；ZCCHC2通过抑制HectH9介导的K63多泛素化和c-Myc的激活来抑制视网膜母细胞瘤的发生[14]；GATA4通过诱导细胞衰老和间充质细胞向上皮细胞的转化，在肝细胞癌中起着重要的抑癌作用[15]；ZNF217与卵巢癌的临床分期、预后不良有关[16]。本研究探讨了锌指蛋白ZNF652在乳腺癌组织及细胞中的表达水平及其生物学功能：一方面，通过TCGA数据库以及RT-qPCR和Western blot，发现ZNF652在人乳腺癌组织和细胞中呈高表达，且高表达与乳腺癌远处转移、恶性程度密切相关；另一方面，通过CCK8、Transwell等一系列体外表型实验，证明ZNF652促进乳腺癌细胞的增殖、侵袭和迁移，进一步提示ZNF652可作为癌基因参与乳腺肿瘤发生发展过程。

ZNF652在乳腺癌细胞中的表达水平及促癌作用与Neilsen等的研究不一致，其可能原因是两项研究中的抗体选择不同且针对检测的ZNF652转录本不同造成的[17-18]。ZNF652的组织表达水平仍需在更多乳腺癌样本中进行验证，其生物学作用需在不同乳腺癌细胞中进行重复。ZNF652在多种肿瘤及癌旁组织中差异表达，且表达水平与预后相关[19-20]，但其在乳腺癌中的生物学功能和机制尚未明确。Raman等[21]证实ZNF652可通过C端富含脯氨酸的保守结构域与ETO家族蛋白CBFA2T3（core-binding factor subunit alpha 2 to translocation 3）相互作用形成转录复合物，由于HEB（HeLa E-box-binding protein）启动子包含ZNF652结合基序，该复合物可抑制HEB转录并调控其表达。CBFA2T3也可通过其NHR1结构域与HEB蛋白直接相互作用来抑制HEB表达[22-23]。CBFA2T3位于16q24.3区域，而16号染色体长臂处的杂合性缺失发生在至少一半的乳腺肿瘤中[24-25]，我们推测CBFA2T3在ZNF652结合HEB的过程中发挥转录共调控因子的作用：当CBFA2T3未发生LOH时，ZNF652与CBFA2T3相互作用抑制HEB转录；而当CBFA2T3发生LOH而不能与ZNF652结合时，ZNF652可能直接结合HEB，激活HEB发挥促癌作用。

本文通过免疫荧光实验证实ZNF652蛋白定位于细胞核，提示其可能在乳腺癌细胞中发挥转录调控作用。有研究者通过染色质免疫共沉淀结合测序技术分析乳腺癌细胞系中ZNF652启动子结合位点的全基因组图谱[26]，确定了ZNF652的体内识别基序（MAAGGGTTAA），并发现约2000个基因在转录起始位点（TSS）的50 kb范围内包含一个或多个该基序。基因路径分析表明，这些基因主要通过Wnt/β-catenin信号通路、ATM信号通路、细胞周期蛋白和细胞周期调控等参与乳腺癌发生发展。其中，细胞周期调控和Wnt/β-catenin通路是决定乳腺癌细胞增殖转移能力的重要通路[27-30]。因此，ZNF652促进乳腺癌细胞增殖转移的分子机制可以围绕其调控CDK或Cylin等下游基因表达及Wnt通路关键蛋白β-catenin的激活与质核转移而进行研究。

综上所述，本研究探讨了ZNF652在乳腺癌组织及细胞中的表达及生物学功能，为深入探索ZNF652的分子机制奠定了基础，进一步完善了乳腺癌细胞的转录调控机制网络。

Biography

雷婷，硕士，E-mail: 20181126814@stu.gzucm.edu.cn

Funding Statement

国家自然科学基金青年基金（81802634）；全军保健专项科研课题（18BJZ14）；全军卫勤保障能力创新与生成专项（20WQ029）

Supported by Natural Science Foundation for the Youth (NSFY) of China (81802634)

Contributor Information

雷 婷 (Ting LEI), Email: 20181126814@stu.gzucm.edu.cn.

李 林海 (Linhai LI), Email: mature303@126.com.

References

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