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Journal of Southern Medical University logoLink to Journal of Southern Medical University
. 2022 Sep 20;42(9):1410–1417. [Article in Chinese] doi: 10.12122/j.issn.1673-4254.2022.09.19

Nur77通过NF-κB/IL-6信号途径促进胃癌细胞的侵袭与迁移

Nur77 promotes invasion and migration of gastric cancer cells through the NF-κB/IL-6 pathway

Wei LI 1,*, Yongkang SHI 1, Yuhua GUO 1, Shengwang TIAN 1
PMCID: PMC9550556  PMID: 36210716

Abstract

Objective

To analyze the association of Nur77 with overall survival of gastric cancer patients and investigate the role of Nur77 in invasion and migration of gastric cancer cells.

Methods

Oncomine database was used to analyze the expression of Nur77 in gastric cancer and gastric mucosa tissues, and the distribution characteristics of Nur77 protein between gastric cancer and normal tissues were compared using Human Protein Atlas. GEPIA2 was used to analyze the relationship of Nur77 expression and the patients' survival. The expression of Nur77 in gastric cancer cell lines GES-1, AGS and MKN-45 were detected by Western blotting. The regulatory interactions between IL-6 and Nur77 were verified by transfecting the cells with specific Nur-77 siRNA and Nur-77-overexpressing plasmid. The changes in migration ability of the cells following Nur-77 knockdown were assessed with scratch assay. The effect of Nur-77 overexpression or IL-6 knockdown, or their combination, on migration and invasion of the gastric cancer cells were examined using Transwell assay. The effect of Nur77 expression level on NF-κB/IL-6 pathway activation was analyzed using Western blotting.

Results

Oncomine database showed that gastric cancer tissues expressed a significantly higher level of Nur77 mRNA than normal tissues (P < 0.05). Nur77 expression was detected mostly in the nucleus, and a high Nur77 expression was associated with a poor survival outcome of the patients (P < 0.05). In gastric cancer cells, the high expression of Nur77 participated in the regulation of IL-6. Nur77 silencing significantly lowered the migration ability of the cells (P < 0.05), and IL-6 silencing significantly attenuated the enhanced migration caused by Nur77 overexpression (P < 0.05). Nur77 participates in the activation of NF-κB/IL-6 signaling pathway by regulating the expression of p-p65, p65, p-Stat3 and Stat3.

Conclusion

A high Nur77 expression is strongly correlated with a poor prognosis of gastric cancer patients. Nur77 promotes the invasion and migration of gastric cancer cells possibly by regulating the NF-κB/IL-6 signaling pathway.

Keywords: gastric cancer, Nur77, nuclear factor-κB/interleukin-6, invasion, migration

胃癌是全球常见消化道恶性肿瘤类型之一[1-3]。由于幽门螺杆菌感染高发、饮食结构不良等因素，我国年新发胃癌人数约40万，给社会和家庭造成沉重负担[2, 4, 5]。近年来我国早期筛查和诊治手段有广泛应用和显著提高，早期胃癌患者5年生存率可达90%以上，但主要受限于早期症状不明显造成多数患者初诊即为中晚期，目前5年总体生存率仅为35.1%[2, 4, 6, 7]。因此，深入研究胃癌侵袭和转移的机制以寻找新的治疗靶标对提高患者生存率就显得尤为重要。由NR4A1基因编码的转录调控因子Nur77是核受体超家族的重要成员之一，在多种细胞生命活动和信号转导中起到重要作用，参与调节炎症、自噬、肿瘤发生和进展等过程中[8-10]。近年来已在乳腺癌、结肠癌、黑色素瘤等研究中分别发现Nur77充当关键核转录因子或者活化促癌信号通路广泛参与肿瘤转移发生，但其在胃癌中的作用研究尚未见报道，本研究中首次聚焦于Nur77参与的免疫调节对胃癌恶性进展的影响[11-13]。本研究将基于生物信息学数据分析Nur77在胃癌表达程度及其与患者预后之间联系，并利用靶向处理研究Nur77对胃癌细胞迁移、侵袭能力的影响，以及探讨胃癌细胞中Nur77发挥作用的相关分子机制。

1. 材料和方法

1.1. 材料

1.1.1. 细胞及培养

人胃癌细胞系AGS、MKN-45以及人胃粘膜上皮细胞GES-1（上海中乔新舟生物科技），所有细胞均附有短串联重复序列（STR）鉴定检验报告；AGS细胞采用含10%胎牛血清（FBS）F12K基础培养基，MKN-45细胞为含20%FBS的RPMI 1640培养基，GES-1细胞为10%FBS的高糖DMEM（D-葡萄糖浓度为4.5 g/L）培养，含终浓度为1%青霉素和链霉素，置恒温培养箱37 ℃、5% CO2条件下培养和传代。

1.1.2. 主要耗材和试剂

细胞培养基、青霉素和链霉素混合液（Gibco；FBS（Biological Industries）；RIPA裂解液、制胶液等免疫印迹实验相关试剂，4%多聚甲醛（北京索莱宝公司）；高敏型ECL化学发光检测曝光液蛋白Marker、柱式总核酸提取、逆转录以及实时定量聚合酶链式反应（qRT-PCR）试剂盒（南京诺唯赞公司）；结晶紫溶液、一抗稀释液（上海碧云天公司）；兔抗人Nur77、鼠抗人β-actin抗体（武汉三鹰公司）；兔抗人p65、p-p65、Stat3、p-Stat3抗体（CST）；兔抗人IL-6、HRP偶联的抗鼠和抗兔二抗（南京川博公司）；人IL-6 ELISA检测试剂盒（杭州联科公司）；基质胶Matrigel和Transwell小室（Corning）；LipofectamineTM2000转染试剂（Thermo Fisher）；siRNA-Nur77（5'-TCGAGGACTTCCAGGTGTA-3）、' siRNA-IL-6（5'-CCCAGGAGAAGAUUCCAAATT-3）' 以及阴性对照，IL-6引物由上海生工生物工程有限公司合成；Nur77过表达及对照空载质粒由上海吉凯基因化学技术有限公司构建。

1.2. 方法

1.2.1. 生物信息学验证

利用Oncomine数据库（https://www.oncomine.org/）获取胃癌组织与正常胃组织中Nur77（基因名NR4A1）的研究数据[14]，样本含胃黏膜组织29例，胃混合腺癌8列，分析阈值设置如下：t检验，P= 0.01，变化倍数为1.5倍，基因等级为10%，类型为mRNA；基因转录表达相关性分析基于Ooi Gastric数据[15]；在Human Protein Atlas网站（https://www.proteinatlas.org/）中，基于免疫组化结果从蛋白表达水平观察Nur77在胃癌组织与正常胃组织中的表达分布差异，所用抗体为HPA070142；利用GEPIA2在线分析工具（http://gepia2.cancer-pku.cn/）分析Nur77与胃癌患者总生存期（OS）的相关性：依据胃癌患者Nur77表达值的中位数，分为高表达和低表达2组，计算风险比和相应P值并制作生存曲线；Nur77与IL-6表达相关性设置相关系数为Pearson。

1.2.2. 蛋白质印迹检测Nur77处理前后胃癌细胞的NF-κB/IL-6信号通路

细胞用RIPA裂解后提取总蛋白，蛋白经SDS-PAGE电泳后转膜和0.5%脱脂奶粉封闭1 h后用一抗稀释液稀释相应抗体4 ℃孵育过夜于次日洗膜后孵育对应的二抗（稀释比为1∶5000）室温水平摇床继续孵育1 h后洗净后采用ECL化学发光自显，利用软件将目的条带灰度数值化，并与β-actin的灰度值作归一化处理后计算表达差异。

1.2.3. qRT-PCR检测靶向调控Nur77表达后IL-6表达

将对数生长期的MKN-45细胞接种于6孔板中，待细胞覆盖率达60%左右将细胞分为4组：阴性对照组（Negative control，转染无序序列）、干扰组（转染siRNA-Nur77）；空载体组（转染空载体）、过表达组（转染Overexpression Nur77）进行处理，待24 h后按说明书提取细胞总RNA，采用紫外分光光度计在260/280 nm处检测RNA纯度。按照逆转录以及PCR试剂盒的操作步骤进行反转录及qRT-PCR反应。qRT-PCR反应条件为：95 ℃预变性30 s，40次循环反应（95 ℃变性10 s，60 ℃退火30 s），融解曲线（95 ℃变性15 s，60 ℃退火60 s，95 ℃变性15 s）。以β-actin为内参，IL-6引物序列如下：上游序列，5'-GCCACTCACCTCTTCAGAACG-3'；下游序列，5'-TGCCTCTTTGCTGCTTTCA-3'，用2-∆∆Ct法计算IL-6表达变化，实验重复3次后计算平均值。

1.2.4. ELISA检测Nur77干扰处理前后IL-6分泌量

将胃癌细胞接种于6孔板（2.5×105/孔），细胞分组同1.2.3处理24 h后更换为无血清培养液继续处理24 h。收集细胞上清液，按ELISA试剂盒说明书提供的操作步骤检测IL-6的分泌量，每组实验均独立重复3次。

1.2.5. 划痕实验观察Nur77干扰后胃癌细胞的迁移能力

将胃癌细胞以2.5×105/孔接种于6孔板中，待细胞密度达60%时分为阴性对照组和siRNA-Nur77组进行处理，24 h后用10 μL移液枪头垂直于6孔板划痕，吸取PBS抵壁轻轻洗涤2次后加入无血清培养基，选取固定视野在倒置显微镜下对划痕进行拍照记为0 h划痕宽度，继续培养24 h后再次拍照。计算各组划痕愈合百分比=（0 h划痕宽度-24 h划痕宽度）/0 h划痕宽度×100%。

1.2.6. Transwell实验观察Nur77和IL-6对胃癌细胞的侵袭能力影响

胃癌细胞分为4组：空载体组和过表达Nur77组（转染质粒处理24 h后siRNA-Negative control继续处理24 h）；空载体转染后干扰IL-6处理组，过表达Nur77结合干扰IL-6处理组（转染质粒处理24 h后siRNA-IL-6继续处理24 h）。按照1∶8的比例用基质胶（4 ℃预融化）和RPMI 1640培养基混合后以50 μL体积每孔滴入Transwell小室中央，放置细胞培养箱中静置2 h后，下室加入完全培养基，上室加入上述处理各组5×104细胞重悬于无血清培养基中，培养48 h后取出侵袭小室，吸净上室培养基，PBS洗涤3次，4%多聚甲醛室温固定20 min，0.1%结晶紫染色30 min后清洗3次，棉签轻轻擦净上室，倒置显微镜下计数膜背面细胞数，200倍镜下随机计数5个视野取平均值，每组设重复孔3个。

1.2.7. 统计学分析

采用SPSS 22.0软件进行数据分析，计量资料以均数±标准差表示。如果数据符合正态分布并且通过方差齐性检验，两组以上均数比较采用单因素方差分析（one-way ANOVA），独立样本采用t检验；计数资料组间比较采用χ检验，P < 0.05为差异有统计学意义。

2. 结果

2.1. Oncomine数据库分析

与正常胃黏膜组织相比，胃癌肿瘤组织中Nur77的mRNA表达较高（P=0.001；图 1A）；免疫组化结果显示，Nur77在正常胃组织中部分细胞中有散在分布，整体呈现低或弱表达水平，胃癌组织中肿瘤细胞高表达Nur77，特异性较好，在细胞核内多可见Nur77阳性染色（图 1B）。GEPIA2数据库在线分析结果中可见Nur77高表达组患者的生存率远低于低表达组（P < 0.05，图 1C）。与上述结果较为一致的是，蛋白质印迹结果显示胃癌AGS和MKN-45细胞中Nur77蛋白表达水平均要明显高于胃黏膜上皮细胞GES-1（图 1D）。

图 1.

图 1

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胃癌中Nur77表达及其对患者预后影响

Expression of Nur77 in gastric cancer and its association with the patients survival outcomes. A: The expression of Nur77 mRNA in 8 mixed-type gastric adenocarcinoma (1) and 29 normal gastric mucosa (2) tissue specimens. B: Immunohistochemistry for Nur77 in gastric mucosa (a, b) and gastric cancer (c, d). C: Relationship between Nur77 expression and overall survival rate of gastric cancer patients. D: Expression levels of Nur77 in AGS, MKN-45 and GES-1 cells. *P < 0.05 vs gastric mucosa.

2.2. 胃癌组织及细胞中Nur77与IL-6表达之间调控关系

通过分析Oncomine数据发现在胃癌侵袭、转移中关键促进因子IL-6与Nur77表达存在紧密联系，其表达相关性R=0.490（图 2A）。使用GEPIA2数据库进一步验证发现，Nur77（NR4A1基因）与IL-6之间呈正相关关系，R=0.384，（P < 0.001，图 2B）。RT-PCR结果显示，siRNA-Nur77组MKN-45细胞中IL-6的mRNA表达水平较阴性对照组明显升高，而外源性上调Nur77后IL-6可见大幅上升（P < 0.001，图 2C）。蛋白质印迹法检测结果显示，siRNA-Nur77组胃癌细胞中IL-6蛋白的表达水平较阴性对照组明显下调，而siRNA-IL-6处理对胃癌细胞中Nur77表达无显著影响（图 2D）。

图 2.

图 2

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胃癌中Nur77与IL-6表达之间联系

Association between Nur77 and IL-6 expressions in gastric cancer. A: The association between Nur77 and IL-6 mRNA levels in different types of gastric cancer. 1. Diffuse Gastric Adenocarcinoma (47 samples), 2. Gastric Adenocarcinoma (78 samples), 3. Gastric Adenosquamous Carcinoma (1 sample), 4. Gastric Cancer (3 samples), 5. Gastric Intestinal Type Adenocarcinoma (54 samples), 6. Gastric Large Cell Neuroendocrine Carcinoma (1 sample), 7. Gastric Mixed Adenocarcinoma (15 samples), 8. Gastric Neuroendocrine Neoplasm, NOS (1 sample); B. Correlation analysis of Nur77 and IL-6 mRNA in gastric cancer; C. Changes of IL-6 mRNA expression in MKN-45 cells before or after transfection with siRNA-Nur77 or Nur77 plasmid (24 h); D. Protein expression changes brought on siRNA-Nur77 or siRNA-IL-6 treatment in gastric cancer cells, respectively (24 h); NC: Negative control; siNur77: siRNA-Nur77 treatment; si-IL-6: siRNA-IL-6 treatment; Vector: Empty vector; OE-Nur77: overexpreesion of Nur77 treatment; **P < 0.001.

2.3. Nur77促进胃癌细胞侵袭与转移依赖IL-6表达

与图 2C、2D结果相一致的是，ELISA结果显示转染上调Nur77的胃癌细胞培养基中IL-6的分泌水平较空载质粒组有明显升高，而干扰Nur77可显著抑制IL-6的表达（P < 0.001，图 3A）。细胞划痕愈合实验结果显示，siRNA-Nur77组胃癌AGS、MKN-45细胞的划痕在24 h时划痕较各自阴性对照组更明显（图 3B）；AGS、MKN-45细胞各阴性对照组和siRNA-Nur77组平均划痕愈合率相比为（65.54±4.63）% vs（. 26.03±5.80）%，（68.63±1.56）% vs（. 30.71±2.78）%，差异有统计学意义（P < 0.001）。Transwell侵袭实验显示AGS和MKN-45细胞过表达Nur77组平均穿膜细胞数分别为414±12个、439±10个，相较空载组284±15和267±9个细胞，差异有统计学意义（P < 0.001）。在空载组以及过表达Nur77胃癌细胞中siRNA-IL-6处理均可显著下调侵袭细胞数（P < 0.001；图 3C、D）。

图 3.

图 3

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Nur77及IL-6在胃癌迁移和侵袭中作用

Role of Nur77 and IL-6 in migration and invasion of gastric cancer. A: Effects of Nur77 silencing or overexpression on IL-6 secretion in gastric cancer cells detected by ELISA. B: Scratch assay for assessing the effects of Nur77 silencing on migration of gastric cancer cells. C, D: Transwell assay for assessing the effect of Nur77 overexpression, IL-6 silencing, or both on invasion of gastric cancer cells (Original magnification: × 200). NC: Negative control; si-Nur77: siRNA-Nur77 treatment; si-IL-6: siRNA-IL-6 treatment; Vector: Empty vector; OE-Nur77: overexpreesion of Nur77 treatment; **P < 0.001; ##P < 0.001.

图 4.

图 4

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Nur77表达对胃癌细胞中NF-κB/IL-6信号活化的影响

Effects of Nur77 expression on NF-κB/IL-6 signal activation in gastric cancer cells. Expression and quantitative analysis of p-p65, p65, p-Stat3 and Stat3 proteins in the AGC and MKN-45 cells in each group. NC: Negative control; si-Nur77: siRNA-Nur77 treatment; Vector: Empty vector; OE-Nur77: overexpreesion of Nur77 treatment; **P < 0.001 vs NC; ##P < 0.001 vs vector.

2.4. Nur77表达改变对胃癌细胞NF-κB/IL-6信号通路活化的影响

免疫印迹结果显示，在胃癌AGC细胞中下调Nur77表达可显著抑制p-p65、p65的表达（分别下降约69%和43%；P < 0.001），同时可见NF-κB/IL-6活化下游标记分子Stat3活化（磷酸化）的明显下降以及Stat3分子表达受到显著抑制（分别下降约72%和80%；P < 0.001）；而与空载体组细胞相比，过表达Nur77则明显上调了p-p65、p65、p-Stat3和Stat3蛋白的表达强度（分别上升约31%、122%、275%和57%；P < 0.001）。胃癌MKN-45细胞分别在干扰和过表达Nur77后表现出与AGC细胞较为一致的上述蛋白表达变化趋势。以上结果表明，胃癌细胞中Nur77可能参与NF-κB/IL-6信号通路活化调控。。

3. 讨论

最新基于生物信息学的研究认为，在多数肿瘤类型中Nur77处于广泛低表达状态，但是不同肿瘤甚至同种亚型间又存在较大的表达差异，这可能与其伴随肿瘤进展不同时期发挥的特定功能有关[16]。本研究首先整理Oncomine网站数据分析发现，胃癌组织中Nur77的mRNA表达强度要远高于正常胃黏膜上皮组织；免疫组化和免疫印迹结果也表明，其作为核受体蛋白主要集中于细胞核中；与正常细胞相比，胃癌细胞中高表达Nur77蛋白。进一步在GEPIA2数据库中根据Nur77表达强度分为高、低组后，我们发现高表达Nur77组胃癌患者预后要远差于低表达组。研究表明对于包括胃癌在内的肿瘤患者而言，远处转移和复发无疑是造成不良预后的主要原因。目前关于Nur77在肿瘤细胞中作用尚存在较大争议，例如在乳腺癌、肺癌和肝癌细胞中靶向干扰或者抑制Nur77表达和功能均可显著降低TGF-β表达，下调上皮间充质转化（EMT）和侵袭能力；结肠癌研究中指出在缺乏TGF-β存在的情况下Nur77可参与泛素化降解分化抑制因子1（ID1）蛋白从而发挥抑癌作用，但在TGF-β作用下Nur77参与上调ID1表达从而促进肿瘤转移和奥沙利铂抵抗形成；在缺氧情况下，Nur77直接结合到抑癌因子p63促进结肠癌EMT和转移发生；而肝癌中低表达的Nur77则是肿瘤细胞糖酵解、增殖、转移等一系列进程的关键分子基础[11, 12, 17, 18]。本研究中我们分别通过siRNA下调和质粒过载转染处理，划痕及Transwell实验证实胃癌细胞中高表达的Nur77参与迁移和侵袭，提示Nur77高表达患者预后较差可能与较强的胃癌细胞恶性生物学行为有着潜在联系。

研究表明，在消化道恶性肿瘤特别是胃癌发生过程中慢性炎症充当始动和促进因素，而NF-κB信号通路因广泛参与细胞增殖、分化、基因组稳定性以及免疫反应等一系列过程中被认为在其中发挥着核心调控作用[19-22]。目前研究指出，当胃部组织受到如幽门螺杆菌等微生物侵入以及后续组织损伤的刺激时，NF-κB信号会在在感染部位被高度激活以增强机体抗菌能力和维持组织功能稳态，但持续感染造成的慢性炎症则又可能导致组织进一步损伤，并通过例如形成细胞压力和积累DNA损伤等造成遗传稳定性和表观遗传学修饰状态的改变，最终形成致瘤微环境直至胃癌[21, 23-26]。在胃癌进展中NF-κB信号常处于异常和持续激活状态，伴随着促炎细胞因子表达增加，其中下游标志性靶分子IL-6可在促进肿瘤血管新生、恶性增殖、侵袭与转移过程中发挥重要作用，与患者不良预后密切相关，但是目前对于胃癌中NF-κB信号活化的具体分子基础尚需进一步探究[27-30]。本研究基于Oncomine和GEPIA2数据发现，不同类型胃癌组织中Nur77与IL-6的mRNA表达之间均存在显著正相关关系。由于在细胞中Nur77处于迅速降解并时刻受严格控制的状态，众多炎症或者免疫调节相关研究指出其与IL-6之间多为负向调控，如帕金森细胞模型中下调Nur77后可见p65、IL-6的表达上调；而在Nur77敲除小鼠体内包括IL-6在内的多种促炎性因子出现显著升高；免疫反应中Nur77的表达稳定会持续抑制IL-6的表达和分泌[3, 31, 32]。与上述研究结果不同的是，我们通过免疫印迹实验发现，在胃癌细胞中下调Nur77处理可以有效抑制IL-6的表达，但siRNA-IL-6处理对Nur77本身表达无显著影响。进一步通过ELISA和Transwell实验证实，胃癌中Nur77分子参与IL-6表达和分泌上调，而Nur77对胃癌细胞侵袭能力增强依赖于IL-6的合成。后续机制研究中也初步证实，Nur77过表达后p-p65和p65蛋白上调，同时IL-6作用后标志性活化下游p-Stat3和Stat3均明显增加，Nur77抑制的结果相反。这表明在胃癌迁移和侵袭过程中，Nur77可能通过活化NF-κB信号通路上调IL-6表达，从而增强胃癌细胞迁移和侵袭的能力。

综上所述，本研究首次在胃癌中发现高表达Nur77，并初步揭示了胃癌中Nur77表达与患者不良预后存在联系；Nur77可通过NF-κB/IL-6信号途径参与胃癌细胞迁移、侵袭进程。围绕Nur77对NF-κB信号通路活化调控的具体分子途径，有待本课题组后续进一步探究。本研究为阐述Nur77在胃癌恶性进展中的作用及作用机制提供了研究基础，并为胃癌的早期诊断、预后判断或治疗提供可能的新靶向位点。

Funding Statement

江苏省常州市金坛第一人民医院院级课题项目（YJKT2018002）

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