中国医科大学学报  2024, Vol. 53 Issue (5): 414-420

文章信息

韩超, 胡晓云, 刘畅, 于洋洋
HAN Chao, HU Xiaoyun, LIU Chang, YU Yangyang
延胡索通过靶向CXCL17激活AMPK信号通路下调PD-L1抑制EB病毒感染诱导的胃癌免疫逃逸
Rhizoma corydalis downregulates PD-L1 by targeting CXCL17 to activate AMPK signaling pathway and inhibits EBV-induced immune escape in gastric cancer
中国医科大学学报, 2024, 53(5): 414-420
Journal of China Medical University, 2024, 53(5): 414-420

文章历史

收稿日期:2023-10-08
网络出版时间:2024-05-14 14:55:20
延胡索通过靶向CXCL17激活AMPK信号通路下调PD-L1抑制EB病毒感染诱导的胃癌免疫逃逸
韩超1 , 胡晓云2 , 刘畅3 , 于洋洋3     
1. 中国医科大学附属第一医院胃肠肿瘤外科, 沈阳 110001;
2. 中国医科大学药学院药理学教研室, 辽宁省分子靶向抗肿瘤药物药理学研究与评价重点实验室, 沈阳 110122;
3. 中国医科大学附属第一医院放射治疗科, 沈阳 110001
摘要目的 探讨延胡索对EB病毒(EBV)阳性胃癌细胞免疫逃逸的作用及其靶向CXCL17影响EBV阳性胃癌细胞免疫逃逸的机制。方法 GEO2R在线分析软件筛选EBV阳性胃癌组织中的差异表达基因。采用EBV阴性胃癌AGS细胞和EBV阳性胃癌SUN-719细胞进行实验。实时qPCR和Western blotting检测EBV阴性和EBV阳性胃癌细胞中CXCL17表达。将CXCL17 siRNA转染EBV阳性胃癌细胞,Western blotting检测细胞PD-L1表达;将EBV阳性胃癌细胞与T细胞共培养,CCK-8检测细胞活力,流式细胞术检测细胞凋亡率。用延胡索提取物(2、4、8 μg/mL)处理EBV阳性胃癌细胞,Western blotting检测细胞CXCL17和PD-L1表达;将EBV阳性胃癌细胞与T细胞共培养,CCK-8检测细胞活力,流式细胞术检测细胞凋亡率。将CXCL17过表达质粒转染延胡索提取物(8 μg/mL)处理的EBV阳性胃癌细胞,Western blotting检测细胞PD-L1和p-AMPK表达;将EBV阳性胃癌细胞与T细胞共培养,CCK-8检测细胞活力,流式细胞术检测细胞凋亡率。结果 CXCL17在EBV阳性胃癌组织和细胞中表达上调(P < 0.05)。沉默CXCL17降低EBV阳性胃癌细胞PD-L1表达,抑制与T细胞共培养的EBV阳性胃癌细胞增殖并促进细胞凋亡(P < 0.05)。延胡索处理降低EBV阳性胃癌细胞CXCL17和PD-L1表达,抑制与T细胞共培养的EBV阳性胃癌细胞增殖并促进细胞凋亡(P < 0.05);过表达CXCL17逆转了延胡索处理对EBV阳性胃癌细胞PD-L1表达和细胞增殖的抑制作用及细胞凋亡的促进作用(P < 0.05);过表达CXCL17还降低了延胡索处理的EBV阳性胃癌细胞p-AMPK表达(P < 0.05)。结论 CXCL17在EBV阳性胃癌细胞中表达上调,延胡索通过下调EBV阳性胃癌细胞CXCL17表达抑制胃癌细胞免疫逃逸,其机制可能与激活AMPK信号通路有关。
关键词延胡索    胃癌    EB病毒    免疫逃逸    CXCL17    AMPK信号通路    
Rhizoma corydalis downregulates PD-L1 by targeting CXCL17 to activate AMPK signaling pathway and inhibits EBV-induced immune escape in gastric cancer
1. Department of Surgical Oncology, The First Hospital of China Medical University, Shenyang 110001, China;
2. Pharmacology Teaching and Research Department, School of Pharmacy, China Medical University, Key Laboratory of Pharmacological Research and Evaluation of Molecular Targeted Antitumor Drugs in Liaoning Province, Shenyang 110122, China;
3. Department of Radiotherapy, The First Hospital of China Medical University, Shenyang 110001, China
Abstract: Objective To explore the effect of Rhizoma corydalis on the immune escape of Epstein-Barr virus (EBV) positive gastric cancer cells and its mechanism of targeting CXCL17 to affect immune escape of EBV-positive gastric cancer cells. Methods GEO2R online analysis software was used to screen differentially expressed genes in EBV-positive gastric cancer tissues. EBV-negative AGS gastric cancer cells and EBV-positive SUN-719 gastric cancer cells were used for the experiments. RT-qPCR and western blotting were used to detect the expression of CXCL17 in EBV-negative and EBV-positive gastric cancer cells. Transfection of CXCL17 siRNA into EBV-positive gastric cancer cells, detection of PD-L1 expression through western blotting, coculture of EBV-positive gastric cancer cells with T cells, detection of cell viability using the CCK-8 assay, and detection of cell apoptosis rate through flow cytometry were conducted. EBV-positive gastric cancer cells were treated with different concentrations of a Rhizoma corydalis extract (2, 4, and 8 μg/mL). The expression of CXCL17 and PD-L1 was detected through western blotting, and EBV-positive gastric cancer cells were cocultured with T cells. Cell viability was determined using CCK-8, and cell apoptosis rate through flow cytometry. The CXCL17 overexpression plasmid was transfected into EBV-positive gastric cancer cells treated with Rhizoma corydalis extract (8 μg/mL). The expression of PD-L1 and p-AMPK was detected through western blotting, and EBV-positive gastric cancer cells were cocultured with T cells. Cell viability was determined using CCK-8, and cell apoptosis rate with flow cytometry. Results CXCL17 expression was upregulated in EBV-positive gastric cancer tissues and cells (P < 0.05). Silencing of CXCL17 reduced the expression of PD-L1 in EBV-positive gastric cancer cells, inhibited the proliferation of EBV-positive gastric cancer cells cocultured with T cells, and promoted cell apoptosis (P < 0.05). Rhizoma corydalis treatment reduced the expression of CXCL17 and PD-L1 in EBV-positive gastric cancer cells, inhibited the proliferation of EBV-positive gastric cancer cells cocultured with T cells, and promoted apoptosis (P < 0.05). Overexpression of CXCL17 reversed the inhibitory effect of the Rhizoma corydalis treatment on PD-L1 expression and cell proliferation in EBV-positive gastric cancer cells, as well as the promoting effect of cell apoptosis (P < 0.05). Overexpression of CXCL17 also reduced the expression of p-AMPK in EBV-positive gastric cancer cells treated with Rhizoma corydalis (P < 0.05). Conclusion CXCL17 expression is upregulated in EBV-positive gastric cancer cells, and Rhizoma corydalis inhibits immune escape in gastric cancer cells by downregulating CXCL17 expression in EBV-positive gastric cancer cells, which may be related to the activation of the AMPK signaling pathway.

胃癌在全球范围内常见癌症排名中居第5位,在癌症死亡原因排名中居第4位[1]。胃癌中EB病毒(epstein-barr virus,EBV)感染所致的EBV阳性胃癌占10%[2]。另外,EBV阳性胃癌是EBV相关死亡的最常见原因之一,与EBV阴性胃癌比较具有男性占优势、显著炎症浸润和相对较好预后的特征[3]。研究[4]表明,EBV感染通过调节程序性死亡受体配体1(programmed death-ligand 1,PD-L1)表达促进肿瘤免疫逃逸。PD-L1能够在肿瘤细胞表面形成屏障,建立与T细胞表面受体程序性死亡受体(programmed death-1,PD-1)的相互作用,从而抑制T细胞的细胞毒性作用[5]。因此,抗PD-1/PD-L1疗法可以通过促进免疫细胞的再活化来缓解EBV诱导的免疫抑制,改善晚期肿瘤患者的治疗反应。然而,临床研究[6]表明,目前抗PD-1/PD-L1疗法对晚期胃癌的疗效仍不理想。筛选参与EBV诱导的免疫抑制靶点及靶向该靶点的治疗药物可能为EBV阳性胃癌免疫逃逸的治疗提供新思路。趋化因子是一组小的细胞因子,在募集和激活免疫效应物中发挥作用,且参与调节炎症或免疫相关疾病和癌症[7]。CXCL17是最后鉴定的趋化因子,是否属于趋化因子家族还存在争议[8]。CXCL17在乳腺癌、肝细胞癌和结肠癌中高表达,导致患者预后不良[9-11]。研究[12]表明,CXCL17在EBV阳性胃癌中表达上调,有望作为EBV阳性胃癌的预后指标。靶向CXCL17的药物可能成为EBV阳性胃癌的有效治疗药物。中草药含有丰富的抗癌化合物,可作为理想的抗癌药物[13]。延胡索是悠久历史的中草药,具有活血、补气和止痛功能[14]。延胡索在胶质瘤、结肠癌和乳腺癌等肿瘤中发挥抗癌活性[15]。HERB在线数据库检索发现延胡索是靶向CXCL17的草药。本研究探讨延胡索靶向CXCL17对EBV阳性胃癌细胞免疫逃逸的作用及可能机制,旨在为改善EBV诱导的胃癌免疫逃逸的药物开发提供理论依据。

1 材料与方法 1.1 主要试剂和仪器

AGS细胞、SUN-719细胞和细胞培养液均购自武汉普诺赛生命科技有限公司,延胡索提取物购自南京道斯夫生物科技有限公司,总RNA提取试剂、逆转录试剂盒和qPCR试剂盒购自南京诺唯赞生物科技股份有限公司,RIPA裂解液、BCA蛋白定量试剂盒、ECL化学发光试剂盒、CCK-8试剂盒和Annexin V-FITC细胞凋亡检测试剂盒购自上海碧云天生物科技公司,CXCL17、PD-L1、p-AMPK、AMPK和GAPDH一抗购自美国Abcam公司,二抗购自武汉三鹰公司,普通PCR仪购自美国ABI公司,RT-qPCR仪和流式细胞仪购自美国Thermo公司,酶标仪购自美国BioTek公司,凝胶扫描成像系统购自美国Bio-Rad公司。

1.2 方法

1.2.1 生物信息学分析

通过GEO2R (https://www.ncbi.nlm.nih.gov/geo/geo2r/)在线分析软件(设置参数log2FC > 4,调整P < 0.01)分析GSE51575数据集中EBV阳性胃癌组织中的差异表达基因。

1.2.2 细胞培养

EBV阴性胃癌AGS细胞用含10%胎牛血清和1%青链霉素的Ham’s F-12培养基培养于37 ℃含5%CO2的恒温细胞培养箱中。EBV阳性胃癌SUN-719细胞用含10%胎牛血清和1%青链霉素的RPMI-1640培养基培养于37 ℃含5%CO2的恒温细胞培养箱中。

1.2.3 实时qPCR检测细胞mRNA表达

Trizol法提取细胞总RNA,按照逆转录试剂盒说明书将总RNA反转录为cDNA,按照qPCR试剂盒说明书进行实时qPCR反应,反应条件为:预变性95 ℃ 45 s,变性95 ℃ 30 s,退火60 ℃ 45 s,延伸72 ℃ 30 s,共40个循环。以GAPDH为内参,根据2-ΔΔCt法计算CXCL17 mRNA的相对表达量。

1.2.4 Western blotting检测蛋白表达

用RIPA裂解液提取细胞总蛋白,BCA法检测蛋白浓度,SDS-PAGE电泳分离蛋白,将蛋白转移至PVDF膜上,5%脱脂牛奶室温封闭1 h,CXCL17、PD-L1、p-AMPK、AMPK和GAPDH一抗4 ℃孵育过夜,PBST洗膜3次,二抗室温孵育1 h,PBST洗膜3次,ECL法发光。Image J软件计算电泳条带灰度值,以GAPDH为内参,目的蛋白的相对表达量采用目的蛋白电泳条带灰度值与内参蛋白电泳条带灰度值比值表示。

1.2.5 EBV阳性胃癌SUN-719细胞分组及处理

SUN-719细胞分为si-NC组、si-CXCL17组、对照组、延胡索低剂量组、延胡索中剂量组、延胡索高剂量组、延胡索高剂量+空载体组和延胡索高剂量+过表达CXCL17组。si-NC组和对照组细胞不做处理。si-NC组和si-CXCL17组细胞分别按照Lipofectamine3000转染试剂说明书转染si-NC和si-CXCL17 siRNA。延胡索低剂量组、延胡索中剂量组和延胡索高剂量组分别用2、4、8 μg/mL延胡索提取物处理。延胡索高剂量+空载体组和延胡索高剂量+过表达CXCL17组在给予8 μg/mL延胡索提取物的基础上分别按照Lipofectamine3000转染试剂说明书转染空载体和CXCL17过表达质粒。转染48 h后收集细胞用于后续实验。

1.2.6 CCK-8检测细胞活力

将处理后细胞均匀铺板于96孔板中,每组设置3个复孔,共铺板4块相同的96孔板。分别于0(培养过夜后即刻)、24、48和72 h取出一块96孔板,弃培养基,每孔加入10 μL CCK-8试剂和100 μL新鲜培养基,37 ℃孵育1.5 h,酶标仪检测450 nm处吸光度值。

1.2.7 流式细胞术检测细胞凋亡

收集处理后细胞,PBS洗涤后计数,取1×106个细胞,Bing buffer重悬细胞,加入5 μL Annexin V,室温避光孵育10 min,加入5 μL PI,室温避光孵育5 min。加入PBS混匀后采用流式细胞仪检测。

1.3 统计学分析

利用SPSS 22.0软件进行统计分析,计量数据采用x±s表示。两组间比较采用独立样本t检验。多组间比较采用单因素方差分析,各组间两两比较采用Tukey事后检验,P < 0.05为差异有统计学意义。

2 结果 2.1 EBV感染对胃癌细胞CXCL17表达的影响

GEO2R软件分析结果表明,CXCL17在EBV阳性的胃癌组织中表达上调(表 1)。实时qPCR检测结果表明,与EBV阴性胃癌AGS细胞比较,EBV阳性胃癌SUN-719细胞CXCL17 mRNA表达显著升高(P < 0.05,图 1A)。Western blotting检测结果表明,与EBV阴性胃癌AGS细胞比较,EBV阳性胃癌SUN-719细胞CXCL17蛋白表达显著升高(P < 0.05,图 1B)。

表 1 GEO2R在线分析软件筛选的EBV阳性的胃癌组织中表达上调的基因 Tab.1 Upregulated genes in EBV-positive gastric cancer tissues screened with the GEO2R online analysis software
Gene log2FC Adjusted P
CXCL17 6.02 0.000 2
IGJ 4.13 0.000 7
MIA 4.63 0.002 5
PIGR 5.09 0.003 5
CTSE 4.30 0.004 8
DMBT1 5.69 0.007 0
CLDN18 5.02 0.008 0
OLFM4 5.21 0.009 1

A, CXCL17 mRNA expression; B, CXCL17 protein expression. *P < 0.05 vs. AGS group. 图 1 EBV阴性胃癌AGS细胞和EBV阳性胃癌SUN-719细胞CXCL17表达 Fig.1 Expression of CXCL17 in EBV-negative AGS gastric cancer cells and EBV-positive SUN-919 gastric cancer cells

2.2 沉默CXCL17对EBV阳性胃癌细胞免疫逃逸的影响

Western blotting检测结果表明,与si-NC组比较,si-CXCL17组SUN-719细胞PD-L1蛋白表达显著降低(P < 0.05,图 2A)。CCK-8检测结果表明,与si-NC组比较,si-CXCL17组与T细胞共培养的SUN-719细胞活力显著降低(P < 0.05,图 2B)。流式细胞术检测结果表明,与si-NC组比较,si-CXCL17组与T细胞共培养的SUN-719细胞凋亡率显著升高(P < 0.05,图 2C)。

A, Western blotting; B, CCK-8;C, flow cytometry. * P < 0.05 vs. si-NC group. 图 2 沉默CXCL17对SUN-719细胞免疫逃逸的影响 Fig.2 Effect of silencing CXCL17 on immune escape in SUN-719 cells

2.3 延胡索对EBV阳性胃癌细胞CXCL17表达的影响

Western blotting检测结果表明,与对照组比较,延胡索低剂量组、延胡索中剂量组和延胡索高剂量组SUN-719细胞CXCL17蛋白表达显著降低(均P < 0.05,图 3)。

*P < 0.05 vs. control group.RC-L, low-dose rhizoma corydalis group; RC-M, middle-dose rhizoma corydalis group; RC-H, high-dose rhizoma corydalis group. 图 3 延胡索对SUN-719细胞CXCL17表达的影响 Fig.3 Effect of Rhizoma corydalis on CXCL17 expression in SUN-719 cells

2.4 延胡索对EBV阳性胃癌细胞免疫逃逸的影响

Western blotting检测结果表明,与对照组比较,延胡索低剂量组、延胡索中剂量组和延胡索高剂量组SUN-719细胞PD-L1蛋白表达显著降低(均P < 0.05,图 4A)。CCK-8检测结果表明,与对照组比较,延胡索低剂量组、延胡索中剂量组和延胡索高剂量组与T细胞共培养的SUN-719细胞活力显著降低(均P < 0.05,图 4B)。流式细胞术检测结果表明,与对照组比较,延胡索低剂量组、延胡索中剂量组和延胡索高剂量组与T细胞共培养的SUN-719细胞凋亡率显著升高(均P < 0.05,图 4C)。

A, Western blotting; B, CCK-8;C, flow cytometry. * P < 0.05 vs. control group. RC-L, low-dose Rhizoma corydalis group; RC-M, middle-dose Rhizoma corydalis group; RC-H, high-dose rhizoma corydalis group. 图 4 延胡索对SUN-719细胞免疫逃逸的影响 Fig.4 Effect of Rhizoma corydalis on immune escape of SUN-719 cells

2.5 过表达CXCL17逆转了延胡索对EBV阳性胃癌细胞免疫逃逸的抑制作用

Western blotting检测结果表明,与对照组比较,延胡索高剂量组和延胡索高剂量+空载体组SUN-719细胞PD-L1蛋白表达显著降低;与延胡索高剂量组和延胡索高剂量+空载体组比较,延胡索高剂量+过表达CXCL17组SUN-719细胞PD-L1蛋白表达显著升高(均P < 0.05,图 5A)。CCK-8检测结果表明,与对照组比较,延胡索高剂量组和延胡索高剂量+空载体组与T细胞共培养的SUN-719细胞活力显著降低;与延胡索高剂量组和延胡索高剂量+空载体组比较,延胡索高剂量+过表达CXCL17组与T细胞共培养的SUN-719细胞活力显著升高(均P < 0.05,图 5B)。流式细胞术检测结果表明,与对照组比较,延胡索高剂量组和延胡索高剂量+空载体组与T细胞共培养的SUN-719细胞凋亡率显著升高;与延胡索高剂量组和延胡索高剂量+空载体组比较,延胡索高剂量+过表达CXCL17组与T细胞共培养的SUN-719细胞凋亡率显著降低(均P < 0.05,图 5C)。

A, Western blotting; B, CCK-8;C, flow cytometry. * P < 0.05 vs. control group; # P < 0.05 vs. RC-H group; P P < 0.05 vs. RC-H+Vector group. RC-H, high-dose Rhizoma corydalis; ov-CXCL17, overexpression CXCL17. 图 5 过表达CXCL17逆转了延胡索对SUN-719细胞免疫逃逸的抑制作用 Fig.5 Overexpression of CXCL17 reverses the inhibitory effect of Rhizoma corydalis on SUN-719 cell immune escape

2.6 过表达CXCL17对延胡索处理的EBV阳性胃癌细胞AMPK信号通路的影响

Western blotting检测结果表明,与对照组比较,延胡索高剂量组和延胡索高剂量+空载体组SUN-719细胞p-AMPK蛋白表达显著升高;与延胡索高剂量组和延胡索高剂量+空载体组比较,延胡索高剂量+过表达CXCL17组SUN-719细胞p-AMPK蛋白表达显著降低(均P < 0.05,图 6)。

* P < 0.05 vs. control group; # P < 0.05 vs. RC-H group; P < 0.05 vs. RC-H+Vector group. RC-H, high-dose Rhizoma corydalis; ov-CXCL17, overexpression CXCL17. 图 6 过表达CXCL17对延胡索处理的SUN-719细胞AMPK信号通路的影响 Fig.6 Effect of overexpression of CXCL17 on the AMPK signaling pathway in SUN-719 cells treated with Rhizoma corydalis

3 讨论

EBV是第一种被证实的与人类肿瘤相关的病毒[16]。EBV感染通过诱导PD-L1表达上调影响T细胞免疫识别和清除,最终促进肿瘤免疫逃逸[17-18]。本研究生物信息学分析结果表明,CXCL17在EBV阳性的胃癌组织中表达上调。实时qPCR和Western blotting检测结果表明,CXCL17在EBV阳性胃癌SUN-719细胞中表达水平较EBV阴性胃癌AGS细胞上调。体外实验检测结果表明,沉默CXCL17的EBV阳性胃癌SUN-719细胞PD-L1表达下调,且沉默CXCL17降低了与T细胞共培养的SUN-719细胞活力,增加了SUN-719细胞凋亡率。这些结果表明沉默CXCL17逆转了EBV诱导的胃癌细胞免疫逃逸,提示CXCL17可能是EBV诱导的胃癌免疫逃逸的靶点。

Western blotting检测结果表明,延胡索处理降低SUN-719细胞CXCL17蛋白表达。延胡索处理的EBV阳性胃癌SUN-719细胞PD-L1表达下调,且延胡索处理降低了与T细胞共培养的SUN-719细胞活力,增加SUN-719细胞凋亡率。此外,研究结果还表明,过表达CXCL17上调延胡索处理的SUN-719细胞PD-L1表达,且过表达CXCL17逆转了延胡索处理对与T细胞共培养的SUN-719细胞活力的抑制作用和细胞凋亡的促进作用。这些结果表明延胡索通过靶向抑制CXCL17来抑制EBV诱导的胃癌细胞免疫逃逸。

AMPK是真核生物中主要的能量传感器和能量稳态的调节者,可被包括ATP消耗增加或ATP产生减少在内的能量应激激活。AMPK激活后使下游靶标磷酸化,直接或间接调节限速代谢酶、转录和翻译因子、增殖和生长途径以及表观遗传调节因子的活性[19]。激活AMPK信号通路能够抑制胃癌细胞增殖、迁移和侵袭[20]。研究[21]表明,AMPK激活可诱导PD-L1磷酸化,导致PD-L1的异常糖基化和蛋白酶体降解。还有研究[11]发现CXCL17抑制AMPK信号通路激活。因此,CXCL17诱导的PD-L1表达可能与抑制AMPK激活有关。Western blotting检测结果表明,延胡索处理增加SUN-719细胞AMPK磷酸化,过表达CXCL17逆转了延胡索处理对SUN-719细胞AMPK的激活作用。这些结果提示延胡索可能通过抑制CXCL17激活AMPK信号通路下调PD-L1表达,从而抑制EBV诱导的胃癌细胞免疫逃逸。

综上所述,CXCL17在EBV阳性胃癌细胞中表达上调,延胡索通过下调EBV阳性胃癌细胞CXCL17表达抑制胃癌细胞免疫逃逸,其机制可能与激活AMPK信号通路有关。

参考文献
[1]
SUNG H, FERLAY J, SIEGEL RL, et al. Global cancer statistics 2020:globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. DOI:10.3322/caac.21660
[2]
NAKANO H, SAITO M, NAKAJIMA S, et al. PD-L1 overexpression in EBV-positive gastric cancer is caused by unique genomic or epigenomic mechanisms[J]. Sci Rep, 2021, 11(1): 1982. DOI:10.1038/s41598-021-81667-w
[3]
GONG LP, CHEN JN, DONG M, et al. Epstein-Barr virus-derived circular RNA LMP2A induces stemness in EBV-associated gastric cancer[J]. EMBO Rep, 2020, 21(10): e49689. DOI:10.15252/embr.201949689
[4]
ANASTASIADOU E, STROOPINSKY D, ALIMPERTI S, et al. Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas[J]. Leukemia, 2019, 33(1): 132-147. DOI:10.1038/s41375-018-0178-x
[5]
JIANG XJ, WANG J, DENG XY, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape[J]. Mol Cancer, 2019, 18(1): 10. DOI:10.1186/s12943-018-0928-4
[6]
FUCHS CS, DOI T, JANG RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial[J]. JAMA Oncol, 2018, 4(5): e180013. DOI:10.1001/jamaoncol.2018.0013
[7]
MOLLICA POETA V, MASSARA M, CAPUCETTI A, et al. Chemo-kines and chemokine receptors: new targets for cancer immunotherapy[J]. Front Immunol, 2019, 10: 379. DOI:10.3389/fimmu.2019.00379
[8]
DENISOV SS. CXCL17:the black sheep in the chemokine flock[J]. Front Immunol, 2021, 12: 712897. DOI:10.3389/fimmu.2021.712897
[9]
GUO YJ, ZHOU YJ, YANG XL, et al. The role and clinical significance of the CXCL17-CXCR8 (GPR35) axis in breast cancer[J]. Biochem Biophys Res Commun, 2017, 493(3): 1159-1167. DOI:10.1016/j.bbrc.2017.09.113
[10]
YAO HY, LV YF, BAI XF, et al. Prognostic value of CXCL17 and CXCR8 expression in patients with colon cancer[J]. Oncol Lett, 2020, 20(3): 2711-2720. DOI:10.3892/ol.2020.11819
[11]
WANG LP, LI HT, ZHEN ZJ, et al. CXCL17 promotes cell metastasis and inhibits autophagy via the LKB1-AMPK pathway in hepatocellular carcinoma[J]. Gene, 2019, 690: 129-136. DOI:10.1016/j.gene.2018.12.043
[12]
MU L, HU S, LI GP, et al. Characterization of the prognostic values of CXCL family in epstein-barr virus associated gastric cancer[J]. Oxid Med Cell Longev, 2022, 2022: 2218140. DOI:10.1155/2022/2218140
[13]
LUO H, VONG CT, CHEN HB, et al. Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine[J]. Chin Med, 2019, 14: 48. DOI:10.1186/s13020-019-0270-9
[14]
WU LY, YANG Y, MAO ZJ, et al. Processing and compatibility of Corydalis yanhusuo: phytochemistry, pharmacology, pharmacokinetics, and safety[J]. Evid Based Complementary Altern Med, 2021, 2021: 1271953. DOI:10.1155/2021/1271953
[15]
TIAN B, TIAN M, HUANG SM. Advances in phytochemical and modern pharmacological research of Rhizoma Corydalis[J]. Pharm Biol, 2020, 58(1): 265-275. DOI:10.1080/13880209.2020.1741651
[16]
FAN CM, TANG YY, WANG JP, et al. The emerging role of Epstein-Barr virus encoded microRNAs in nasopharyngeal carcinoma[J]. J Cancer, 2018, 9(16): 2852-2864. DOI:10.7150/jca.25460
[17]
THOMPSON ED, ZAHURAK M, MURPHY A, et al. Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma[J]. Gut, 2017, 66(5): 794-801. DOI:10.1136/gutjnl-2015-310839
[18]
CARBONE A, GLOGHINI A, CARLO-STELLA C. Are EBV-related and EBV-unrelated Hodgkin lymphomas different with regard to susceptibility to checkpoint blockade?[J]. Blood, 2018, 132(1): 17-22. DOI:10.1182/blood-2018-02-833806
[19]
YAN Y, ZHOU XE, XU HE, et al. Structure and physiological regulation of AMPK[J]. Int J Mol Sci, 2018, 19(11): 3534. DOI:10.3390/ijms19113534
[20]
HU XL, ZHU YJ, HU CH, et al. Ghrelin affects gastric cancer progression by activating AMPK signaling pathway[J]. Biochem Genet, 2021, 59(3): 652-667. DOI:10.1007/s10528-020-10022-x
[21]
ZHANG RN, YANG YJ, DONG WJ, et al. D-mannose facilitates immunotherapy and radiotherapy of triple-negative breast cancer via degradation of PD-L1[J]. Proc Natl Acad Sci USA, 2022, 119(8): e2114851119. DOI:10.1073/pnas.2114851119