Value of immune－inflammatory factors in predicting intrahepatic cholangiocarcinoma

Guiling LIU; Jie DOU; Huijuan MENG; Bingqi MA

doi:10.3969/j.issn.1001-5256.2023.09.030

Volume 39 Issue 9

Sep. 2023

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Article Navigation > Journal of Clinical Hepatology > 2023 > 39(9): 2231-2236

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Value of immune－inflammatory factors in predicting intrahepatic cholangiocarcinoma

DOI: 10.3969/j.issn.1001-5256.2023.09.030

1.
Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Weifang Medical University，Weifang，Shandong 261031，China
2.
Department of Dermatology，Affiliated Hospital of Weifang Medical University，Weifang，Shandong 261031，China

Research funding:

Weifang Science and Technology Development Program （Medical Science） (2022YX026);

Scientific Research and Innovation Project of Affiliated Hospital of Weifang Medical University (2022BSQD07);

Medical and Health Science and Technology Development Plan of Shandong Province (202004011537)

More Information

Corresponding author: MA Bingqi， mabingqi@126.com （ORCID： 0000－0001－9314－6559）
Received Date: 2023-03-28
Accepted Date: 2023-04-30
Published Date: 2023-09-19

Abstract

Abstract

Intrahepatic cholangiocarcinoma （ICC） is one of the most common primary liver malignancies， with an increasing incidence rate in the past two decades. Surgical resection is the main treatment method for ICC， but more than half of the patients have lost the opportunity for surgery at the time of initial diagnosis， with the only choice of locoregional or systemic treatment. At present， there is still a lack of satisfactory treatment outcomes for ICC. In ICC and other solid tumors， it has been found that some immune－inflammatory factors （IIFs） can effectively reflect the inflammatory state within the tumor， and these IIFs are significantly associated with tumor progression and prognostic markers. These IIFs are all calculated based on hematological parameters such as routine blood test results， C－reactive protein， albumin， and tumor markers， and they can be classified into three categories， i.e.， direct inflammatory factors， tumor markers， and combined inflammatory factors. Comparative analysis has shown that combined inflammatory factors has a better value than direct inflammatory factors and tumor markers in predicting the prognosis of ICC patients. It is recommended to use prognostic inflammatory and tumor score， systemic inflammation score， and systemic inflammation response index as the scoring systems for evaluating the survival and prognosis of ICC patients.
- Cholangiocarcinoma,
- Biomarkers， Tumor,
- Prognosis

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慢性乙型肝炎(CHB)目前仍然是全球性公共卫生问题^[1-2]。中草药及其活性成分在治疗CHB方面发挥着重要作用，具有广阔的应用前景^[3]。灵猫方是上海中医药大学附属曙光医院肝病科治疗CHB的有效验方。前期研究^[4-8]发现，灵猫方可有效改善CHB患者的临床证候，提高患者的生化和病毒学应答，增强免疫应答。

网络药理学通过预测中草药活性成分的作用靶点，揭示中草药多成分、多靶点的作用关系；通过构建“成分-靶点-通路”网络，初步分析中草药成分、作用靶点及相关通路^[9]。为此本研究联合网络药理学与动物实验，探寻灵猫方治疗CHB的物质基础及作用机制，为灵猫方治疗CHB的开发和应用奠定基础。

1. 资料与方法

1.1 网络药理学分析

1.1.1 灵猫方活性成分及靶点筛选

中药系统药理学数据库和分析平台(traditional Chinese medicine systems pharmacology database and analysis platform，TCMSP)获取仙灵脾、女贞子、黄芪、猫爪草、胡黄连、青皮化学组成成分^[10]，根据口服利用度(oral bioavailability，OB)≥30%且类药性(drug-likeness，DL)≥0.18两个属性进行初步筛选；Genecards进行二次筛选并获取作用靶点；Uniprot蛋白质数据库进行靶点验证。

1.1.2 灵猫方-CHB靶点交集分析

Genecards数据库获取CHB相关靶点信息；Uniprot蛋白质数据库进行靶点验证；Bioinformatics将灵猫方与CHB相关靶点取交集并绘制韦恩图。

1.1.3 灵猫方-CHB靶点功能与通路富集分析

Bioinformatics数据库获取生物过程、细胞成分和分子功能3个参数进行基因本体(gene onotology, GO)富集分析；DAVID 6.8进行KEGG通路富集分析。

1.1.4 灵猫方-CHB免疫过程分析

CytoScape 3.8.0对交集靶点进行免疫过程分析，设定生物种类为“Homo sapiens”，ClueGO设定为“Immue System Process”，可信度设定为“P≤0.01”得到ClueGO免疫网络。

1.2 动物实验

1.2.1 动物

C57BL/6N雄性小鼠，3周龄，30只，SPF级，购于北京维通利华实验动物技术有限公司上海分公司。实验动物生产许可证编号：SCXK(浙)2019-0001，实验动物使用许可证编号：SYXK(沪)2017-0014，实验动物合格证编号：20211012Abzz0619000774。北京维通利华实验动物技术有限公司上海分公司SPF级饲养室饲养、造模与观察。所有实验均遵照国家相关实验动物的使用、福利和伦理学要求等规定。

1.2.2 药物、试剂

实验所用药物为仙灵脾15 g、女贞子15 g、黄芪15 g、猫爪草15 g、胡黄连9 g、青皮9 g。参照既往实验基础，以人鼠剂量9.1倍换算，每只小鼠每次按照11.83 g/kg体质量灌胃。所用药物均为中药配方颗粒，均由江阴天江药业有限公司生产(生产批号：仙灵脾20056134、女贞子21066074、黄芪20116104、猫爪草19076164、胡黄连20092211、青皮21046274)。IFNα试剂盒(GenXspan，货号GXP557484)；IFNβ试剂盒(GenXspan，货号GXP557388)；无内毒素质粒大提试剂盒(TIANGEN，货号DP117)；PrcccDNA ShB2m、pCMV-Cre质粒为本实验室所有；大肠杆菌DH5α为本实验室保存。

1.2.3 质粒准备

PrcccDNA ShB2m及pCMV-Cre质粒均用无内毒素质粒大提试剂盒制备，操作步骤大致如下：从转染的细菌平板中挑取生长良好的单菌落，PrcccDNA ShB2m在含50 μg/mL氨苄、pCMV-Cre在含50 μg/mL卡那的LB液体培养基中37 ℃摇菌(220 r/min)过夜。4 ℃离心弃上清后，依次加入溶液P1、P2、P3，QF缓冲液洗脱，异丙醇沉淀，100%乙醇清洗并溶于TE缓冲液，即获取无内毒素的高浓度质粒。

1.2.4 HBV小鼠模型构建及分组

采用水动力转染技术建立HBV小鼠模型。采用随机数字表法分为3组，每组10只：模型及灵猫方组小鼠尾静脉高压水注射1.5 mL含6 μg PrcccDNA ShB2m及pCMV-Cre质粒的生理盐水，正常组注射等量生理盐水。第3天采集小鼠眼眶静脉血，ELISA分析血清中HBsAg、HBeAg的水平。灵猫方组小鼠按10 mL/kg体质量灌胃，2次/d，正常组与模型组小鼠以等体积饮用水灌胃，共灌胃3 d。

1.2.5 血清ELISA检测

结束后禁食12 h，用2%戊巴比妥钠3 mL/kg腹腔注射麻醉，打开腹腔，经下腔静脉采血，3000 r/min离心15 min后吸取血清，-80 ℃低温保存。按照ELISA试剂盒说明书检测各样本HBsAg、HBeAg、IFNα、IFNβ水平。

1.3 统计学方法

使用SPSS 24.0软件对数据进行统计学分析。计量资料均以x±s表示，两组间比较采用独立样本t检验；组间多重比较采用One-way ANOVA结合最小显著性差异法LSD多重比较分析。P＜0.05为差异有统计学意义。

2. 结果

2.1 灵猫方活性成分及靶点筛选

TCMSP显示灵猫方含有488种化学成分，经初步筛选后获得75种活性成分，二次筛选后获得30种活性成分，Uniprot数据库验证后获得22种活性成分，包括槲皮素(quercetin)、淫羊藿苷(Icariin)、山柰酚(kaempferol)等(表 1)。Genecards获取灵猫方成分作用靶点8144个，合并后删除重复项共得到靶点6078个，Uniprot数据库验证后获得6059个作用靶点。

表 1 灵猫方22种活性成分

Table 1. 22 active ingredients in Lingmao Formula

分子代码	活性成分	OB(%)	DL
MOL000006	木樨草素(luteolin)	36.16	0.25
MOL000098	槲皮素(quercetin)	46.43	0.28
MOL000211	丁子香萜(mairin)	55.38	0.78
MOL000354	异鼠李素(isorhamnetin)	49.60	0.31
MOL000358	β-谷甾醇(beta-sitosterol)	36.91	0.75
MOL000359	谷甾醇(sitosterol)	36.91	0.75
MOL000392	芒柄花黄素(formononetin)	69.67	0.21
MOL000398	异黄烷酮(isoflavanone)	109.99	0.30
MOL000417	毛蕊异黄酮(calycosin)	47.75	0.24
MOL000422	山柰酚(kaempferol)	41.88	0.24
MOL000433	FA	68.96	0.71
MOL000449	豆甾醇(Stigmasterol)	43.83	0.76
MOL000953	CLR	37.87	0.68
MOL001645	乙酸亚油醇酯(linoleyl acetate)	42.10	0.20
MOL001803	甜橙黄酮(sinensetin)	50.56	0.45
MOL004328	柚皮素(naringenin)	59.29	0.21
MOL004425	灵猫方苷(icariin)	41.58	0.61
MOL004427	灵猫方次甙A7(icariside A7)	31.91	0.86
MOL004576	花旗松素(taxifolin)	57.84	0.27
MOL005190	圣草酚(eriodictyol)	71.79	0.24
MOL005438	菜油甾醇(campesterol)	37.58	0.71
MOL005828	川陈皮素(nobiletin)	61.67	0.52

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2.2 灵猫方-CHB靶点交集分析

以“CHB”为搜索内容，Genecards数据库获取530个疾病靶点，Uniprot数据库验证后获得481个CHB相关靶点。灵猫方活性成分作用靶点与CHB相关靶点取交集，通过Bioinformatics绘制韦恩图，得到灵猫方-CHB共同靶点387个(图 1)。

图 1 基于GeneCards数据库预测的灵猫方-CHB靶点基因交集

Figure 1. Prediction of Lingmao Formula-CHB gene intersection from GeneCards database

下载: 全尺寸图片幻灯片

2.3 灵猫方治疗CHB生信分析

对387个靶点进行GO生物功能富集分析，获取可信度最高的前5个数据，结果显示灵猫方主要参与的生物学过程包括：炎症反应、免疫应答、固有免疫应答、脂多糖细胞应答、抗病毒反应等；细胞成分涉及细胞外间隙、胞外区、质膜外侧面、细胞表面、浆膜等；分子功能包括：细胞因子活性、蛋白结合、抗原肽结合、转录因子结合、同类蛋白结合等。KEGG信号通路分析获取77个信号通路，主要靶点富集通路有乙型肝炎通路、Toll样受体信号通路(图 2，表 2)。

图 2 灵猫方-CHB靶点基因GO及KEGG分析

注：a，灵猫方-CHB靶点基因GO分析图；b，灵猫方-CHB靶点基因KEGG分析图。

Figure 2. GO and KEGG analysis of Lingmao Formula-CHB target genes

下载: 全尺寸图片幻灯片

表 2 KEGG通路富集结果

Table 2. Enrichment results of KEGG pathway

ID	通路名称	基因数量	P值	基因
hsa05161	乙型肝炎	32	7.81×10^-14	PCNA, CXCL8, IFNA2, PTEN, FASLG, TNF, RELA, IFIH1, CCND1, STAT4, MAPK1, JAK1, JUN, TGFB1, IFNB1, STAT1, STAT3, MMP9, TGFBR1, NFKB1, MAVS, IL6, IRF3, IRF7, BCL2, BAX, FAS, TP53, TLR4, TLR3, TLR2, IFNAR1

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2.4 灵猫方-CHB免疫过程分析

CytoScape 3.8.0内置ClueGO插件可视化呈现灵猫方与CHB 387个交集靶点的免疫过程网络图，以及由KEGG富集分析获取的灵猫方治疗乙型肝炎32个交集靶点的免疫过程网络图(图 3)。灵猫方治疗乙型肝炎的免疫过程主要涉及Ⅰ型IFN信号通路，以及T淋巴细胞免疫相关过程。

图 3 药物-疾病免疫过程网络

注：a，灵猫方-CHB免疫过程图；b，灵猫方-乙型肝炎免疫过程图。

Figure 3. Lingmao Formula-CHB immune process network

下载: 全尺寸图片幻灯片

2.5 动物实验

质粒转染3 d后采集小鼠眼眶静脉血，ELISA分析显示：HBsAg滴度模型组与灵猫方组在治疗前无明显差异(P＞0.05)；予以灵猫方干预3 d后，与模型组比较，灵猫方组HBsAg滴度明显下降(P＜0.05)，且HBsAg下降幅度较模型组亦有明显提升(P＜0.001)(表 3)。HBeAg滴度模型组与灵猫方组在治疗前无明显差异(P＞0.05)；予以灵猫方干预3 d后，与模型组比较，灵猫方组HBeAg滴度明显下降(P＜0.05)，且HBeAg下降幅度较模型组亦有明显提升(P＜0.05)(表 3)。

表 3 灵猫方对HBV模型鼠HBsAg、HBeAg的影响

Table 3. Effect of Lingmao Formula on HBsAg and HBeAg in HBV model mouse

组别	动物数(只)	治疗前	治疗后	下降幅度
HBsAg(IU/mL)
模型组	10	1 813.88±590.89	1 395.43±566.21	418.45±184.63
灵猫方组	10	1 767.53±496.81	882.25±323.06	885.28±219.56
t值		0.170	2.227	-4.603
P值		0.868	0.043	＜0.001
HBeAg(S/CO)
模型组	10	58.69±12.10	29.89±5.95	28.80±9.08
灵猫方组	10	65.34±12.89	23.29±4.57	42.05±14.21
t值		-1.064	2.488	-2.224
P值		0.305	0.026	0.043

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灵猫方干预3 d后，正常组IFNα水平与模型组比较无明显差异(P＞0.05)，灵猫方组IFNα水平较正常组与模型组均显著上升(P值均＜0.001)；正常组IFNβ水平与模型组无明显差异(P＞0.05)，灵猫方组IFNβ水平较正常组与模型组均显著上升(P值均＜0.001)(表 4)。

表 4 灵猫方对HBV模型鼠Ⅰ型IFN的影响

Table 4. Effect of Lingmao formula on typeⅠIFN in HBV model mouse

组别	动物数(只)	IFNα(ng/L)	IFNβ(ng/L)
正常组	10	49.44±13.23¹⁾	171.80±8.75¹⁾
模型组	10	54.59±10.47¹⁾	178.37±14.28¹⁾
灵猫方组	10	85.62±13.34	243.19±21.73
F值		24.838	62.052
P值		＜0.001	＜0.001
注：与灵猫方组比较，1) P＜0.001。

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3. 讨论

中医学认为CHB病机特点是湿热疫毒隐伏血分，郁久伤阴导致“肝肾阴虚”，久病“阴损及阳”或素体脾肾亏虚感受湿热疫毒导致“脾肾阳虚”；本病的病性属本虚标实，虚实夹杂。20世纪70年代上海中医药大学附属曙光医院肝病科率先提出补肾为主、清化为辅的治疗原则，灵猫方便是在此基础之上创立。前期研究表明，灵猫方可促进pHBV1.3质粒转染HepG2细胞的Ⅰ、Ⅲ型IFN表达，增强固有免疫功能^[4]；提高CHB患者外周血NK细胞数量及其胞内外TLR3的表达水平，调节机体免疫功能^[7]。

本研究筛选出387个灵猫方治疗CHB的作用靶点，GO富集分析发现灵猫方主要参与免疫应答及抗病毒反应等生物学过程；KEGG富集分析筛选出32个灵猫方治疗乙型肝炎的作用靶点；对387个交集靶点及32个CHB相关靶点进行ClueGO分析发现，灵猫方主要通过调控Ⅰ型IFN信号通路及T淋巴细胞免疫应答，从而实现治疗CHB的作用。

CHB免疫发病机制十分复杂，至今尚未完全阐明^[11-12]。IFN系统在HBV天然免疫应答中发挥着至关重要的作用^[13]。Ⅰ型IFN通过与Ⅰ型IFN受体(IFNAR1)结合，激活JAK/STAT通路，诱导多种IFN刺激基因，从而抑制HBV的复制^[14]。其中TRIM14通过阻断DDB1-HBx-Smc复合物的形成来抑制HBV复制^[15]，而APOBEC3A/B则在HBV cccDNA的核降解中发挥关键作用^[16]。

本研究从灵猫方对Ⅰ型IFN的调控作用，阐释灵猫方治疗CHB的机制，为临床运用灵猫方治疗CHB提供了依据。限于网络药理学方法论的局限性以及中药组分在煎煮时发生化学反应的复杂性，本研究未将灵猫方煎煮后的化学成分以及灵猫方活性成分在体内的代谢物纳入分析，后续将在此基础上进一步筛选，进而明晰灵猫方治疗CHB的主要调控靶点。

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Value of immune－inflammatory factors in predicting intrahepatic cholangiocarcinoma

DOI: 10.3969/j.issn.1001-5256.2023.09.030