C1q肿瘤坏死因子相关蛋白3（C1QTNF3）在肝癌中的表达及其对预后的预测价值

金丽莹; 王姝涵; 杨洋

doi:10.12449/JCH250520

C1q肿瘤坏死因子相关蛋白3（C1QTNF3）在肝癌中的表达及其对预后的预测价值

DOI: 10.12449/JCH250520

金丽莹^{1, 2},
王姝涵^{1, 2},
杨洋^{1, 2, , ,}

1.
延边大学肿瘤研究中心，吉林延吉 133002
2.
民族地区高发肿瘤病理生理学国家民委重点实验室，吉林延吉 133002

基金项目:

国家自然科学基金 (82160552)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：杨洋负责设计论文框架，起草和修改论文；王姝涵负责数据收集，统计学分析，绘制图表；金丽莹负责实验操作，研究过程的实施，拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
杨洋， yangyang@ybu.edu.cn （ORCID： 0000-0002-0754-935X）

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出版历程
- 收稿日期: 2024-12-23
- 录用日期: 2025-02-21
- 出版日期: 2025-05-25

The expression of C1QTNF3 in liver cancer and its prognostic value

Liying JIN^{1, 2},
Shuhan WANG^{1, 2},
Yang YANG^{1, 2
, ,
,}

1.
Department of Cancer Research Center，Yanbian University，Yanji，Jilin 133002，China
2.
Key Laboratory of Pathophysiology of High-incidence Tumors in Ethnic Areas，State Ethnic Affairs Commission，Yanji，Jilin 133002，China

Research funding:

National Natural Science Foundation of China (82160552)

More Information

Corresponding author: YANG Yang， yangyang@ybu.edu.cn （ORCID： 0000-0002-0754-935X）

摘要

摘要: 目的探究C1q肿瘤坏死因子相关蛋白3（C1QTNF3）在肝癌组织中的表达情况，分析其与患者临床病理特征的关系，并进一步评估其在肝癌预后中的潜在预测价值。方法分别于TIMER、UALCAN、TNMplot及GEO数据库收集资料，采用生物信息学分析C1QTNF3基因在泛癌、正常组织与肝癌组织，以及癌组织及其癌旁组织中的表达水平。选取90例肝癌患者的肝癌组织及其癌旁组织标本，收集患者年龄、性别、肿瘤直径、肿瘤数目等临床资料。计量资料组间比较采用成组t检验或配对t检验；计数资料组间比较采用χ²检验。Kaplan-Meier法绘制生存曲线，Log-rank检验分析C1QTNF3表达水平与肝癌患者生存期的关系。Cox回归模型分析影响肝癌患者预后的危险因素，受试者操作特征曲线（ROC曲线）分析不同时间点C1QTNF3表达对肝癌患者预后的预测能力。结果生物信息学分析结果显示，C1QTNF3基因在多种恶性肿瘤组织中表达上调，尤其在肝癌组织中（P<0.001）；C1QTNF3基因在肝癌组织中的表达量高于正常组织及其癌旁组织（P值均<0.01）。90例肝癌患者免疫组化染色结果显示，C1QTNF3主要表达于细胞质，少量表达于细胞核，且在癌旁组织中主要呈阴性表达，在肝癌组织中呈阳性表达。C1QTNF3蛋白在肝癌组织中的阳性表达率（76.67% vs 33.33%）和强阳性表达率（54.44% vs 5.56%）均显著高于癌旁组织（χ²值分别为34.141、51.217，P值均<0.01）。肿瘤直径≥5 cm、晚期、肝硬化、HBsAg阴性和GGT≥50 U/L肝癌患者的C1QTNF3蛋白强阳性表达率均显著高于肿瘤直径<5 cm、早期、无肝硬化、HBsAg阳性和GGT<50 U/L的肝癌患者（P值均<0.05）。单因素Cox回归分析结果显示，肿瘤直径、复发情况和C1QTNF3表达是肝癌患者预后的影响因素（P值均<0.05）；多因素Cox回归分析结果显示，C1QTNF3表达水平和复发情况是影响肝癌患者生存期的独立危险因素（P值均<0.05）。生存曲线结果显示，所有肝癌患者中，C1QTNF3高表达（强阳性）者相较于低表达者，总生存率和无瘤生存率均更短（χ²值分别为17.010、13.647，P值均<0.001）；在肿瘤直径≥5 cm、早/晚期、复发、肝硬化、HBsAg阳性、ALT<40 U/L、ALT≥40 U/L和GGT≥50 U/L的肝癌患者中，C1QTNF3高表达者的总生存率均显著降低（χ²值分别11.086、5.578、5.295、19.159、16.391、13.774、10.119、8.152、12.035，P值均<0.05）。ROC曲线结果显示，C1QTNF3表达在5年时的预测潜力最强，ROC曲线下面积为0.77。结论 C1QTNF3在肝癌组织中呈高表达，其表达水平和复发情况与肝癌患者的生存期密切相关，C1QTNF3蛋白高表达患者生存率更低。
- 肝肿瘤 /
- 脂肪因子类 /
- 预后
Abstract: Objective To investigate the expression of C1q tumor necrosis factor-related protein 3 （C1QTNF3） in liver cancer tissue， its association with the clinicopathological features of patients， and its potential value in predicting the prognosis of liver cancer. Methods Related data were collected from TIMER， UALCAN， TNMplot， and GEO databases， and the bioinformatics methods were used to measure the expression level of C1QTNF3 in pan-cancer， normal tissue/liver cancer tissue， and cancerous tissue/paracancerous tissue. Cancerous and paracancerous tissue samples were collected from 90 patients with liver cancer， and related clinical data were collected， including age， sex， tumor diameter， and tumor number. The independent-samples t test or the paired t-test was used for comparison of continuous data between groups， and the chi-square test was used for comparison of categorical data between groups. The Kaplan-Meier method was used to plot survival curves， and the Log-rank test was used to investigate the association between the expression level of C1QTNF3 and the survival of patients with liver cancer. The Cox regression model was used to identify the risk factors for the prognosis of patients with liver cancer， and the receiver operating characteristic （ROC） curve was used to analyze the ability of C1QTNF3 expression at different time points for predicting the prognosis of patients with liver cancer. Results The bioinformatics analysis showed that the expression of C1QTNF3 was upregulated in various malignant tumors， especially in liver cancer tissue （P<0.001）， and the expression level of C1QTNF3 in liver cancer tissue was significantly higher than that in normal tissue and paracancerous tissues （all P<0.01）. The immunohistochemical staining results of 90 patients with liver cancer showed that C1QTNF3 was mainly expressed in cytoplasm， with a small amount in nucleus， and it had negative expression in paracancerous tissue and positive expression in liver cancer tissue. The positive expression rate and strong positive expression rate of C1QTNF3 protein in liver cancer tissue were significantly higher than those in paracancerous tissue （positive expression rate： 76.67% vs 33.33%， χ²=34.141， P<0.01； strong positive expression rate： 54.44% vs 5.56%， χ²=51.217， P<0.01）. The liver cancer patients with a tumor diameter of ≥5 cm， an advanced stage， the presence of liver cirrhosis， negative HBsAg， and gamma-glutamyl transpeptidase （GGT）≥50 U/L had a significantly higher strong positive expression rate of C1QTNF3 protein than those with a tumor diameter of <5 cm， an early stage， the absence of liver cirrhosis， positive HBsAg， and GGT<50 U/L （all P<0.05）. The univariate Cox regression analysis showed that tumor diameter， recurrence， and C1QTNF3 expression were influencing factors for the prognosis of patients with liver cancer （all P<0.05）， and the multivariate Cox regression analysis showed that the expression level of C1QTNF3 and recurrence were independent risk factors for the survival of patients with liver cancer （both P<0.05）. The survival curve analysis showed that for all patients with liver cancer， the patients with high （strong positive） expression of C1QTNF3 had significantly lower overall survival rate and disease-free survival rate than those with low expression （χ²=17.010 and 13.647， both P<0.001）； for liver cancer patients with a tumor diameter of ≥5 cm， an early/advanced stage， recurrence， the presence of liver cirrhosis， positive HBsAg， alanine aminotransferase （ALT） <40 U/L， ALT≥40 U/L， and GGT≥50 U/L， the patients with high expression of C1QTNF3 had a significant reduction in overall survival rate （χ²=11.086， 5.578， 5.295， 19.159， 16.391， 13.774， 10.119， 8.152， and 12.035， all P<0.05）. The ROC curve analysis showed that C1QTNF3 expression had the strongest predictive potential at 5 years， with an area under the ROC curve of 0.77. Conclusion C1QTNF3 is highly expressed in liver cancer tissue， and the expression level of C1QTNF3 and recurrence are closely associated with the survival of patients with liver cancer. Patients with high expression of C1QTNF3 protein tend to have a lower survival rate.
- Liver Neoplasms /
- Adipokines /
- Prognosis

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注： a，TIMER数据库；*，P<0.05；**，P<0.01；***，P<0.001。b，UALCAN数据库。c～d，TNMplot数据库。e，GEO数据库。

图 1 C1QTNF3 mRNA在泛癌和肝癌组织中的表达

Figure 1. Expression of C1QTNF3 mRNA in pan-cancer and liver cancer tissues

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注： a，癌旁组织；b，肝癌组织弱阳性表达；c，肝癌组织阳性表达；d，肝癌组织强阳性表达。

图 2 C1QTNF3在肝组织中的表达情况（免疫组化染色，×200）

Figure 2. Expression of C1QTNF3 in liver tissue（immunohistochemical staining，×200）

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图 3 C1QTNF3蛋白高、低表达的生存曲线

Figure 3. Survival curves of high and low expression of C1QTNF3 protein

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图 4 C1QTNF3蛋白表达水平预测肝癌预后的ROC曲线

Figure 4. ROC curves of the predictive value of C1QTNF3 protein expression level for the prognosis of liver cancer

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表 1 C1QTNF3在肝癌组织及癌旁组织中阳性表达率和强阳性表达率的比较

Table 1. Comparison of the positive expression rate and the strong positive expression rate of C1QTNF3 in liver cancer tissues and adjacent tissues

C1QTNF3蛋白	肝癌组织（n=90）	癌旁组织（n=90）	χ²值	P值
阳性率［例（%）］	69（76.67）	30（33.33）	34.141	<0.01
强阳性率［例（%）］	49（54.44）	5（5.56）	51.217	<0.01

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表 2 C1QTNF3蛋白高表达与肝癌临床病理特征之间的关系

Table 2. The relationship between high expression of C1QTNF3 protein and clinicopathological features of liver cancer

临床病理特征	例数	强阳性［例（%）］	χ²值	P值
性别			0.155	0.694
男	74	41（55.4）
女	16	8（50.0）
年龄			0.278	0.598
≥50岁	39	20（51.3）
<50岁	51	29（56.9）
肿瘤直径			8.674	0.003
<5 cm	44	17（38.6）
≥5 cm	46	32（69.6）
肿瘤数目			0.026	0.873
≤1个	74	40（54.1）
>1个	16	9（56.3）
包膜			0.453	0.501
有	47	24（51.1）
无	43	25（58.1）
组织学分级			0.487	0.485
Ⅰ～Ⅱ级	58	30（51.7）
Ⅲ级	32	19（59.4）
临床分期			5.570	0.018
早期	61	28（45.9）
晚期	29	21（72.4）
复发情况			3.178	0.075
有	53	33（62.3）
无	37	16（43.2）
肝硬化			4.840	0.028
有	78	46（59.0）
无	12	3（25.0）
HBsAg			5.979	0.014
阳性	77	38（49.4）
阴性	13	11（84.6）
抗-HBc			2.962	0.085
阳性	80	41（51.3）
阴性	10	8（80.0）
抗-HCV			0.016	0.898
阳性	2	1（50.0）
阴性	88	48（54.5）
TBil			3.789	0.052
<17.1 μmol/L	66	40（60.6）
≥17.1 μmol/L	24	9（37.5）
ALT			0.083	0.773
<40 U/L	41	23（56.1）
≥40 U/L	49	26（53.1）
AFP			0.000	0.988
<400 μg/L	57	31（54.4）
≥400 μg/L	33	18（54.5）
GGT			6.912	0.009
<50 U/L	35	13（37.1）
≥50 U/L	55	36（65.5）

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表 3 肝癌患者预后Cox风险回归模型单因素分析

Table 3. Univariate analysis of Cox risk regression model for prognosis of liver cancer patients

参数	B值	SE	Wald	HR（95%CI）	P值
性别	0.384	0.584	1.828	1.468（0.841～2.561）	0.176
年龄	0.042	0.215	0.038	1.043（0.684～1.589）	0.846
肿瘤直径	0.548	0.214	6.541	1.730（1.137～2.634）	0.011
分化程度	0.023	0.222	0.011	0.977（0.633～1.510）	0.918
临床分期	0.223	0.229	0.949	0.800（0.511～1.253）	0.330
肿瘤数目	0.110	0.278	0.156	0.896（0.520～1.544）	0.692
包膜	0.002	0.213	0.000	0.998（0.658～1.515）	0.993
复发情况	0.740	0.221	11.206	2.095（1.359～3.230）	0.001
肝硬化	0.378	0.316	1.431	0.686（0.369～1.273）	0.232
抗-HBc	0.142	0.339	0.177	0.867（0.447～1.684）	0.674
抗-HCV	0.603	0.724	0.695	0.547（0.132～2.260）	0.404
TBil	0.036	0.240	0.022	0.965（0.603～1.543）	0.881
ALT	0.021	0.215	0.010	1.022（0.670～1.558）	0.921
AFP	0.378	0.221	2.911	1.459（0.945～2.252）	0.088
GGT	0.313	0.219	2.038	1.367（0.890～2.101）	0.153
HBsAg	0.252	0.303	0.691	0.777（0.430～1.407）	0.406
C1QTNF3表达	0.788	0.218	13.038	2.198（1.434～3.371）	<0.001

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表 4 肝癌患者预后Cox风险回归模型多因素分析

Table 4. Multivariate analysis of Cox risk regression model for prognosis of liver cancer patients

参数	B值	SE	Wald	HR（95%CI）	P值
ALT	0.292	0.240	1.482	0.747（0.467～1.195）	0.223
肿瘤直径	0.274	0.232	1.399	1.315（0.835～2.072）	0.237
复发情况	0.835	0.249	11.249	2.305（1.415～3.756）	0.001
C1QTNF3表达	0.701	0.233	9.060	2.016（1.277～3.182）	0.003

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