文章快速检索     高级检索
   复旦学报(医学版)  2019, Vol. 46 Issue (5): 605-610      DOI: 10.3969/j.issn.1672-8467.2019.05.006
0
Contents            PDF            Abstract             Full text             Fig/Tab
引用本文
胡安邦, 李卫青, 洪国岱, 苏琳, 邹纯朴, 陈晓, 焦肖宁, 朱杨壮壮, 胥孜杭. 血清COL4A3蛋白与非小细胞肺癌(NSCLC)患者临床病理特征及预后的相关性[J]. 复旦学报医学版, 2019, 46(5): 605-610.
HU An-bang, LI Wei-qing, HONG Guo-dai, SU Lin, ZOU Chun-pu, CHEN Xiao, JIAO Xiao-ning, ZHU-YANG Zhuang-zhuang, XU Zi-hang. Correlation between serum COL4A3 protein and clinicopathological features and prognosis in patients with non-small cell lung cancer (NSCLC)[J]. Fudan University Journal of Medical Sciences, 2019, 46(5): 605-610.
血清COL4A3蛋白与非小细胞肺癌(NSCLC)患者临床病理特征及预后的相关性
胡安邦1 , 李卫青2 , 洪国岱3 , 苏琳4 , 邹纯朴4 , 陈晓4 , 焦肖宁4 , 朱杨壮壮4 , 胥孜杭4     
1. 上海中医药大学深圳医院-深圳市罗湖区中医院呼吸病科 深圳 518001;
2. 深圳市罗湖区人民医院中医科 深圳 518001;
3. 深圳市罗湖区人民医院肿瘤科 深圳 518001;
4. 上海中医药大学基础医学院内经教研室 上海 201203
收稿日期：2018-11-13
基金项目：国家自然科学基金青年项目（81804017）；上海市青年科技英才扬帆计划（18YF1423500）；中国博士后基金（2018M640416）
摘要：目的 探索血清COL4A3蛋白与非小细胞肺癌（non-small cell lung cancer，NSCLC）患者临床病理特征及预后的相关性。方法 ELISA试剂盒检测90例NSCLC患者和58名健康对照血清中COL4A3蛋白含量。ROC曲线分析血清COL4A3水平以预测NSCLC患者肿瘤转移的敏感性与特异性。Kaplan-Meier生存分析研究血清COL4A3蛋白表达与患者生存期的相关性。对NSCLC患者预后的相关性因素进行单因素和多因素分析。采用MTT实验和Transwell实验分别检测血清COL4A3蛋白对NSCLC细胞增殖和迁移能力的影响。结果 NSCLC患者血清COL4A3水平明显高于健康对照（P < 0.001），且高表达COL4A3的患者总生存期（overall survival，OS）低于低表达患者（P=0.021）。在单因素分析中，NSCLC患者预后与肿瘤大小（P=0.015）、病理组织分级（P=0.042）、淋巴结转移（P=0.015）、临床分期（P < 0.01）以及COL4A3表达（P < 0.01）密切相关；在多因素分析中，NSCLC患者的预后与患者淋巴结转移（P=0.032）、临床分期（P < 0.01）以及血清COL4A3水平（P=0.012）密切相关。COL4A3蛋白可显著增强体外NSCLC细胞增殖和迁移能力，并呈浓度依赖性。结论 血清COL4A3蛋白水平与NSCLC进展密切相关，可能是一种NSCLC患者预后不良的独立标志物。
关键词：非小细胞肺癌(NSCLC)    COL4A3    预后    增殖    迁移    
Correlation between serum COL4A3 protein and clinicopathological features and prognosis in patients with non-small cell lung cancer (NSCLC)
HU An-bang1 , LI Wei-qing2 , HONG Guo-dai3 , SU Lin4 , ZOU Chun-pu4 , CHEN Xiao4 , JIAO Xiao-ning4 , ZHU-YANG Zhuang-zhuang4 , XU Zi-hang4     
1. Department of Respiration, Luohu Traditional Chinese Medicine Hospital of Shenzhen-Shenzhen Hospital, Shanghai University of Traditional Chinese Medicine, Shenzhen 518001, Guangdong Province, China;
2. Department of Traditional Chinese Medicine, Luohu People's Hospital, Shenzhen 518001, Guangdong Province, China;
3. Department of Oncology, Luohu People's Hospital, Shenzhen 518001, Guangdong Province, China;
4. Department of Neijing, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Foundation item: This work was supported by the Youth Program of National Natural Science Foundation of China (81804017), Shanghai Youth Science and Technology Talents Sailing Plan (18YF1423500) and Postdoctoral Science Foundation of China (2018M640416)
Corresponding author: XU Zi-hang, E-mail:xuzihang6207@shutcm.edu.cn.
Abstract: Objective To explore the correlation between serum COL4A3 protein and clinicopathological features and prognosis in patients with non-small cell lung cancer (NSCLC). Methods The serum COL4A3 protein content of 90 NSCLC cases and 58 healthy controls was detected by ELISA kit, and the correlation between serum expression and clinicopathological features was statistically analyzed.The sensitivity and specificity of tumor metastasisin patients with NSCLC were predicted by the ROC curve analysis of serum COL4A3 levels.Kaplan-Meier survival analysis was used to study the correlation between serum COL4A3 protein expression and survival of patients.Univariate and multivariate analysis were used to reveal the relative factors with prognosis in patients with NSCLC.The effects of serum COL4A3 protein on proliferation and migration of NSCLC cells were detected by MTT assay and Transwell assay, respectively. Results The serum COL4A3 of NSCLC patients was significantly higher than that of healthy controls (P < 0.001), and overall survival (OS) in patients with high expression of COL4A3 was significantly shorter than that of patients with low expression of COL4A3 (P=0.021).In univariate analysis, the prognosis of NSCLC patients was closely related to tumor size (P=0.015), pathological tissue grade (P=0.042), lymph node metastasis (P=0.015), clinical stage (P < 0.01) and COL4A3 expression (P < 0.01).While in multivariate analysis, lymph node metastasis (P=0.032), clinical stage (P < 0.01) and serum COL4A3 level (P=0.012) was strongly associated with poor prognosis of NSCLC patients.In addition, the proliferation and migration capacity of NSCLC cells was significantly enhanced by COL4A3 protein in vitro in a dose-dependent manner. Conclusions Serum COL4A3 protein level is closely related to NSCLC progression, which may be an independent marker of poor prognosis in NSCLC patients.
Key words: non-small cell lung cancer (NCLC)    COL4A3    prognosis    proliferation    migration    

近年的流行病学统计结果显示, 无论是在发达国家还是在发展中国家的发达地区, 肺癌已成为发病率和死亡率最高的恶性肿瘤[1-2], 其中非小细胞肺癌(non-small cell lung cancer, NSCLC)是最常见的类型, 约占80%~85%[3]。肺癌起病隐匿, 难以早期诊断, 往往确诊时已处于晚期, 5年生存率极低。除了常规的手术、放疗、化疗以外, 分子靶向治疗越来越受到关注。

Ⅳ型胶原蛋白α3(collagen type Ⅳ alpha 3, COL4A3)属于Ⅳ型胶原蛋白家族, 该基因与肾脏疾病和多种肿瘤密切相关。COL4A3基因位于人染色体2q36-q37上, 含有52个外显子, 编码产物为8 114 bp的mRNA和162 000的蛋白质[4]。COL4A3的分布仅限于具有组织特异性的基底膜, 如肾小球基底膜、耳蜗基底膜、前晶状体囊的眼基底膜、Descemet膜、卵巢和睾丸基底膜, 以及肺泡毛细血管基底膜[5]。2000年, 人类COL4A3的NC1结构域被制成重组蛋白, 命名为“tumstatin”, 可抑制毛细血管内皮细胞的增殖和血管形成, 并诱导内皮细胞特异性凋亡[6], 还可抑制小鼠异种移植模型中人肾细胞癌和前列腺癌的生长[7]。Ⅳ型胶原蛋白具有细胞黏附功能, 参与乳腺癌[8]、胃癌[9]、肺癌[10]、急性骨髓性白血病、胰腺导管腺癌、卵巢癌[11]、肝癌[12]、膀胱癌[13]等多种不同肿瘤的侵袭和转移。在肾脏肿瘤中, COL4A3基因持续高表达可诱导间充质干细胞参与肿瘤基质重塑, 加速肿瘤发展进程。在分化良好的肺肿瘤中, 其肿瘤簇周围也可检测到COL4A3高表达[14]。本研究旨在探讨血清COL4A3蛋白表达与NSCLC患者临床病理及预后的相关性, 其对NSCLC细胞生长、侵袭及转移的作用, 可否作为NSCLC患者预后不良的独立标志物, 以期为肺癌精准治疗提供依据。

资料和方法

研究对象  收集2005年至2017年就诊于深圳市罗湖区人民医院和罗湖区中医院的NSCLC患者, 共计90例, 其中男性60例, 女性30例, 年龄31~86岁, 平均55岁。纳入标准:(1)符合美国国立综合癌症网络(National Comprehensive Cancer Network, NCCN) NSCLC治疗指南(2017年第2版)中的诊断标准, 以及肿瘤-淋巴结-转移(tumor-node-metastasis, TNM)分期; (2)至少有1个明确可测量的病灶(10 mm); (3) Karnofsky (KPS)≥60分, 预计生存期≥3个月; (4)受试者签署知情同意书。排除标准:不符合上述纳入标准的肺癌患者; 妊娠期或哺乳期患者; 合并有心血管、肾和造血、免疫系统等严重原发性疾病、精神病等影响疗效与安全性判断的患者; 失访病例。另择58名健康人作为对照组。

标本采集与检测  采集患者空腹晨血3 mL, 离心后使用COL4A3 ELISA试剂盒(美国Aviva Systems Biology公司), 参照说明书进行检测。

细胞培养   A549细胞购自中国科学院上海细胞库, 采用DMEM培养基(美国Gibco公司), 含有100 U/mL青霉素-链霉素(美国Hyclone公司)和10%胎牛血清(美国Gibco公司), 在37 ℃、5%CO2中培养。

MTT法检测细胞增殖  将A549细胞消化后以3 000个/孔的密度接种于96孔板。贴壁过夜后吸去原有培养液, 加入含不同浓度COL4A3 (5和10 μg/mL)的完全培养液。分别在干预1、3、5、7天后加入MTT试剂。置于37 ℃孵育4 h, 弃去上清, 每孔加入150 μL二甲亚砜(DMSO)溶解甲瓒颗粒, 使用酶标仪检测490 nm处吸光度(D)。

Transwell实验  使用8 μm Transwell过滤器(美国BD公司)测定纤维蛋白原(美国Sigma公司)对细胞迁移和侵袭的影响。将含/不含Matrigel(美国BD公司)涂布的膜放置于上室, 然后将0.5 μL无血清DMEM培养基中的A549细胞(3×104)加入其中。对处理组COL4A3(5和10 μg/mL)进行相同操作。下室填充500 μL含有10%胎牛血清的基础培养基。在37 ℃、5%CO2培养箱中孵育24 h后, 迁移至下部隔室的细胞用甲醇固定, 并用结晶紫染色。在每孔随机选择的区域内以100×放大率进行成像和细胞计数。

克隆形成实验   A549细胞消化后以500个/孔接种于6孔板。贴壁过夜后吸去培养液, 加入含不同浓度COL4A3(5和10 μg/mL)的完全培养液。培养7天后, 使用4%多聚甲醛室温固定30 min, 加入结晶紫染料染色20 min。清洗后于倒置显微镜下观察克隆形成数目, 并拍摄显微成像图像。

统计学处理  使用SPSS 20.0软件统计分析数据, Mann-Whitney U检验统计分析血清COL4A3水平与患者临床病理特征的关系, Kaplan-Meier分析血清COL4A3水平与患者生存期的关系, ROC曲线分析血清COL4A3水平预测NSCLC患者肿瘤转移的敏感性与特异性。P < 0.05为差异有统计学意义, P < 0.01为差异有显著统计学意义。

结果

血清COL4A3水平与NSCLC患者临床病理特征的关系   90名NSCLC患者的血清COL4A3水平为(4.21±1.14) μg/L。对照组血清COL4A3水平为(2.75±0.64) μg/L, 患者与健康人的血清COL4A3水平差异有显著统计学意义(P < 0.001)。评估NSCLC患者的临床病理特征:性别、年龄、吸烟、组织学类型、肿瘤大小、病理分级、淋巴转移、癌症阶段及血清COL4A3水平。血清COL4A3水平与临床病理参数的相关性参见表 1, 其中性别、年龄、吸烟、肿瘤大小、病理分级、淋巴转移及临床分期的比较采用独立样本t检验, 而组织学类型的比较采用单向ANOVA检验。血清COL4A3水平与NSCLC患者的性别、年龄、吸烟、肿瘤大小、病理分级及组织学类型均无关; 而与淋巴结转移(P=0.002)和临床分期(P=0.001)相关。

表 1 NSCLC患者凝血变量与临床病理特征的相关性 Tab 1 Correlation between coagulation variables and clinicopathological characteristics in NSCLC patients
(x±s)
Variable Case (n) COL4A3
(μg/L)		 P
Sex
  Male 60 4.32±1.12 0.182
  Famale 30 4.12±0.89
Age (y)
   > 60 59 4.21±0.98 0.807
  ≤60 31 4.25±1.21
Smoking status
  Yes 66 4.13±1.21 0.204
  No 24 4.32±0.87
Histological type
  Squmous 56 4.34±1.32 0.365
  Adenocarcinoma 34 4.18±1.03
Tumor size (cm)
  ≤3 41 4.23±1.23 0.652
   > 3 49 4.31±1.15
Histological grade
  Ⅰ 20 3.95±1.23 0.243
  Ⅱ 42 4.17±1.32
  Ⅲ 28 4.38±1.43
Lymph node metastasis
  Absent 62 3.88±1.16 0.002
  Present 28 4.45±0.96
Clinical stages
  Ⅰ/Ⅱ 35 3.92±0.98 0.001
  Ⅲ/Ⅳ 55 4.36±1.14
表选项

血清COL4A3预测NSCLC患者肿瘤转移及其对生存时间的影响  从NSCLC患者血清COL4A3的ROC曲线分析中的最佳截断值预测患者肿瘤转移的敏感性(图 1)。当血清COL4A3为4.13 μg/L时, 敏感性为76.2%, 特异性为65.4%, AUC为0.731 (P < 0.001, 95%CI:0.673~0.837), 对患者临床分期具有潜在的预测价值(图 1A)。在90例NSCLC患者中, 中位血清COL4A3水平为4.13 μg/L, COL4A3高表达与COL4A3低表达的患者相比, 生存期差异有统计学意义(P=0.021), 低表达患者的存活时间更长(图 1B)。

A:Clinical stage was predicted by ROC curve analysis of serum COL4A3 in patients with NSCLC, and the optimal cutoff value of COL4A3 concentration was 4.13 μg/L.B:OS of 90 patients was showed by Kaplan-Meier curve (P=0.021). 图 1 血清COL4A3的ROC分析预测临床分期及其对生存期的影响 Fig 1 ROC analysis of serum COL4A3 predicted clinical stage and its effect on overall survival
图选项

单/多因素分析CO1L4A3与肺癌预后相关的因素  单因素分析结果显示, 患者OS与肿瘤大小、病理组织分级、淋巴结转移、临床分期以及血清COL4A3水平密切相关; 多因素分析结果显示, 患者淋巴结转移情况、临床分期以及血清COL4A3水平与肺癌预后密切相关(P < 0.05, 表 2)。提示血清COL4A3水平可能是肺癌患者OS的独立预测因子。

表 2 单因素和多因素分析预测NSCLC患者预后情况 Tab 2 Univariate and multivariate analysis of prognostic valuables for overall survival
Variables Univariate P HR (95%CI) Multivariate P HR (95%CI)
Sex 0.69 1.23 (0.32-2.25) - -
Age 0.15 2.65 (0.37-2.78) - -
Smoking status 0.53 0.72 (0.47-1.78) - -
Histological type 0.81 1.16 (0.26-5.34) - -
Tumor size 0.015 3.87 (2.31-7.87) 0.122 3.4 (0.91-8.45)
Histological grade 0.042 1.25 (0.85-1.87) 0.232 1.21 (0.77-1.83)
Lymph node metastasis 0.015 0.77 (0.11-1.66) 0.032 1.45 (0.15-3.45)
Clinical stage < 0.01 0.06 (0.02-0.31) < 0.01 0.15 (0.08-0.32)
Plasma COL4A3 level < 0.01 1.51 (1.13-2.24) 0.012 1.51 (1.16-2.44)
表选项

COL4A3促进NSCLC细胞增殖和转移  血清COL4A3高表达与NSCLC患者不良预后的相关性较强。用MTT实验检测人NSCLC细胞株A549的增殖情况, 发现低浓度COL4A3(5 μg/mL)可促进细胞增殖, 高浓度COL4A3(10 μg/mL)促进细胞增殖的作用更强(图 2A)。克隆形成实验结果显示, COL4A3对A549细胞增殖的促进作用呈浓度依赖性, 即浓度越高促进作用越明显(图 2B)。Transwell实验发现, COL4A3对A549细胞转移的抑制作用有明显的浓度依赖趋势(图 2C)。

A and B:The growth and proliferation of A549 cells were detected by MTT and clone formation assay; C:The effect of COL4A3 on the metastatic ability of A549 cells was detected by Transwell assay (×100).The results represented 3 independent experiments of x±s.vs.PBS control group, (1)P < 0.05, (2)P < 0.01, (3)P < 0.001. 图 2 COL4A3可促进NSCLC细胞增殖并增强其转移能力 Fig 2 COL4A3 promoted proliferation and enhanced metastasis of NSCLC cells
图选项
讨论

COL4A3基因高表达与多种疾病相关, 如Alport综合征、节段性肾小球硬化、2型糖尿病、高原红细胞增多症及阿尔兹海默症等, 其也是多种肿瘤发生发展的风险基因[15-17]。COL4A3属于Ⅳ型胶原蛋白家族成员, Ⅳ型胶原蛋白在细胞外基质-基底膜(basal membrane, BM)的形成和维持中发挥重要作用, 是构成BM的主要成分和骨架。当肿瘤细胞发生转移时必须穿透上皮细胞BM以及围绕血管的BM, 故肿瘤细胞分泌的Ⅳ型胶原蛋白酶可溶解Ⅳ型胶原蛋白, 是肿瘤细胞侵袭和转移的重要环节[18]。COL4A3作为Ⅳ型胶原蛋白家族成员, 其过度表达被认为与多种恶性肿瘤的转移、侵袭密切相关[19-20]。在肾癌、乳腺癌、胃癌等肿瘤患者血清中可检测出COL4A3高表达, 其与肿瘤大小、淋巴管侵袭、静脉侵袭和TNM分期等肿瘤进展的指标呈现正相关[21-23]。在使用顺铂和吉西他滨化疗的NSCLC患者中, COL4A3低表达患者的中位OS明显高于COL4A3高表达患者[24]。但是COL4A3影响NSCLC肿瘤进程的具体机制目前尚无报道, 其可否成为NSCLC的诊断标志物有待进一步研究。

本研究临床数据显示健康人与NSCLC患者血清COL4A3存在显著差异, NSCLC患者血清COL4A3表达水平明显增高, 高表达组(>4.13 μg/L)的OS明显低于低表达组(< 4.13 μg/L)(P < 0.05)。在NSCLC患者的临床病理特征中, 淋巴结转移和临床分期都与COL4A3表达密切相关:淋巴结转移患者血清COL4A3水平明显高于无转移患者(P < 0.05), 临床分期Ⅰ、Ⅱ期患者血清COL4A3水平明显低于Ⅲ、Ⅳ期患者(P < 0.05)。说明COL4A3的表达水平与NSCLC患者肿瘤进展程度呈正相关。单、多因素分析NSCLC预后相关因素的结果发现, COL4A3水平与NSCLC预后密切相关, 提示血清COL4A3高表达的NSCLC患者可能预后不良。COL4A3高表达可加快NSCLC发展进程。实验室研究发现, COL4A3可明显促进NSCLC细胞生长、增殖, 并呈浓度依赖趋势; COL4A3可明显提高NSCLC细胞的侵袭性, 增强其转移能力, 具有浓度依赖倾向, 初步揭示COL4A3高表达可促进NSCLC细胞增殖、侵袭转移。

虽然COL4A3基因在Alport综合征等疾病中报道颇多, 但其在肿瘤尤其在肺癌中的报道并不深入。目前肺癌治疗仍以铂类化疗药为主[25], 因其严重的不良反应和耐药性成为提高疗效的瓶颈, 肿瘤的精准疗法已成为研究热点[26-27]。血清COL4A3水平与NSCLC进展密切相关, 可能是一种NSCLC患者预后不良的独立标志物。COL4A3能显著促进肺癌细胞的增殖和转移, 有望成为NSCLC治疗的新靶点, 其具体的分子作用机制有待进一步明确。

参考文献
[1]
SIEGEL RL, MILLER K, JEMAL A. Cancer statistics[J]. CA Cancer J Clin, 2018, 68(1): 7-30. [DOI]
[2]
WONG MCS, LAO XQ, HO KF, et al. Incidence and mortality of lung cancer:Global trends and association with socioeconomic status[J]. Sci Rep, 2017, 7(1): 14300. [DOI]
[3]
BLANDIN KNIGHT S, CROSBIE PA, BALATA H, et al. Progress and prospects of early detection in lung cancer[J]. Open Biol, 2017, 7(9): 170070. [DOI]
[4]
NABAIS SA MJ, STOREY H, FLINTER F, et al. Collagen type Ⅳ-related nephropathies in Portugal:pathogenic COL4A3 and COL4A4 mutations and clinical characterization of 25 families[J]. Clin Genet, 2015, 88(5): 456-461. [DOI]
[5]
XIE J, WU X, REN H, et al. COL4A3 mutations cause focal segmental glomerulosclerosis[J]. J Mol Cell Biol, 2015, 7(2): 184. [DOI]
[6]
KAMPHAUS GD, COLORADO PC, PANKA DJ, et al. Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth[J]. J Biol Chem, 2000, 275(2): 1209-1215. [DOI]
[7]
MAESHIMA Y, COLORADO PC, TORRE A, et al. Distinct antitumor properties of a type Ⅳ collagen domain derived from basement membrane[J]. J Biol Chem, 2000, 275(28): 21340-21348. [DOI]
[8]
JINGSONG H, HONG G, YANG J, et al. siRNA-mediated suppression of collagen type iv alpha 2(COL4A2) mRNA inhibits triple-negative breast cancer cell proliferation and migration[J]. Oncotarget, 2017, 8(2): 2585-2593. [PubMed]
[9]
HUANG R, GU W, SUN B, et al. Identification of COL4A1 as a potential gene conferring trastuzumab resistance in gastric cancer based on bioinformatics analysis[J]. Mol Med Rep, 2018, 17(5): 6387-6396. [PubMed]
[10]
REVERT F, REVERT-ROS F, BLASCO R, et al. Selective targeting of collagen Ⅳ in the cancer cell microenvironment reduces tumor burden[J]. Oncotarget, 2018, 9(13): 11020-11045. [PubMed]
[11]
NYSTRÖM H, TAVELIN B, BJÖRKLUND M, et al. Improved tumour marker sensitivity in detecting colorectal liver metastases by combined type Ⅳ collagen and CEA measurement[J]. Tumour Biology, 2015, 36(12): 9839-9847. [DOI]
[12]
MORRISSEY MA, JAYADEV R, MILEY GR, et al. SPARC promotes cell invasion in vivo by decreasing type Ⅳ collagen levels in the basement membrane[J]. PLoS Genetics, 2016, 12(2): e1005905. [DOI]
[13]
MIYAKE M, HORI S, MORIZAWA Y, et al. Collagen type Ⅳ alpha 1(COL4A1) and collagen type Ⅷ alpha 1(COL13A1) produced in cancer cells promote tumor budding at the invasion front in human urothelial carcinoma of the bladder[J]. Oncotarget, 2017, 8(22): 36099-36114.
[14]
JIANG CP, WU BH, CHEN SP, et al. High COL4A3 expression correlates with poor prognosis after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer[J]. Tumor Biol, 2013, 34(1): 415-420. [URI]
[15]
LIU JH, WEI XX, LI A, et al. Novel mutations in COL4A3, COL4A4, and COL4A5 in Chinese patients with Alport Syndrome[J]. PLoS One, 2017, 12(5): e0177685. [DOI]
[16]
SARAVANI S, YARI D, SARAVANI R, et al. Association of COL4A3(rs55703767), MMP-9(rs17576)and TIMP-1(rs6609533) gene polymorphisms with susceptibility to type 2 diabetes[J]. Biomed Rep, 2017, 6(3): 329-334. [PubMed]
[17]
FAN X, MA L, ZHANG Z, et al. Associations of high-altitude polycythemia with polymorphisms in PIK3CD and COL4A3 in Tibetan populations[J]. Hum Genomics, 2018, 12(1): 37. [DOI]
[18]
ZHU YY, CHEN C, LI JJ, et al. The prognostic value of quantitative analysis of CCL5 and collagen Ⅳ in luminal B (HER2-) subtype breast cancer by quantum-dot-based molecular imaging[J]. Int J Nanomedicine, 2018, 13: 3795-3803. [DOI]
[19]
FIDLER AL, DARRIS CE, CHETYRKIN SV, et al. Collagen Ⅳ and basement membrane at the evolutionary dawn of metazoan tissues[J]. ELife, 2017, 6: e24176. [DOI]
[20]
CUMMINGS CF, PEDCHENKO V, BROWN KL, et al. Extracellular chloride signals collagen Ⅳ network assembly during basement membrane formation[J]. J Biol Chem, 2016, 213(4): 479-494. [PubMed]
[21]
LINDOSO RS, COLLINO F, CAMUSSI G. Extracellular vesicles derived from renal cancer stem cells induce a pro-tumorigenic phenotype in mesenchymal stromal cells[J]. Oncotarget, 2015, 6(10): 7959-7969. [PubMed]
[22]
GEORGIOU GK, IGGLEZOU M, SAINIS I, et al. Impact of breast cancer surgery on angiogenesis circulating biomarkers:a prospective longitudinal study[J]. World J Surg Oncol, 2013, 11: 213. [DOI]
[23]
NIE XC, WANG JP, ZHU W, et al. COL4A3 expression correlates with pathogenesis, pathologic behaviors, and prognosis of gastric carcinomas[J]. Hum Pathol, 2013, 44(1): 77-86. [DOI]
[24]
JIANG CP, WU BH, CHEN SP, et al. High COL4A3 expression correlates with poor prognosis after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer[J]. Tumor Biol, 2013, 34(1): 415-420. [URI]
[25]
陈力, 金玉麟, 王琳, 等. miRNA与肺癌顺铂耐药相关性的研究进展[J]. 复旦学报(医学版), 2018, 45(2): 245-249. [DOI]
[26]
PRAHARAJ PP, BHUTIA SK, NAGRATH S, et al. Circulating tumor cell-derived organoids:current challenges and promises in medical research and precision medicine[J]. Biochim Biophys Acta Rev Cancer, 2018, 1869(2): 117-127. [DOI]
[27]
古杰, 胥丰恺, 祝巧良, 等. αB-Crystallin在非小细胞肺癌增殖迁移中的作用及其临床意义[J]. 复旦学报(医学版), 2018, 45(3): 323-329. [DOI]

文章信息

胡安邦, 李卫青, 洪国岱, 苏琳, 邹纯朴, 陈晓, 焦肖宁, 朱杨壮壮, 胥孜杭
HU An-bang, LI Wei-qing, HONG Guo-dai, SU Lin, ZOU Chun-pu, CHEN Xiao, JIAO Xiao-ning, ZHU-YANG Zhuang-zhuang, XU Zi-hang
血清COL4A3蛋白与非小细胞肺癌(NSCLC)患者临床病理特征及预后的相关性
Correlation between serum COL4A3 protein and clinicopathological features and prognosis in patients with non-small cell lung cancer (NSCLC)
复旦学报医学版, 2019, 46(5): 605-610.
Fudan University Journal of Medical Sciences, 2019, 46(5): 605-610.
Corresponding author
XU Zi-hang, E-mail:xuzihang6207@shutcm.edu.cn.
基金项目
国家自然科学基金青年项目（81804017）；上海市青年科技英才扬帆计划（18YF1423500）；中国博士后基金（2018M640416）
Foundation item
This work was supported by the Youth Program of National Natural Science Foundation of China (81804017), Shanghai Youth Science and Technology Talents Sailing Plan (18YF1423500) and Postdoctoral Science Foundation of China (2018M640416)

工作空间