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Application Value of Serum Kreb Von Den Lungen-6 in the Adjuvant Treatment of Lung Injury after Non-small Cell Lung Cancer Surgery
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摘要:目的 探讨血清涎液化糖链抗原-6(kreb von den lungen-6，KL-6)在非小细胞肺癌(non-small cell lung cancer，NSCLC)术后辅助治疗性肺损伤中的诊断价值。方法 回顾性收集2017年11月—2020年7月中国医科大学附属盛京医院诊治的NSCLC患者(包括术后采用辅助治疗者和仅手术者)资料，以药物诱导性肺损伤(drug induced lung injury, DILI)、放射性肺损伤(radiation induced lung injury, RILI)诊断共识为判断NSCLC术后辅助治疗性肺损伤的诊断标准，将NSCLC术后辅助治疗患者分为肺损伤组和无肺损伤组，仅手术者为NSCLC手术组；以年龄和性别匹配同期体检中心的健康成人为健康对照组。肺损伤组于肺损伤确诊当日，无肺损伤组于辅助治疗的第3~4个月，NSCLC手术组分别于术前、术后7~10 d，健康对照组于体检当日，空腹采集静脉血检测血清KL-6。比较各组血清KL-6差异，并以无肺损伤组为对照，采用受试者工作特征(receiver operating characteristic，ROC)曲线评估血清KL-6诊断NSCLC术后辅助治疗性肺损伤的效能。结果 共206例符合纳入和排除标准的患者入选本研究，其中肺损伤组51例，无肺损伤组52例，NSCLC手术组103例；健康对照组103例，基线资料均衡可比。血清KL-6水平由高至低依次为肺损伤组[512.40(322.30，819.20)kU/L]、NSCLC手术组(术前) [204.40(162.70，283.20)kU/L]、健康对照组[177.70(154.20，206.40)kU/L]、无肺损伤组[147.80(114.25，229.80)kU/L]和NSCLC手术组(术后) [143.80(111.90，247.80)kU/L]。除无肺损伤组与NSCLC手术组术后血清KL-6无统计学差异(P=0.879)外，其余两两比较差异均有统计学意义(P均＜0.05)。ROC曲线分析显示，血清KL-6诊断NSCLC术后辅助治疗性肺损伤的曲线下面积(area under the curve，AUC)为0.972(95%CI：0.948~0.997)，灵敏度、特异度、阳性似然比、阴性似然比分别为86.3%(95% CI：73.0%~94.1%)、96.2%(95% CI：86.2%~98.7%)、22.43(95% CI：5.74~87.69)、0.14(95% CI：0.07~0.28)，最佳诊断临界值为310.15 kU/L。结论 NSCLC术后辅助治疗性肺损伤患者血清KL-6显著升高，其在NSCLC术后辅助治疗性肺损伤中具有较高的诊断价值，但仍需大样本前瞻性研究进一步验证。Abstract:Objective To investigate the diagnostic value of serum kreb von den lungen-6 (KL-6) in lung injury from postoperative adjuvant treatment in non-small cell lung cancer (NSCLC).Methods This study is a retrospective analysis including NSCLC with postoperative adjuvant treatment and NSCLC with merely surgical treatment patients diagnosed and treated in Shengjing Hospital of China Medical University from November 2017 to July 2020. Consensus on the diagnosis of drug induced lung injury and radiation induced lung injury was used as the diagnostic criteria for lung injury from postoperative adjuvant treatment. NSCLC patients with postoperative adjuvant treatment were divided into the lung-injury group and the non lung-injury group. those only with surgery were as NSCLC-surgery group. Match the healthy adults of the physical examination center at the same period as the healthy control group based on the age and gender. Fasting venous blood was collected from NSCLC patients and healthy adults for detection of serum KL-6. The time of venous blood collection was on the day of lung-injury diagnosis for the lung-injury group, after 3 to 4 months of adjuvant treatment for the non lung-injury group, before and 7 to 10 days after surgery for NSCLC-surgery group, and on the day of physical examination for the healthy control group. The levels of serum KL-6 in each group were compared, and the non lung-injury group was used as the control, the diagnostic threshold value of serum KL-6 for adjuvant therapeutic lung injury was preliminarily established based on the receiver operating characteristic(ROC) curve.Results A total of 206 NSCLC patients who met the selection and exclusion criteria were enrolled, of which 51 cases were in lung-injury group, 52 cases were in non lung-injury group, and 103 cases were in NSCLC-surgery group. Meanwhile, 103 cases in healthy control group were enrolled. There was no significant difference among the basic clinical data of the four groups. The levels of serum KL-6 in the descending order were lung-injury group [512.40 (322.30, 819.20)kU/L], pre-operation of the NSCLC-surgery group [204.40 (162.70, 283.20)kU/L], healthy control group [177.70 (154.20, 206.40)kU/L], non lung-injury group [147.80 (114.25, 229.80)kU/L], and post-operation of the NSCLC-surgery group [143.80 (111.90, 247.80)kU/L]. There was no significant difference in serum KL-6 between the non lung-injury group and post-operation of the NSCLC-surgery group (P=0.879), while the difference between other groups were statistically significant (all P < 0.05). The ROC curve analysis showed that the area under the curve (AUC) of serum KL-6 for the diagnosis of lung injury from NSCLC postoperative adjuvant treatment was 0.972 (95% CI: 0.948-0.997), and the diagnostic sensitivity, specificity, the positive and negative likelihood ratio were 86.3% (95% CI: 73.0%-94.1%), 96.2% (95% CI: 86.2%-98.7%), 22.43 (95% CI: 5.74-87.69), 0.14 (95% CI: 0.07-0.28), respectively. The best diagnostic cut-off value was 310.15 kU/L.Conclusions Serum KL-6 is significantly increased in the patients with lung injury from NSCLC postoperative adjuvant treatment, and it has high application value in the diagnosis of lung injury from postoperative adjuvant treatment in NSCLC, but it still needs further verification by prospective studies with large samples.
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胃肠间质瘤(gastrointestinal stromal tumors，GISTs)是胃肠道最常见的间叶组织肿瘤, 起源于消化道肌层Cajal细胞(interstitial cells of Cajal，ICCs)或其同源干细胞[1]，可发生于胃肠道任何部位，大多数位于胃(70%)和小肠(10%~25%)[2]，少数位于直肠、食管及结肠[3]。其发病率约为(1~2)/10万，占胃肠道肿瘤的1%~3%，胃肠道肉瘤的80%[4]，但近年来呈明显上升趋势[5]。GISTs生长缓慢、症状隐匿、临床表现多样、无特异性，早期诊断极为困难，误诊率高达91.7%[6]，故发现时多为中晚期，直接影响治疗效果及预后。此外，GISTs对传统放化疗并不敏感，手术完整切除是唯一可能治愈的方法，但仍有40%~80%的GISTs于术后19~25个月出现复发、转移[7]。
大部分GISTs的发生与KIT和/或PDGFRA基因功能性突变有关[8-10]。酪氨酸激酶受体抑制剂使GISTs治疗取得了革命性进展，但仍有14%的GISTs原发耐药[11]。另外，由于两基因存在多位点和/或二次突变, 导致靶向治疗耐药率及复发率逐年升高，成为影响疗效的关键因素。研究发现，术后服用伊马替尼(imatinib)的GISTs患者中位无进展生存期约为2年，2年内继发耐药率为40%~50%。舒尼替尼(sunitinib)对伊马替尼耐药病例疾病控制率仅为65%(7%有效，58%疾病无进展)，且持续时间短，易耐药[12]。regorafenib、sorafenib等均对一线、二线耐药的GISTs效果尚不确切且不良反应多[13]。因此，GISTs的治疗面临着瓶颈制约，寻找新的治疗方法成为当前GISTs治疗研究热点。
1. 胃肠间质瘤与ETV1表达
KIT基因编码Ⅲ型酪氨酸激酶家族跨膜受体。正常情况下，c-kit蛋白必须与配体——干细胞因子结合，发生自身磷酸化，激活有丝分裂活化蛋白激酶和磷脂酰肌醇3激酶，进而激发激酶磷酸化链式反应，促进细胞增殖。c-kit基因突变后，其蛋白活化不再受配体限制，表现为持续、自动磷酸化，使c-kit信号转导系统病态增强，促使细胞增殖并抑制凋亡，最终导致肿瘤形成[14-15]。
ETS转录家族有30多个成员，是目前最大的信号依赖转录调控因子家族之一。这些信号分子拥有由85个氨基酸组成的特异DNA结合区，可与靶基因启动区(一般为富含嘌呤序列GGAA/T)结合，调控靶基因转录，参与肿瘤发生、演进[16-17]。ETV1位于染色体7p21.2, 是ETS家族PEA3亚科转录因子。ETV1可结合的靶基因较多，通过调节靶基因的表达, 在调控肿瘤细胞增殖、分化、迁移中起重要作用。研究表明，ETV1在肿瘤组织中如前列腺癌、黑色素瘤、乳腺癌中表达量较正常组织显著升高[18-22]。
ETV1在GISTs肿瘤组织及GISTs细胞株中均呈高表达, 且显著高于其他肿瘤。GISTs细胞株中，ETV1对靶基因的作用由复杂的调控网络调节，其中，Ras/Raf/MAPK信号通路是调控ETV1的主要通路[23-25]。GISTs患者中联合使用伊马替尼与MEK抑制剂，GISTs生长会受到明显抑制。研究发现[26]，ETV1表达与KIT基因转录呈正反馈循环：ETV1可刺激KIT基因转录，KIT蛋白促进ETV1表达，且增强ETV1稳定性，减缓降解。ICCs转变为GISTs过程由KIT基因与ETV1协调配合实现，即KIT基因功能性突变和ETV1变化同步、协调进行，从而导致GISTs的发生[27]。阻断ETV1基因表达后, 细胞分裂减少、凋亡增加, 表明ETV1对GISTs发生、发展起至关重要的作用。另有研究表明[28]，ETV1对于野生型GISTs尚有辅助诊断的作用, 且ETV1表达可能作为GISTs患者根治术后3年无病生存率的评估指标。
综上所述，ETV1可能与GISTs发生、发展相关，但能否将ETV1作为耐药性GISTs治疗新靶点，ETV1可否作为评估GISTs恶性程度、预测肿瘤进展的指标仍有待基础、临床进一步研究。深入探索ETV1在GISTs发生、发展中可能的作用机制，将为GISTs诊疗提供更多思路。
2. 胃肠间质瘤与FOXF1表达
FOX基因家族属于叉头框(forkhead box)基因, 在分子结构上具有明显的叉头DNA结合区[29]，共包含19个亚族, 50个成员，功能涉及胚胎发育、细胞周期调控、糖类/脂类代谢、免疫调节、衰老等多种生物过程。FOX家族基因在人体内主要发挥转录因子的作用, 调控多种靶基因表达，与肿瘤发展、侵袭、转移密切相关[30]。FOXF1基因是FOX基因家族中的一员，位于人类染色体16q24.1, 编码FOXF1转录因子。FOXF1能抑制肿瘤细胞增殖、转移, 其失活会促进肿瘤进展，表现为促瘤效应[31]。研究表明[32]，在所有入组的GISTs组织中，无论KIT/PDGFRA突变状况如何，FOXF1均为阳性表达。这说明FOXF1可能在GISTs中普遍表达，但在其他肉瘤中很少观察到FOXF1表达。即FOXF1在GISTs中普遍表达，且具有相对特异性。因此FOXF1可能成为GISTs敏感的、具有一定特异性的新型分子标志物。
3. FOXF1与ETV1
研究发现[32]，FOXF1可能是ETV1的上游调节因子，FOXF1主要结合位点是增强子，通过与增强子结合后调控KIT、ETV1表达，进而调节GISTs发生及发展。FOXF1下调不仅导致ICCs/GISTs谱系基因转录减少，且ETV1表达也呈下降趋势。用伊马替尼抑制KIT及其下游MAPK通路信号转导，或MEK162(MEK抑制剂)对MAPK信号通路进行短期抑制后，均可导致ETV1蛋白降解。上述通路重新激活后，ETV1蛋白水平也相应恢复[33-34]。整个过程中，FOXF1蛋白表达水平无显著波动，即FOXF1直接影响ETV1的表达，但ETV1变化并未对FOXF1造成明显影响。这些发现表明，FOXF1可能位于GISTs生长信号分子ETV1上游，调控ETV1的表达。但FOXF1在GISTs中表达的意义、与GISTs病理特征相关性、是否可作为GISTs治疗新方向，目前尚无相关研究进行探究。
4. 小结
FOXF1、ETV1、KIT三者在GISTs生长调控中的作用可表述为FOXF1位于信号通路的最上游，可正向调控ETV1表达，ETV1继而调控KIT表达，且二者形成正反馈。这表明，FOXF1、ETV1很有可能是GISTs药物治疗的新靶点，为处于治疗瓶颈中的GISTs患者带来新的希望。但如何以FOXF1、ETV1为靶点开发治疗的GISTs药物，尤其是多重耐药GISTs，仍需更大样本、前瞻性基础、临床研究进一步探索。
作者贡献：吴丽娜、秦晓松负责研究设计、数据分析、论文撰写；高弋、李沃松负责标本留取及临床资料收集；刘勇指导研究设计、数据分析及修改论文。利益冲突：无 -
表 1 患者一般资料比较
指标 肺损伤组(n=51) 无肺损伤组(n=52) NSCLC手术组(n=103) 健康对照组(n=103) P值 年龄(x±s, 岁) 58.51±7.14 53.06±8.70 59.26±7.08 54.61±8.90 ＜0.001 性别(男/女，n) 33/18 32/20 66/37 62/41 0.926 病理类型(腺癌/鳞癌，n) 43/8 40/12 82/21 - 0.634 TNM分期(Ⅱ/Ⅲ期，n) 23/28 27/25 48/55 - 0.756 术后辅助治疗方式(单纯放疗/同步放化疗，n) 18/33 17/35 - - 0.780 合并慢性阻塞性肺疾病[n(%)] 4(7.84) 1(1.92) 3(2.91) 0(0) 0.037 合并结缔组织病[n(%)] 1(1.96) 0(0) 0(0) 0(0) 0.166 NSCLC：同图 1；-：不适用 
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