Terlizzi Michela, Colarusso Chiara, De Rosa Ilaria, De Rosa Nicolina, Somma Pasquale, Curcio Carlo, Sanduzzi Alessandro, Micheli Pietro, Molino Antonio, Saccomanno Antonello, Salvi Rosario, Aquino Rita P, Pinto Aldo, Sorrentino Rosalinda
Department of Pharmacy, University of Salerno, ImmunePharma S.r.l., Fisciano, SA, Italy.
PhD Program in Drug Discovery and Development, Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
Oncotarget. 2018 Apr 10;9(27):19356-19367. doi: 10.18632/oncotarget.25049.
Late diagnosis limits therapeutic options and survival rate of non-small cell lung cancer (NSCLC) patients. Therefore the identification of biomarkers represents an emerging medical need. A highly sensitive and specific test was developed to identify/quantify a novel/selective diagnostic biomarker for NSCLC patients, caspase-4. This test was validated by using i) plasma from 125 NSCLC patients and 79 healthy (non-pathological) subjects, ii) plasma from 139 smokers and iii) from 70 chronic-obstructive pulmonary disease (COPD) patients. Caspase-4 quantification was also assessed in the lung tumor mass of 98 paired NSCLC patients compared to 10 non-tumor lung tissues (i.e. tuberculosis). Circulating caspase-4 was detected in both healthy and NSCLC patients; however at different range values: 2.603-3.372 ng/ml for NSCLC patients (95% CI) compared to 0.3994-0.6219 ng/ml for healthy subjects (95% CI). The sensitivity of the test ranged from 97.07% to 100%; the specificity was 88.1% with a positive predictive value of 92.54%, accuracy of 95.19% and AUC of 0.971. Smokers (95% CI, 0.3947-0.6197 ng/ml) and COPD patients (95% CI, 1.703-2.995 ng/ml) showed intermediate values of circulating caspase-4. Tissue levels of caspase-4 in the tumor mass showed that 72 (72.7%) out of 99 patients were positive. More importantly, higher levels (cut-off value = 0.307 ng/ml) of caspase-4 in the tumor mass were associated to reduced overall survival (median 0.92 years) compared to NSCLC patients with lower levels (median 3.02 years). We report for the first time caspase-4 as a novel diagnostic and prognostic biomarker, opening new therapeutic perspectives for NSCLC patients.
晚期诊断会限制非小细胞肺癌（NSCLC）患者的治疗选择和生存率。因此，鉴定生物标志物成为一项新出现的医学需求。人们开发了一种高灵敏度和特异性的检测方法，用于鉴定/定量一种针对NSCLC患者的新型/选择性诊断生物标志物——半胱天冬酶-4。该检测方法通过以下方式进行验证：i）使用125例NSCLC患者和79名健康（非患病）受试者的血浆；ii）139名吸烟者的血浆；iii）70例慢性阻塞性肺疾病（COPD）患者的血浆。与10个非肿瘤肺组织（即肺结核组织）相比，还对98例配对NSCLC患者的肺肿瘤组织中的半胱天冬酶-4进行了定量评估。在健康受试者和NSCLC患者中均检测到循环中的半胱天冬酶-4；然而其范围值不同：NSCLC患者为2.603 - 3.372 ng/ml（95%置信区间），而健康受试者为0.3994 - 0.6219 ng/ml（95%置信区间）。该检测方法的灵敏度范围为97.07%至100%；特异性为88.1%，阳性预测值为92.54%，准确度为95.19%，曲线下面积（AUC）为0.971。吸烟者（95%置信区间，0.3947 - 0.6197 ng/ml）和COPD患者（95%置信区间，1.703 - 2.995 ng/ml）的循环半胱天冬酶-4水平处于中间值。肿瘤组织中的半胱天冬酶-4组织水平显示，99例患者中有72例（72.7%）呈阳性。更重要的是，与半胱天冬酶-4水平较低的NSCLC患者（中位数为3.02年）相比，肿瘤组织中半胱天冬酶-4水平较高（临界值 = 0.307 ng/ml）与总生存期缩短（中位数为0.92年）相关。我们首次报道半胱天冬酶-4是一种新型的诊断和预后生物标志物，为NSCLC患者开辟了新的治疗前景。
