Le Quynh-Thu, Shi Gongyi, Cao Hongbin, Nelson Daniel W, Wang Yingyun, Chen Eunice Y, Zhao Shuchun, Kong Christina, Richardson Donna, O'Byrne Ken J, Giaccia Amato J, Koong Albert C
Department of Radiation Oncology, Stanford University Medical Center, 875 Blake Wilbur Drive, Stanford, CA 94305-5847, USA.
J Clin Oncol. 2005 Dec 10;23(35):8932-41. doi: 10.1200/JCO.2005.02.0206. Epub 2005 Oct 11.
To identify a 15-KDa novel hypoxia-induced secreted protein in head and neck squamous cell carcinomas (HNSCC) and to determine its role in malignant progression.
We used surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS) and tandem MS to identify a novel hypoxia-induced secreted protein in FaDu cells. We used immunoblots, real-time polymerase chain reaction (PCR), and enzyme-linked immunoabsorbent assay to confirm the hypoxic induction of this secreted protein as galectin-1 in cell lines and xenografts. We stained tumor tissues from 101 HNSCC patients for galectin-1, CA IX (carbonic anhydrase IX, a hypoxia marker) and CD3 (a T-cell marker). Expression of these markers was correlated to each other and to treatment outcomes.
SELDI-TOF studies yielded a hypoxia-induced peak at 15 kDa that proved to be galectin-1 by MS analysis. Immunoblots and PCR studies confirmed increased galectin-1 expression by hypoxia in several cancer cell lines. Plasma levels of galectin-1 were higher in tumor-bearing severe combined immunodeficiency (SCID) mice breathing 10% O2 compared with mice breathing room air. In HNSCC patients, there was a significant correlation between galectin-1 and CA IX staining (P = .01) and a strong inverse correlation between galectin-1 and CD3 staining (P = .01). Expression of galectin-1 and CD3 were significant predictors for overall survival on multivariate analysis.
Galectin-1 is a novel hypoxia-regulated protein and a prognostic marker in HNSCC. This study presents a new mechanism on how hypoxia can affect the malignant progression and therapeutic response of solid tumors by regulating the secretion of proteins that modulate immune privilege.
鉴定头颈部鳞状细胞癌（HNSCC）中一种新的15 kDa缺氧诱导分泌蛋白，并确定其在恶性进展中的作用。
我们使用表面增强激光解吸电离飞行时间质谱（SELDI-TOF-MS）和串联质谱来鉴定FaDu细胞中一种新的缺氧诱导分泌蛋白。我们使用免疫印迹、实时聚合酶链反应（PCR）和酶联免疫吸附测定来证实该分泌蛋白在细胞系和异种移植中作为半乳糖凝集素-1的缺氧诱导。我们对101例HNSCC患者的肿瘤组织进行半乳糖凝集素-1、CA IX（碳酸酐酶IX，一种缺氧标志物）和CD3（一种T细胞标志物）染色。这些标志物的表达相互关联，并与治疗结果相关。
SELDI-TOF研究在15 kDa处产生了一个缺氧诱导峰，经质谱分析证明是半乳糖凝集素-1。免疫印迹和PCR研究证实了几种癌细胞系中缺氧导致半乳糖凝集素-1表达增加。与呼吸室内空气的小鼠相比，呼吸10%氧气的荷瘤严重联合免疫缺陷（SCID）小鼠血浆中半乳糖凝集素-1水平更高。在HNSCC患者中，半乳糖凝集素-1与CA IX染色之间存在显著相关性（P = 0.01），半乳糖凝集素-1与CD3染色之间存在强烈负相关性（P = 0.01）。在多变量分析中，半乳糖凝集素-1和CD3的表达是总生存的显著预测指标。
半乳糖凝集素-1是一种新的缺氧调节蛋白，也是HNSCC中的一种预后标志物。本研究提出了一种新机制，即缺氧如何通过调节调节免疫特权的蛋白质分泌来影响实体瘤的恶性进展和治疗反应。
