Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.
PLoS One. 2012;7(6):e38737. doi: 10.1371/journal.pone.0038737. Epub 2012 Jun 13.
Tumor cells acquire the capacity of resistance to chemotherapy or radiotherapy via cell-matrix and cell-cell crosstalk. Integrins are the most important cell adhesion molecules, in which αV integrin mainly mediating the tight contact between tumor cells.
METHODOLOGY/PRINCIPAL FINDINGS: To investigate the role of αV integrin in multi-cellular radioresistance (MCR) of human nasopharyngeal carcinoma (NPC), we performed immunohistochemistry and Western blotting to find that the expression of αV integrin in the tumor tissue of radioresistant patients is much higher than that in radiosensitive patients. In vitro, we cultured human NPC cell line CNE-2 cells as multi-cellular spheroids (MCSs) or as monolayer cells (MCs), and found that the expression of αV integrin in MCSs is significantly higher than that in MCs. MTT, flow cytometry and clonogenic survival assays showed that MCSs are less sensitive to X-ray irradiation than MCs while blocking of αV integrin in MCSs dramatically reversed their radioresistance. Furthermore, as detected by Western blotting, MCSs displayed sustained activation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway in presence of irradiation. Blocking of αV integrin in MCSs decreased the expression of phosphorylated JNK. Additionally, blocking of SAPK/JNK signaling pathway synergistically induced apoptosis of MCSs exposed to irradiation by increasing the expression of cleaved caspase-3. In vivo, we found that irradiation combined with αV integrin blocking treatment significantly enhanced the radiosensitivity of NPC xenografts.
Our results indicate a novel role of αV integrin in multi-cellular radioresistance of NPCs.
肿瘤细胞通过细胞基质和细胞-细胞通讯获得对化疗或放疗的耐药性。整合素是最重要的细胞黏附分子，其中αV 整合素主要介导肿瘤细胞之间的紧密接触。
方法/主要发现：为了研究αV 整合素在人鼻咽癌（NPC）多细胞放射抵抗（MCR）中的作用，我们通过免疫组织化学和 Western blot 发现，放射抵抗患者肿瘤组织中αV 整合素的表达明显高于放射敏感患者。在体外，我们培养人 NPC 细胞系 CNE-2 细胞作为多细胞球体（MCS）或单层细胞（MCs），发现 MCS 中αV 整合素的表达明显高于 MCs。MTT、流式细胞术和集落形成存活分析表明，MCS 对 X 射线照射的敏感性低于 MCs，而阻断 MCS 中的αV 整合素则显著逆转其放射抵抗性。此外，Western blot 检测显示，在照射存在的情况下，MCS 中应激激活蛋白激酶/c-Jun NH2-末端激酶（SAPK/JNK）通路持续激活。在 MCS 中阻断αV 整合素可降低磷酸化 JNK 的表达。此外，阻断 SAPK/JNK 信号通路可通过增加裂解的 caspase-3 的表达，协同诱导暴露于照射下的 MCS 凋亡。在体内，我们发现照射联合αV 整合素阻断治疗显著增强了 NPC 异种移植物的放射敏感性。
我们的结果表明αV 整合素在 NPC 的多细胞放射抵抗中发挥了新的作用。
