Altered O-glycosylation is associated with inherent radioresistance and malignancy of human laryngeal carcinoma
Altered O-glycosylation is associated with inherent radioresistance and malignancy of human laryngeal carcinoma
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O-糖基化改变与人类喉癌固有的放射抗性和恶性有关
DOI：
10.1016/j.yexcr.2017.11.031
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发表时间：
2018-01-15
影响因子：
3.7
通讯作者：
Shen, Li
中科院分区：
文献类型：
--
作者：
Dong, Xiaoxia;Luo, Zhiguo;Shen, Li
放射抗性（固有的或获得性的）仍然是影响喉癌放射治疗临床结果的主要障碍。我们实验室和其他小组的结果表明，异常的糖基化有助于癌症获得性放射抗性。然而，糖基化在喉癌固有放射抗性中的作用尚未完全揭示。在本研究中，我们使用凝集素微阵列分析研究了固有辐射抗性 (Hep-2max) 和辐射敏感 (Hep-2 min) 细胞系的聚糖分析。结果显示，抗辐射细胞系 Hep-2max 比敏感细胞系呈现出更高的核心 1 型 O-聚糖。对 Hep-2max 细胞中苄基-α-GalNAc 应用对 O-聚糖调节的进一步分析表明，O-聚糖生物合成受到部分抑制并增加了放射敏感性。此外，Hep-2 min 细胞中核心 1β1, 3-半乳糖基转移酶 (C1GALT1) 的过度表达增强了细胞迁移、侵袭和放射抗性。相反，在 Hep-2max 细胞中敲低 ClGALT1 能够抑制这些恶性表型。此外，机制研究表明 ClGALT1 修饰整合素 beta 1 上的 O-聚糖并调节其活性。糖基化介导的放射抗性被抗整合素β1阻断抗体进一步抑制。重要的是，我们还观察到核心1型O-聚糖的表达与喉癌患者的晚期肿瘤分期、转移和较差的生存率相关。这些发现表明，O-糖基化的改变可导致固有的放射抗性和进展，因此对于提高喉癌放射治疗的疗效可能很重要。
Radioresistance (inherent or acquired) remains a major obstacle affecting the clinical outcome of radiotherapy for laryngeal carcinoma. Results from our laboratory and other groups suggest that aberrant glycosylation contributes to cancer acquired radioresistance. However, the role of glycosylation in inherent radioresistance of laryngeal carcinoma has not been fully uncovered. In this study, we investigated the glycan profiling of the inherent radioresistant (Hep-2max) and radiosensitive (Hep-2 min) cell lines using lectin microarray analysis. The results revealed that the radioresistant cell line Hep-2max presented higher core 1-type O-glycans than the sensitive one. Further analysis of the O-glycan regulation by benzyl-alpha-GalNAc application in Hep-2max cells showed partial inhibition of the O-glycan biosynthesis and increased radiosensitivity. In addition, core 1 beta 1, 3-galactosyltransferase (C1GALT1) overexpression in Hep-2 min cells enhanced cell migration, invasion, and radioresistance. Conversely, knockdown of ClGALT1 in Hep-2max cells was able to suppress these malignant phenotypes. Moreover, mechanistic investigations showed that ClGALT1 modified the O-glycans on integrin beta 1 and regulated its activity. The glycosylation-mediated radioresistance was further inhibited by anti-integrin beta 1 blocking antibody. Importantly, we also observed that core 1-type O-glycans expression was correlated with advanced tumor stage, metastasis, and poor survival of laryngeal carcinoma patients. These findings suggest that altered O-glycosylation can lead to the inherent radioresistance and progression, and therefore may be important for enhancing the efficacy of radiotherapy in laryngeal carcinoma.