Enhanced Expression of IGFBP-3 Reduces Radiosensitivity and Is Associated with Poor Prognosis in Oral Squamous Cell Carcinoma
Enhanced Expression of IGFBP-3 Reduces Radiosensitivity and Is Associated with Poor Prognosis in Oral Squamous Cell Carcinoma
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DOI：
10.3390/cancers12020494
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发表时间：
2020-02
期刊：
影响因子：
5.2
通讯作者：
J. Sakata;A. Hirosue;R. Yoshida;Y. Matsuoka;K. Kawahara;H. Arita;H. Nakashima;Tatsuro Yamamoto;M. Nagata;Sho Kawaguchi;Shunsuke Gohara;Yuka Nagao;K. Yamana;R. Toya;R. Murakami;Y. Kuwahara;M. Fukumoto;H. Nakayama
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文献类型：
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作者：
J. Sakata;A. Hirosue;R. Yoshida;Y. Matsuoka;K. Kawahara;H. Arita;H. Nakashima;Tatsuro Yamamoto;M. Nagata;Sho Kawaguchi;Shunsuke Gohara;Yuka Nagao;K. Yamana;R. Toya;R. Murakami;Y. Kuwahara;M. Fukumoto;H. Nakayama
胰岛素样生长因子（IGF）结合蛋白-3（IGFBP-3）通过IGF依赖性或非依赖性机制调节多种细胞功能。然而，其在口腔鳞状细胞癌（OSCC）放射敏感性中的生物学作用仍不清楚。本研究旨在探讨IGFBP-3与口腔鳞癌放射敏感性关系的临床意义和分子机制。我们对52例接受术前放化疗和手术治疗的口腔鳞状细胞癌标本进行了IGFBP-3的免疫组化分析（II期研究）。IGFBP-3表达与临床病理特征之间的关系也进行了评估。此外，我们研究了IGFBP-3对X射线照射后的辐射敏感性和DNA损伤的影响。IGFBP-3高表达与放化疗疗效及预后不良显著相关。IGFBP-3基因敲低后，照射后的口腔鳞癌细胞对放射的敏感性明显高于对照组。此外，IGFBP-3在OSCC细胞中的耗竭减少了DNA依赖性蛋白激酶催化亚基（DNA-PKcs）的磷酸化，这是非同源末端连接期间DNA双链断裂修复所需的。IGFBP-3可能在调控DNA修复中发挥重要作用，并可能成为预测口腔鳞癌放疗疗效和预后的潜在生物标志物。
Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) modulates various cell functions through IGF-dependent or independent mechanisms. However, its biological roles in the radiosensitivity of oral squamous cell carcinoma (OSCC) remain largely unknown. The purpose of this study was to determine the clinical significance and molecular mechanisms of the association between IGFBP-3 and OSCC radiosensitivity. We performed an immunohistochemical analysis of IGFBP-3 in 52 OSCC specimens from patients treated with preoperative chemoradiotherapy and surgery (phase II study). Associations between IGFBP-3 expression and clinicopathological features were also evaluated. In addition, we examined the effects of IGFBP-3 on post-X-ray irradiation radiosensitivity and DNA damage in vitro. High IGFBP-3 expression was significantly correlated with poor chemoradiotherapy responses and prognosis. With IGFBP-3 knockdown, irradiated OSCC cells exhibited significantly higher radiosensitivity compared with that of control cells. Moreover, IGFBP-3 depletion in OSCC cells reduced phosphorylation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which is required for DNA double-strand break repair during non-homologous end joining. These findings indicate that IGFBP-3 may have a significant role in regulating DNA repair and is be a potential biomarker for predicting clinical response to radiotherapy and prognosis in OSCC.