ABSTRACT

Mucin 1 (MUC1), a transmembrane glycoprotein, has shown to be as the possible prognostic marker to predict the risk of aggressive head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated the effect of MUC1 in HNSCC cells and the response to X-ray irradiation (IR). Here, we examined the impact of MUC1 overexpression or downexpression on clonogenic survival and apoptosis in response to X-ray irradiation (IR). Radioresistance and radiosensitivity were also observed in HNSCC cells that are MUC1 overexpression and MUC1 downexpression. This enhanced resistance to IR in MUC1-overexpressing cells is primarily due to increased the number of radiation-induced γH2AX/53BP1-positive foci and DNA double-strand break (DSB) repair kinetics. MUC1 overexpression repaired more than 90% of DSBs after 2 Gy radiation by 24 h compared to the empty vector overexpressing cells with less than 50% of DSB repair. However, MUC1 downexpression repaired less than 20% of DSBs compared to the empty vector-overexpresing cells. MUC1 overexpression inhibited proapoptotic protein expression, such as caspase-3, caspase-8, and caspase-9, and induced antiapoptotic protein Bcl-2, followed by resistance to IR-induced apoptosis. Our results showed that targeting MUC1 may be as a promising strategy to counteract radiation resistance of HNSCC cells.

摘要

粘蛋白 1 (MUC1) 是一种跨膜糖蛋白，已被证明是预测侵袭性头颈部鳞状细胞癌 (HNSCC) 风险的可能预后标志物。在本研究中，我们研究了 MUC1 在 HNSCC 细胞中的作用和对 X 射线照射 (IR) 的反应。在这里，我们检查了 MUC1 过表达或下调对 X 射线照射 (IR) 响应的克隆形成存活和细胞凋亡的影响。在 MUC1 过表达和 MUC1 过表达的 HNSCC 细胞中也观察到放射抗性和放射敏感性。这种在 MUC1 过表达细胞中增强的 IR 抗性主要是由于辐射诱导的 γH2AX/53BP1 阳性病灶和 DNA 双链断裂 (DSB) 修复动力学的数量增加。与空载体过表达细胞的 DSB 修复率低于 50% 相比，MUC1 过表达在 2 Gy 辐射后 24 小时修复了 90% 以上的 DSB。然而，与空载体过度表达的细胞相比，MUC1 下调修复了不到 20% 的 DSB。MUC1 过表达抑制促凋亡蛋白的表达，如 caspase-3、caspase-8 和 caspase-9，并诱导抗凋亡蛋白 Bcl-2，随后对 IR 诱导的细胞凋亡产生抗性。我们的结果表明，靶向 MUC1 可能是抵消 HNSCC 细胞辐射抗性的一种有前景的策略。caspase-8 和 caspase-9，并诱导抗凋亡蛋白 Bcl-2，随后对 IR 诱导的细胞凋亡产生抗性。我们的结果表明，靶向 MUC1 可能是抵消 HNSCC 细胞辐射抗性的一种有前景的策略。caspase-8 和 caspase-9，并诱导抗凋亡蛋白 Bcl-2，随后对 IR 诱导的细胞凋亡产生抗性。我们的结果表明，靶向 MUC1 可能是抵消 HNSCC 细胞辐射抗性的一种有前景的策略。