Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in head and neck. Platinum-based chemotherapy is an important treatment for NPC. However, the molecular mechanism of resistance to platinum drug remains unknown. Endoplasmic reticulum resident protein 44(ERp44), an unfolded protein response (UPR)-induced endoplasmic reticulum(ER) protein, is induced during ER stress. This research explored the mechanism of ERp44 in strengthening cisplatin resistance in NPC. Western blot and immunohistochemistry were used to investigate the expression of ERp44 and Glucose-Regulated Protein 78(GRP78) in NPC. We took CCK8 to detect the role of ERp44 on cell chemosensitivity. Flow cytometric analysis and western blot were taken to analyze cell apoptosis. We performed differential centrifugation to isolate exosomes from serum or conditioned media of cells and analyzed the impact of exosomal ERp44 on cells cisplatin sensitivity. Finally, the results were confirmed in vivo. We found the increased expression of ERp44 and GRP78 in NPC and ERp44 was highly expressed in ER-stressed tissues. Cell proliferation was inhibited after cisplatin treatment when ERp44 was knocked down and ERp44 strengthened cisplatin resistance by influencing cell apoptosis and pyroptosis. Then we also collected exosomes and cell viability was increased after the addition of NPC-derived-exosomes with cisplatin treatment. More importantly, our results showed under ERS, NPC cells secreted exosomes containing ERp44 and could transfer them to adjacent cells to strengthen chemoresistance. Our data suggested that exosomal ERp44 derived from ER-stressed NPC cells took an inevitable role in NPC chemoresistance and might act as a treatment target.

中文翻译：

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来自ER应激细胞的外泌体ERp44增强鼻咽癌的顺铂耐药性

鼻咽癌（NPC）是头颈部最常见的恶性肿瘤之一。铂类化疗是鼻咽癌的重要治疗方法。然而，铂类药物耐药的分子机制尚不清楚。内质网驻留蛋白 44(ERp44) 是一种未折叠蛋白反应 (UPR) 诱导的内质网 (ER) 蛋白，在 ER 应激期间被诱导。本研究探讨了 ERp44 增强 NPC 顺铂耐药性的机制。Western印迹和免疫组织化学用于研究ERp44和葡萄糖调节蛋白78（GRP78）在NPC中的表达。我们采用 CCK8 检测 ERp44 对细胞化学敏感性的作用。采用流式细胞术和蛋白质印迹分析细胞凋亡。我们进行差速离心以从细胞的血清或条件培养基中分离外泌体，并分析外泌体 ERp44 对细胞顺铂敏感性的影响。最后，结果在体内得到证实。我们发现 ERp44 和 GRP78 在 NPC 中的表达增加，并且 ERp44 在 ER 应激组织中高表达。当ERp44被敲低时，顺铂处理后细胞增殖受到抑制，ERp44通过影响细胞凋亡和细胞焦亡增强顺铂耐药性。然后我们还收集了外泌体，在添加 NPC 衍生的外泌体和顺铂处理后细胞活力增加。更重要的是，我们的结果显示在 ERS ​​下，NPC 细胞分泌含有 ERp44 的外泌体，并可以将它们转移到相邻细胞以增强化学抗性。