EGFR confers radioresistance in human oropharyngeal carcinoma by activating endoplasmic reticulum stress signaling PERK-eIF2α-GRP94 and IRE1α-XBP1-GRP78
EGFR confers radioresistance in human oropharyngeal carcinoma by activating endoplasmic reticulum stress signaling PERK-eIF2α-GRP94 and IRE1α-XBP1-GRP78
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DOI：
10.1002/cam4.1862
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发表时间：
2018-12-01
期刊：
影响因子：
4
通讯作者：
Qiao, Qiao
中科院分区：
文献类型：
--
作者：
Zhang, Miao;Han, Ning;Qiao, Qiao
恶性肿瘤中表皮生长因子受体（EGFR）的激活与放射耐药有关。具体来说，辐射可以破坏内质网（ER）的稳态，诱发内质网应激（ERS）。然而，egfr介导的ERS信号通路调控对放射敏感性的影响尚未见报道。本研究表明，沉默EGFR可通过抑制内质网应激信号（PERK-eIF2 α - grp94和IRE1 α - xbp1 - grp78）增加放射敏感和放射耐药口咽鳞状细胞癌（OSCC）细胞的放射敏感性。然而，用EGF预处理可以消除这种效应。此外，在OSCC细胞中，EGFR的下调抑制了DNA双断裂修复和自噬，同时增加了辐射诱导的细胞凋亡。相反，激活ERS会抑制上述功能。此外，在OSCC细胞辐照下，EGF增加了内质网应激无关的ERK和AKT信号。80例OSCC患者组织样本的免疫组化分析显示，EGFR和PERK的共同表达与预后不良有关。因此，EGFR似乎通过激活内质网应激信号而赋予OSCC的辐射抗性。这些结果提示，在无应答口咽癌患者中，通过抑制PERK-eIF2 α - grp94和IRE1 α - grp78，可以进一步提高放疗与egfr靶向抑制剂治疗的协同效果。
The activation of epidermal growth factor receptor (EGFR) is associated with radioresistance in malignant tumors. Specifically, radiation can destroy endoplasmic reticulum (ER) homeostasis to induce ER stress (ERS). However, the effect of EGFR-mediated regulation of ERS signaling pathway on radiosensitivity has not yet been reported. The present study showed that silencing EGFR increased radiosensitivity of both radiosensitive and radioresistant oropharyngeal squamous cell carcinoma (OSCC) cells by inhibiting ER stress signaling (PERK-eIF2 alpha-GRP94 and IRE1 alpha-XBP1-GRP78). This effect was abolished by pretreatment with EGF, however. In addition, knockdown of EGFR in OSCC cells inhibited DNA double-stand break repair and autophagy while increased radiation-induced apoptosis. Conversely, activating ERS inhibited the aforementioned functions. Furthermore, EGF increased ER stress-independent ERK and AKT signaling upon irradiation of OSCC cells. Immunohistochemical analysis of 80 tissue samples from OSCC patients showed that co-expression of EGFR and PERK was associated with poor prognosis. It thus appears EGFR confers radioresistance in OSCC by activating ER stress signaling. These results suggested that the cooperative effects of radiotherapy and EGFR-targeted inhibitor therapy can be further improved by inhibiting PERK-eIF2 alpha-GRP94 and IRE1 alpha-GRP78 in non-response oropharyngeal carcinoma patients.