Rab27b contributes to radioresistance and exerts a paracrine effect via epiregulin in glioblastoma.
Rab27b contributes to radioresistance and exerts a paracrine effect via epiregulin in glioblastoma.
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DOI：
10.1093/noajnl/vdaa091
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发表时间：
2020-01
期刊：
影响因子：
--
通讯作者：
Nam JM
中科院分区：
文献类型：
--
作者：
Nishioka S;Wu PH;Yakabe T;Giaccia AJ;Le QT;Aoyama H;Shimizu S;Shirato H;Onodera Y;Nam JM
放射治疗是胶质母细胞瘤的标准治疗方法。然而，GBM细胞的放射抵抗会导致复发和患者预后不良。最近的研究表明，分泌因子在肿瘤细胞的辐射抵抗中起着重要作用。本研究旨在确定与分泌囊泡运输有关的小GTP酶Rab27b是否在GBM的辐射抗性中发挥作用。通过基因芯片分析、细胞存活率分析、细胞凋亡率测定、免疫组织化学染色和体内实验等方法研究Rab27b对GBM辐射抗性的影响。我们利用胶质瘤细胞系的共培养系统进一步研究了X射线照射后Rab27b介导的旁分泌效应。在照射后的U87 MG细胞中，Rab27b被特异性上调。此外，Rab27b基因敲除可抑制照射后GBM细胞的增殖。在U87 MG细胞中敲除Rab27b结合放射治疗可抑制小鼠脑内原位肿瘤的生长，延长受体小鼠的存活时间。有趣的是，Rab27b和表皮生长因子(EGF)家族成员Ereg的共同上调与胶质瘤细胞系的辐射抗性有关。此外，由U87 MG细胞分泌的Ereg通过Rab27b介导的机制激活EGF受体，并以旁分泌的方式促进H4细胞的增殖。我们的结果表明，Rab27b介导了高度恶性的GBM细胞的辐射抗性。Rab27b通过ERG介导的旁分泌信号促进辐射后相邻细胞的增殖。因此，Rab27b-Ereg通路是提高GBM放疗疗效的一个新的潜在靶点。
Radiotherapy is the standard treatment for glioblastoma (GBM). However, radioresistance of GBM cells leads to recurrence and poor patient prognosis. Recent studies suggest that secretion factors have important roles in radioresistance of tumor cells. This study aims to determine whether Rab27b, a small GTPase involved in secretory vesicle trafficking, plays a role in radioresistance of GBM. Microarray analysis, cell viability analysis, apoptosis assay, immunostaining, and in vivo experiments were performed to assess the effect of Rab27b on radioresistance of GBM. We further investigated paracrine effects mediated by Rab27b after X-ray irradiation using coculture systems of glioma cell lines. Rab27b was specifically upregulated in irradiated U87MG cells. Furthermore, Rab27b knockdown decreased the proliferation of GBM cells after irradiation. Knockdown of Rab27b in U87MG cells combined with radiation treatment suppressed orthotopic tumor growth in the mouse brain and prolonged the survival of recipient mice. Interestingly, the co-upregulation of Rab27b and epiregulin (EREG), a member of the epidermal growth factor (EGF) family, correlated with radioresistance in glioma cell lines. Additionally, EREG, which was secreted from U87MG cells via Rab27b-mediated mechanism, activated EGF receptor and contributed to H4 cell proliferation in a paracrine manner. Our results show that Rab27b mediates the radioresistance of highly malignant GBM cells. Rab27b promotes the proliferation of adjacent cells through EREG-mediated paracrine signaling after irradiation. Thus, the Rab27b-EREG pathway is a novel potential target to improve the efficacy of radiotherapy in GBM.
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影响因子：
5.6
作者：
Jabbari, Nasrollah;Nawaz, Muhammad;Rezaie, Jafar
通讯作者：
Rezaie, Jafar
DOI：
10.1016/j.ijrobp.2013.11.215
发表时间：
2014-03-01
影响因子：
7
作者：
Aravindan, Natarajan;Aravindan, Sheeja;Pandian, Vijayabaskar;Khan, Faizan H.;Ramraj, Satish Kumar;Natt, Praveen;Natarajan, Mohan
通讯作者：
Natarajan, Mohan
影响因子：
7.4
作者：
Nam, Jin-Min;Ahmed, Kazi M.;Park, Catherine C.
通讯作者：
Park, Catherine C.
影响因子：
15.9
作者：
Barral, DC;Ramalho, JS;Seabra, MC
通讯作者：
Seabra, MC
影响因子：
16.6
作者：
Onodera Y;Nam JM;Horikawa M;Shirato H;Sabe H
通讯作者：
Sabe H