Glioblastoma Cell-Derived lncRNA-Containing Exosomes Induce Microglia to Produce Complement C5, Promoting Chemotherapy Resistance
Glioblastoma Cell-Derived lncRNA-Containing Exosomes Induce Microglia to Produce Complement C5, Promoting Chemotherapy Resistance
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胶质母细胞瘤细胞来源的含 lncRNA 的外泌体诱导小胶质细胞产生补体 C5，促进化疗耐药
DOI：
10.1158/2326-6066.cir-21-0258
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发表时间：
2021-12-01
影响因子：
10.1
通讯作者：
Cai, Jinquan
中科院分区：
文献类型：
--
作者：
Li, Ziwei;Meng, Xiangqi;Cai, Jinquan
胶质母细胞瘤（GBM）是成人中最常见的恶性原发性脑癌，几乎总是对目前的治疗产生耐药性，包括化疗药物替莫唑胺（TMZ）。GBM复发中TMZ相关的长非编码RNA（lncRNA）（lnc-TALC）促进GBM对TMZ的抗性。外泌体可以将生化货物释放到肿瘤微环境（TME）中，或将其内容物（包括lncRNA）作为细胞间通讯的一种形式转移到其他细胞中。在这项研究中，我们发现lnc-TALC可以掺入外泌体并传递到肿瘤相关巨噬细胞（TAM），并可以促进小胶质细胞的M2极化。这种M2极化与补体成分C5/C5 a的分泌相关，其发生在lnc-TALC与ENO 1结合以促进p38 MAPK磷酸化的下游。此外，C5促进TMZ诱导的DNA损伤的修复，导致化疗抗性，并且C5 a靶向免疫疗法显示出改善的功效，限制了lnc-TALC介导的TMZ抗性。我们的研究结果表明，外泌体传递的lnc-TALC可以重塑GBM微环境并降低肿瘤对TMZ化疗的敏感性，表明GBM细胞和小胶质细胞之间的lnc-TALC介导的串扰可以减弱化疗疗效，并指出潜在的联合治疗策略来克服GBM中的TMZ抗性。
Glioblastoma (GBM), the most common malignant primary brain cancer in adults, nearly always becomes resistant to current treatments, including the chemotherapeutic temozolomide (TMZ). The long noncoding RNA (lncRNA) TMZ-associated lncRNA in GBM recurrence (lnc-TALC) promotes GBM resistance to TMZ. Exosomes can release biochemical cargo into the tumor microenvironment (TME) or transfer their contents, induding lncRNAs, to other cells as a form of intercellular communication. In this study, we found that lnc-TALC could be incorporated into exosomes and transmitted to tumor-associated macrophages (TAM) and could promote M2 polarization of the microglia. This M2 polarization correlated with secretion of the complement components C5/C5a, which occurred downstream of lnc-TALC binding to ENO1 to promote the phosphorylation of p38 MAPK. In addition, C5 promoted the repair of TMZ-induced DNA damage, leading to chemotherapy resistance, and C5a-targeted immunotherapy showed improved efficacy that limited lnc-TALC-mediated TMZ resistance. Our results reveal that exosome-transmitted lnc-TALC could remodel the GBM microenvironment and reduce tumor sensitivity to TMZ chemotherapy, indicating that the lnc-TALC-mediated cross-talk between GBM cells and microglia could attenuate chemotherapy efficacy and pointing to potential combination therapy strategies to overcome TMZ resistance in GBM.