Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
The Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan; Center for General Education, Cheng-Shiu University, Kaohsiung, Taiwan.
Oral Oncol. 2018 Nov;86:141-149. doi: 10.1016/j.oraloncology.2018.09.015. Epub 2018 Sep 25.
Over the last decades, significant advances in targeted therapies have helped provide more effective treatment for head and neck cancer patients. However, chemo-resistance to cisplatin significantly contributes to treatment failure in the clinical management of patients. In response to chemotherapeutic agents, certain molecules inside the cell are released or secreted from damaged or dead/dying cells, named damage-associated molecular patterns (DAMPs), thereby initiating an immune response through interaction with pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs). In present study, we investigated the link between cisplatin-induced DAMPs and TLR3 signaling. We found that cisplatin could be a potential activator of TLR3 and cisplatin treatment results in activation of PRRs' signaling and down-stream associated cytokine/chemokine, IFNβ, and CCL5 in TLR3 OC2 cells, but not in TLR3 FaDu cells. Furthermore, knockdown of the TLR3 gene attenuates the expression of IFNβ and CCL5 mRNA and enhances the cytotoxicity of cisplatin in TLR3 OC2 cells. To determine whether TLR3 status affects the stress response of OC2 cells to cisplatin, we generated TLR3 knockdown OC2 cells (psi-TLR3 cells) with a psiRNA-hTLR3 plasmid containing shRNA to TLR3 and control OC2 cells (psi-NT cells) expressing non-silencing shRNA. OC2 cells were more sensitive to cisplatin treatment after TLR3 knockdown. In our animal model, OC2 psi-NT cells were more tumorigenic than were OC2 psi-TLR3 cells. Together, our in vitro and in vivo data imply TLR3 may contribute to tumor development and protect cisplatin-induced DNA damage response leading to cisplatin resistance in head and neck cancer cells.
在过去的几十年中，靶向治疗的重大进展帮助为头颈部癌症患者提供了更有效的治疗。然而，顺铂的化疗耐药性显著导致了患者临床治疗的失败。作为对化疗药物的反应，细胞内的某些分子从受损或死亡/凋亡的细胞中释放或分泌出来，被称为损伤相关分子模式（DAMPs），从而通过与模式识别受体（PRRs）相互作用引发免疫反应，如 Toll 样受体（TLRs）。在本研究中，我们研究了顺铂诱导的 DAMPs 与 TLR3 信号之间的联系。我们发现，顺铂可能是 TLR3 的潜在激活剂，顺铂处理导致 TLR3 OC2 细胞中 PRRs 信号及其下游相关细胞因子/趋化因子 IFNβ和 CCL5 的激活，但在 TLR3 FaDu 细胞中则没有。此外，TLR3 基因的敲低减弱了 IFNβ和 CCL5 mRNA 的表达，并增强了 TLR3 OC2 细胞中顺铂的细胞毒性。为了确定 TLR3 状态是否影响 OC2 细胞对顺铂的应激反应，我们用含有 TLR3 shRNA 的 psiRNA-hTLR3 质粒生成了 TLR3 敲低 OC2 细胞（psi-TLR3 细胞）和表达非沉默 shRNA 的对照 OC2 细胞（psi-NT 细胞）。TLR3 敲低后，OC2 细胞对顺铂处理更加敏感。在我们的动物模型中，与 OC2 psi-TLR3 细胞相比，OC2 psi-NT 细胞的致瘤性更强。总之，我们的体外和体内数据表明，TLR3 可能有助于肿瘤的发展，并保护顺铂诱导的 DNA 损伤反应，导致头颈部癌细胞对顺铂产生耐药性。
