Department of Otolaryngology, Zhongshan Hospital, Fudan University, Shanghai, China.
Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
Cell Death Dis. 2022 Feb 24;13(2):183. doi: 10.1038/s41419-022-04640-z.
Exosomes serve as a crucial mode of communication between tumor-associated macrophages (TAMs) and cancer cells. This study attempted to explore the function of M1-derived exosomes and clarify their specific mechanism in head and neck squamous cell carcinoma (HNSCC). Moreover, the functional roles of M1-derived exosomes and their key molecule long noncoding RNA (lncRNA) HOXA transcript at the distal tip (HOTTIP) in HNSCC were investigated by conducting a series of in vitro and in vivo experiments. The dual-luciferase test was utilized to clarify the binding capacities between HOTTIP/mRNA and miRNAs. Accordingly, HOTTIP was found to be upregulated in M1-derived exosomes. Meanwhile, the in vitro experiments indicated that M1 exosomes suppressed proliferation, migration and invasion but induced apoptosis of cancer cells. This function was noted to be enhanced by HOTTIP-overexpressed M1 exosomes but was weakened by HOTTIP-knockdown ones, indicating that HOTTIP serves as a key molecule in M1 exosomes. Therefore, the function of HOTTIP in cancer cells was explored, for which overexpression of HOTTIP was found to inhibit proliferation, migration and invasion but induced apoptosis of cancer cells in vitro. A mechanism study further showed that M1 exosomes and HOTTIP activated the TLR5/NF-κB signaling pathway by competitively sponging miR-19a-3p and miR-19b-3p. Furthermore, cancer cells expressing HOTTIP were noted to induce the polarization of both local M1 and M2 macrophages; however, M1 exosomes were observed to reprogram local TAMs into M1 macrophages. More importantly, both cancer cells expressing HOTTIP and M1 exosomes reeducated circulating monocytes to express the M1 phenotype. The corresponding data demonstrated that the M1 exosomal lncRNA HOTTIP suppresses HNSCC progression by upregulating the TLR5/NF-κB signaling pathway through competitively sponging miR-19a-3p and miR-19b-3p. In particular, M1 exosomes and HOTTIP induce the polarization of M1 in circulating monocytes, thus providing novel insight into HNSCC immunotherapy.
外泌体在肿瘤相关巨噬细胞（TAMs）与癌细胞之间的通讯中起着至关重要的作用。本研究试图探讨 M1 衍生的外泌体的功能，并阐明其在头颈部鳞状细胞癌（HNSCC）中的特定机制。此外，通过一系列体外和体内实验研究了 M1 衍生的外泌体及其关键分子长链非编码 RNA（lncRNA）HOXA 转录远端起始点（HOTTIP）在 HNSCC 中的功能作用。双荧光素酶试验用于阐明 HOTTIP/mRNA 和 miRNAs 之间的结合能力。结果表明，HOTTIP 在 M1 衍生的外泌体中上调。同时，体外实验表明，M1 外泌体抑制癌细胞的增殖、迁移和侵袭，但诱导癌细胞凋亡。这种功能通过过表达 HOTTIP 的 M1 外泌体增强，但通过敲低 HOTTIP 的 M1 外泌体减弱，表明 HOTTIP 是 M1 外泌体的关键分子。因此，研究了 HOTTIP 在癌细胞中的功能，发现过表达 HOTTIP 可抑制癌细胞的增殖、迁移和侵袭，但诱导其凋亡。机制研究进一步表明，M1 外泌体和 HOTTIP 通过竞争性海绵吸附 miR-19a-3p 和 miR-19b-3p 激活 TLR5/NF-κB 信号通路。此外，表达 HOTTIP 的癌细胞被发现可诱导局部 M1 和 M2 巨噬细胞的极化；然而，M1 外泌体可将局部 TAMs 重编程为 M1 巨噬细胞。更重要的是，表达 HOTTIP 的癌细胞和 M1 外泌体可将循环单核细胞重新编程为表达 M1 表型。相应的数据表明，M1 外泌体 lncRNA HOTTIP 通过竞争性海绵吸附 miR-19a-3p 和 miR-19b-3p 上调 TLR5/NF-κB 信号通路，从而抑制 HNSCC 进展。特别是，M1 外泌体和 HOTTIP 诱导循环单核细胞中 M1 的极化，从而为 HNSCC 免疫治疗提供了新的思路。
