Unveiling the role of hypoxic macrophage-derived exosomes in driving colorectal cancer progression.
Unveiling the role of hypoxic macrophage-derived exosomes in driving colorectal cancer progression.
复制标题
DOI：
10.3389/fimmu.2023.1260638
复制
发表时间：
2023
影响因子：
7.3
通讯作者：
Zhang, Huan
中科院分区：
文献类型：
--
作者：
Jiang, Jiang;Wang, Wenfang;Zhu, Lan;Shi, Bowen;Chen, Yong;Xia, Yihan;Feng, Weiming;Yao, Weiwu;Lu, Aiguo;Zhang, Huan
肿瘤细胞和巨噬细胞在低氧条件下的相互作用是大肠癌发生发展的关键因素。先前的研究已经强调了来源于缺氧肿瘤细胞的外泌体通过诱导巨噬细胞向M2样表型极化来促进肿瘤进展的重要性。低氧巨噬细胞源性外泌体（HMDE）对CRC进展的确切影响尚未完全阐明。本研究的目的是研究HMDE在CRC进展中的作用。我们发现，在缺氧条件下，来自巨噬细胞的外泌体的释放增加。此外，缺氧诱导的巨噬细胞来源的exosomes在促进CRC的进展中起着至关重要的作用。我们还证明了HMDE具有诱导细胞周期转换和抑制细胞凋亡的能力，从而促进CRC细胞的生长。此外，这些影响的潜在分子机制已被确定。HIF-1α的过表达导致其在缺氧环境中与Hsp 90启动子的不同区域（-521--516 bp和-401--391 bp）直接相互作用。该结合事件导致HMDE内Hsp 90的过表达和随后Hsp 90蛋白水平的升高。重要的是，Hsp 90和Lats 1之间的关键相互作用导致Lats 1的失活和雅普磷酸化的抑制。最终，这一系列事件导致Hippo信号通路的失活。我们的体内和体外研究提供了令人信服的证据，证明缺氧巨噬细胞来源的外泌体Hsp 90通过抑制Hippo信号通路在促进CRC进展中的关键作用。这些发现代表了我们对缺氧条件下巨噬细胞和CRC细胞之间复杂相互作用的理解的重大进展。
The crosstalk between tumor cells and macrophages under hypoxic conditions has been acknowledged as a pivotal determinant in the progression of colorectal cancer (CRC). Previous research has underscored the significance of exosomes derived from hypoxic tumor cells in facilitating tumor progression through inducing the polarization of macrophages towards the M2-like phenotype. The precise influence of hypoxic macrophage-derived exosomes (HMDEs) on the progression of CRC has not yet been fully elucidated. The objective of this study was to investigate the role of HMDEs in the progression of CRC. We discovered that there was an elevated release of exosomes derived from macrophages in hypoxic conditions. Additionally, the hypoxia-induced macrophage-derived exosomes played a crucial role in promoting the progression of CRC. We have also demonstrated that HMDEs have the ability to induce cell cycle transition and inhibit cell apoptosis, thereby promoting the growth of CRC cells. Furthermore, the underlying molecular mechanisms of these effects have been identified. The overexpression of Hif-1α results in its direct interaction with distinct regions (-521− -516 bp and -401− -391 bp) of the Hsp90 promoter during hypoxic circumstances. This binding event led to the overexpression of Hsp90 and the subsequent elevation of Hsp90 protein levels within HMDEs. Importantly, the crucial interaction between Hsp90 and Lats1 resulted in the deactivation of Lats1 and the inhibition of Yap phosphorylation. Ultimately, this series of events lead to the deactivation of the Hippo signaling pathway. Our in vivo and in vitro studies presented compelling evidence for the crucial role of hypoxic macrophage-derived exosomal Hsp90 in promoting CRC progression through the inhibition of the Hippo signaling pathway. These findings represented a significant advancement in our comprehension of the complex interplay between macrophages and CRC cells under hypoxic conditions.
登录
查看更多内容
缺氧通过骨膜素促进神经胶质瘤相关巨噬细胞浸润，并通过上调 TGF-β 和 M-CSFR 促进随后的 M2 极化
影响因子：
--
作者：
Guo X;Xue H;Shao Q;Wang J;Guo X;Chen X;Zhang J;Xu S;Li T;Zhang P;Gao X;Qiu W;Liu Q;Li G
通讯作者：
Li G
影响因子：
5.6
作者：
Hoter A;El-Sabban ME;Naim HY
通讯作者：
Naim HY
影响因子：
5
作者：
Chen, JX;Meyrick, B
通讯作者：
Meyrick, B
影响因子：
7.4
作者：
Jin, Guohua;Zhang, Jianguang;Cao, Tingting;Chen, Bang;Tian, Yu;Shi, Yang
通讯作者：
Shi, Yang
影响因子：
5.6
作者：
Birbo B;Madu EE;Madu CO;Jain A;Lu Y
通讯作者：
Lu Y