Reduced hyaluronan cross-linking induces breast cancer malignancy in a CAF-dependent manner.
Reduced hyaluronan cross-linking induces breast cancer malignancy in a CAF-dependent manner.
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透明质酸交联减少以 CAF 依赖性方式诱导乳腺癌恶性肿瘤
DOI：
10.1038/s41419-021-03875-6
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发表时间：
2021-06-07
影响因子：
9
通讯作者：
Gao F
中科院分区：
文献类型：
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作者：
Zhang G;He Y;Liu Y;Du Y;Yang C;Gao F
透明质酸（HA）交联是HA的一种构象状态，HA是HA与来自肿瘤坏死因子诱导蛋白6（TSG 6）介导的间-α-胰蛋白酶抑制剂（I-α-I）的重链（HC）之间的共价复合物。交联HA已被鉴定为生理和炎症条件下的保护因子。然而，肿瘤微环境中HA交联的状态尚未完全阐明。作为细胞外基质（ECM）的主要成分，HA主要由癌症相关成纤维细胞（CAF）合成。我们的研究旨在阐明HA交联在乳腺癌恶性肿瘤中的作用。与正常乳腺组织相比，交联HA水平在乳腺癌中显著降低，并与肿瘤恶性程度相关。当NFbs被激活成CAF时，交联的HA和TSG 6的水平都被抑制。通过上调TSG 6，CAFs恢复了高水平的交联HA，并显着抑制乳腺癌恶性肿瘤，而NFbs促进恶性肿瘤时，交联HA水平降低。此外，使用合成的HA-HC复合物直接验证了HA交联在肿瘤恶性中的抑制作用。总的来说，我们的研究发现，缺乏交联HA诱导乳腺癌恶性肿瘤的CAF依赖性的方式，这表明恢复HA交联可能是一个潜在的治疗策略。
Hyaluronan (HA) cross-linking is a conformational state of HA, a covalent complex between HA and heavy chains (HCs) from inter-α-trypsin inhibitor (I-α-I) mediated by tumor necrosis factor-induced protein 6 (TSG6). Cross-linked HA has been identified as a protective factor in physiological and inflammatory conditions. However, the state of HA cross-linking in tumor microenvironment has not been fully elucidated. As a major constituent of the extracellular matrix (ECM), HA is mainly synthesized by cancer-associated fibroblasts (CAFs). Our study aimed to clarify the role of HA cross-linking in breast cancer malignancy. Compared to normal mammary gland tissues, cross-linked HA levels were significantly decreased in breast cancer and associated with tumor malignancy. When NFbs were activated into CAFs, the levels of cross-linked HA and TSG6 were both suppressed. Through upregulating TSG6, CAFs restored the high level of cross-linked HA and significantly inhibited breast cancer malignancy, whereas NFbs promoted the malignancy when the cross-linked HA level was reduced. Furthermore, the inhibitory role of HA cross-linking in tumor malignancy was directly verified using the synthesized HA-HC complex. Collectively, our study found that the deficiency of cross-linked HA induced breast cancer malignancy in a CAF-dependent manner, suggesting that recovering HA cross-linking may be a potential therapeutic strategy.
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影响因子：
10.5
作者：
Brichkina A;Bertero T;Loh HM;Nguyen NT;Emelyanov A;Rigade S;Ilie M;Hofman P;Gaggioli C;Bulavin DV
通讯作者：
Bulavin DV
影响因子：
11.2
作者：
Dang TT;Prechtl AM;Pearson GW
通讯作者：
Pearson GW
影响因子：
5.5
作者：
McCarthy JB;El-Ashry D;Turley EA
通讯作者：
Turley EA
影响因子：
6.9
作者：
Gao, Feng;Liu, Yiwen;Wei, Guo
通讯作者：
Wei, Guo
影响因子：
21.3
作者：
通讯作者：
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