Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through Toll-like receptor 9.
Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through Toll-like receptor 9.
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DOI：
10.1016/j.jhep.2015.02.009
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发表时间：
2015-07
影响因子：
25.7
通讯作者：
Tsung, Allan
中科院分区：
文献类型：
--
作者：
Liu, Yao;Yan, Wei;Tohme, Samer;Chen, Man;Fu, Yu;Tian, Dean;Lotze, Michael;Tang, Daolin;Tsung, Allan
低氧诱导肿瘤生长的机制尚不清楚。低氧诱导细胞内多种损伤相关分子模式(DAMP)的移位和释放，如核HMGB1和线粒体DNA(MtDNA)。在炎症中，含有DNA的免疫复合物激活Toll样受体(TLR)-9被证明是由HMGB1介导的。因此，我们推测HMGB1通过激活TLR9信号通路，结合缺氧肿瘤细胞胞浆中的线粒体DNA，促进肿瘤生长。给C57BL6小鼠注射Hepa1-6癌细胞。TLR9和HMGB1可被shRNA或直接拮抗剂抑制。以体外培养的HuH7和Hepa1-6细胞为研究对象，探讨HMGB1和mtDNA相互作用对TLR9信号通路的激活作用。在低氧期间，HMGB1从细胞核移位到胞浆，并与受损线粒体释放的线粒体DNA结合。该复合体随后激活TLR9信号通路，促进肿瘤细胞增殖。HMGB1或mtDNA的缺失导致TLR9信号通路的缺陷，从而导致肿瘤细胞增殖下降。此外，HMGB1和mtDNA的增加导致TLR-9的激活和随后的肿瘤细胞增殖。此外，TLR9在体外缺氧的肿瘤细胞和人类肝细胞癌(HCC)标本中都过表达；在小鼠体内注射后，从肝癌细胞中敲除HMGB1或TLR9都能抑制体内肿瘤的生长。我们的数据揭示了一种新的机制，即HMGB1和mtDNA的相互作用在缺氧时激活TLR9信号，从而诱导肿瘤生长。
The mechanisms of hypoxia-induced tumor growth remain unclear. Hypoxia induces intracellular translocation and release of a variety of damage associated molecular patterns (DAMPs) such as nuclear HMGB1 and mitochondrial DNA (mtDNA). In inflammation, Toll-like receptor (TLR)-9 activation by DNA-containing immune complexes has been shown to be mediated by HMGB1. We thus hypothesize that HMGB1 binds mtDNA in the cytoplasm of hypoxic tumor cells and promotes tumor growth through activating TLR9 signaling pathways. C57BL6 mice were injected with Hepa1-6 cancer cells. TLR9 and HMGB1 were inhibited using shRNA or direct antagonists. Huh7 and Hepa1-6 cancer cells were investigated in vitro to investigate how the interaction of HMGB1 and mtDNA activates TLR9 signaling pathways. During hypoxia, HMGB1 translocates from the nucleus to the cytosol and binds to mtDNA released from damaged mitochondria. This complex subsequently activates TLR9 signaling pathways to promote tumor cell proliferation. Loss of HMGB1 or mtDNA leads to a defect in TLR9 signaling pathways in response to hypoxia, resulting in decreased tumor cell proliferation. Also, the addition of HMGB1 and mtDNA leads to the activation of TLR-9 and subsequent tumor cell proliferation. Moreover, TLR9 is overexpressed in both hypoxic tumor cells in vitro and in human hepatocellular cancer (HCC) specimens; and, knockdown of either HMGB1 or TLR9 from HCC cells suppressed tumor growth in vivo after injection in mice. Our data reveals a novel mechanism by which the interactions of HMGB1 and mtDNA activate TLR9 signaling during hypoxia to induce tumor growth.
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影响因子：
4.8
作者：
Li, NY;Ragheb, K;Robinson, JP
通讯作者：
Robinson, JP
影响因子：
4.3
作者：
Bubici, C;Papa, S;Franzoso, G
通讯作者：
Franzoso, G
DOI：
10.1073/pnas.0807694106
发表时间：
2009-02-24
影响因子：
11.1
作者：
Tal, Michal Caspi;Sasai, Miwa;Iwasaki, Akiko
通讯作者：
Iwasaki, Akiko
影响因子：
5.2
作者：
Tanaka, Junichiro;Sugimoto, Kazushi;Takei, Yoshiyuki
通讯作者：
Takei, Yoshiyuki
DOI：
10.1158/1078-0432.ccr-13-0495
发表时间：
2013-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kang R;Zhang Q;Zeh HJ 3rd;Lotze MT;Tang D
通讯作者：
Tang D