Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Hepatology. 2012 Jun;55(6):1863-75. doi: 10.1002/hep.25572.
Hypoxia is often found in solid tumors and is associated with tumor progression and poor clinical outcomes. The exact mechanisms related to hypoxia-induced invasion and metastasis remain unclear. We elucidated the mechanism by which the nuclear-damage-associated molecular pattern molecule, high-mobility group box 1 (HMGB1), released under hypoxic stress, can induce an inflammatory response to promote invasion and metastasis in hepatocellular carcinoma (HCC) cells. Caspase-1 activation was found to occur in hypoxic HCC cells in a process that was dependent on the extracellular release of HMGB1 and subsequent activation of both Toll-like receptor 4 (TLR4)- and receptor for advanced glycation endproducts (RAGE)-signaling pathways. Downstream from hypoxia-induced caspase-1 activation, cleavage and release of proinflammatory cytokines interleukin (IL)-1β and -18 occurred. We further demonstrate that overexpression of HMGB1 or treatment with recombinant HMGB1 enhanced the invasiveness of HCC cells, whereas stable knockdown of HMGB1 remarkably reduced HCC invasion. Moreover, in a murine model of HCC pulmonary metastasis, stable knockdown of HMGB1 suppressed HCC invasion and metastasis.
These results suggest that in hypoxic HCC cells, HMGB1 activates TLR4- and RAGE-signaling pathways to induce caspase-1 activation with the subsequent production of multiple inflammatory mediators, which, in turn, promote cancer invasion and metastasis.
缺氧通常存在于实体肿瘤中，并与肿瘤进展和不良临床结局相关。与缺氧诱导的侵袭和转移相关的确切机制尚不清楚。我们阐明了在缺氧应激下释放的核损伤相关分子模式分子高迁移率族蛋白 B1（HMGB1）如何诱导炎症反应，从而促进肝癌（HCC）细胞的侵袭和转移。研究发现，在缺氧 HCC 细胞中，HMGB1 的细胞外释放和随后的 Toll 样受体 4（TLR4）和晚期糖基化终产物受体（RAGE）信号通路的激活，导致半胱天冬酶-1 的激活。缺氧诱导的半胱天冬酶-1 激活后，促炎细胞因子白细胞介素（IL）-1β和 -18 的切割和释放发生。我们进一步证明，HMGB1 的过表达或用重组 HMGB1 处理增强了 HCC 细胞的侵袭性，而 HMGB1 的稳定敲低则显著降低了 HCC 的侵袭性。此外，在 HCC 肺转移的小鼠模型中，HMGB1 的稳定敲低抑制了 HCC 的侵袭和转移。
这些结果表明，在缺氧 HCC 细胞中，HMGB1 激活 TLR4 和 RAGE 信号通路，诱导半胱天冬酶-1 的激活，随后产生多种炎症介质，进而促进癌症的侵袭和转移。
