Local immunosuppressive microenvironment enhances migration of melanoma cells to lungs in DJ-1 knockout mice.
Local immunosuppressive microenvironment enhances migration of melanoma cells to lungs in DJ-1 knockout mice.
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DOI：
10.1371/journal.pone.0115827
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Fu WM
中科院分区：
文献类型：
--
作者：
Chien CH;Lee MJ;Liou HC;Liou HH;Fu WM
DJ-1是一种通过抗凋亡促进癌细胞存活的癌蛋白。然而，DJ-1也在调节IL-1β表达中发挥作用，由失调的DJ-1构建的炎症微环境是否影响癌症进展仍不清楚。因此，本研究旨在比较野生型（WT）和DJ-1敲除（KO）小鼠中黑色素瘤细胞的转移能力，并检查DJ-1 KO小鼠中建立的炎症微环境是否在癌细胞迁移到肺部中发挥作用。首先，将B16 F10黑色素瘤细胞（6×104）注射到小鼠股静脉中，比较WT和DJ-1 KO小鼠之间的肺结节形成、肺IL-1β和血清细胞因子水平以及髓源性抑制细胞（MDSC）蓄积。其次，用白细胞介素-1 β（IL-1β）中和抗体治疗荷癌小鼠，以观察IL-1β是否参与癌症迁移。最后，分别用DJ-1 shRNA和重组IL-1β处理体外培养的RAW 264.7巨噬细胞和B16 F10黑色素瘤细胞，以探讨其分子机制。我们的结果表明，IL-1β增强了培养的黑色素瘤细胞的存活和集落形成，并且在DJ-1 KO小鼠和DJ-1敲低的培养的巨噬细胞中IL-1β水平均升高。升高的IL-1β与DJ-1 KO小鼠肺中免疫抑制性MDSC的较高积累和黑色素瘤模块的形成相关，并且两者都可以通过用IL-1β中和抗体治疗小鼠而降低。以上结果表明，DJ-1基因敲除小鼠体内构建的免疫抑制组织微环境可促进肿瘤的肺转移，IL-1β在促进肿瘤转移中起重要作用。
DJ-1 is an oncoprotein that promotes survival of cancer cells through anti-apoptosis. However, DJ-1 also plays a role in regulating IL-1β expression, and whether inflammatory microenvironment built by dysregulated DJ-1 affects cancer progression is still unclear. This study thus aimed to compare the metastatic abilities of melanoma cells in wild-type (WT) and DJ-1 knockout (KO) mice, and to check whether inflammatory microenvironment built in DJ-1 KO mice plays a role in migration of cancer cells to lungs. First, B16F10 melanoma cells (at 6×104) were injected into the femoral vein of mice, and formation of lung nodules, levels of lung IL-1β and serum cytokines, and accumulation of myeloid-derived suppressor cells (MDSCs) were compared between WT and DJ-1 KO mice. Second, the cancer-bearing mice were treated with an interleukin-1 beta (IL-1β) neutralizing antibody to see whether IL-1β is involved in the cancer migration. Finally, cultured RAW 264.7 macrophage and B16F10 melanoma cells were respectively treated with DJ-1 shRNA and recombinant IL-1β to explore underlying molecular mechanisms. Our results showed that IL-1β enhanced survival and colony formation of cultured melanoma cells, and that IL-1β levels were elevated both in DJ-1 KO mice and in cultured macrophage cells with DJ-1 knockdown. The elevated IL-1β correlated with higher accumulation of immunosuppressive MDSCs and formation of melanoma module in the lung of DJ-1 KO mice, and both can be decreased by treating mice with IL-1β neutralizing antibodies. Taken together, these results indicate that immunosuppressive tissue microenvironment built in DJ-1 KO mice can enhance lung migration of cancer, and IL-1β plays an important role in promoting the cancer migration.
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影响因子：
5.4
作者：
Denes A;Drake C;Stordy J;Chamberlain J;McColl BW;Gram H;Crossman D;Francis S;Allan SM;Rothwell NJ
通讯作者：
Rothwell NJ
影响因子：
6.1
作者：
Kim, Jong-hyeon;Choi, Dong-joo;Joe, Eun-Hye
通讯作者：
Joe, Eun-Hye
影响因子：
50.3
作者：
Kim, RH;Peters, M;Mak, TW
通讯作者：
Mak, TW
DOI：
10.1126/sageke.2006.2.pe2
发表时间：
2006-01-11
期刊：
Science of aging knowledge environment : SAGE KE
影响因子：
--
作者：
Moore, Darren J;Dawson, Valina L;Dawson, Ted M
通讯作者：
Dawson, Ted M
影响因子：
5.8
作者：
Bjorkdahl, O;Wingren, AG;Dohlsten, M
通讯作者：
Dohlsten, M