SENP3 loss promotes M2 macrophage polarization and breast cancer progression.
SENP3 loss promotes M2 macrophage polarization and breast cancer progression.
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SENP3 缺失促进 M2 巨噬细胞极化和乳腺癌进展。
DOI：
10.1002/1878-0261.12967
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发表时间：
2022-03
影响因子：
6.6
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Xiao M;Bian Q;Lao Y;Yi J;Sun X;Sun X;Yang J
肿瘤相关巨噬细胞（TAM）在促进癌症进展中起着至关重要的作用。在细胞因子刺激下，TAM优先分化为抗炎和促肿瘤的M2亚型。这种优先极化的机制尚不清楚。在这里，我们报告了巨噬细胞特异性缺失SUMO特异性蛋白酶Sentrin/SUMO特异性蛋白酶3，促进了由白细胞介素4 (IL - 4)/IL - 13诱导的骨髓源性巨噬细胞（BMDM）中巨噬细胞向M2的极化，并在离体模型（小鼠Py8119细胞系）和小鼠原位肿瘤模型中进行了研究。值得注意的是，在离体和体内模型中，巨噬细胞中Sentrin/SUMO特异性蛋白酶3 （SENP3）的缺失加速了乳腺癌恶性。在机制上，我们确定了Akt丝氨酸/苏氨酸激酶1 （Akt1）是SENP3的底物，并发现在SENP3缺失时Akt1的SUMOylation增强导致Akt1超磷酸化和激活，从而促进M2极化。临床资料分析表明，TAM中SENP3水平越低，与M2标志物CD206水平呈较强的负相关，临床预后越差。因此，由于SENP3缺乏而增加的Akt1 SUMOylation调节乳腺癌微环境中巨噬细胞向M2亚型的极化，从而促进肿瘤进展。细胞因子诱导的肿瘤相关巨噬细胞极化对癌症进展至关重要。本文研究了SUMO特异性肽酶3 （SENP3）在巨噬细胞极化中的作用。SENP3的缺失导致Akt1的sumo化和超磷酸化，进而促进IL - 4等细胞因子的M2极化。总之，SENP3的缺失导致了乳腺癌患者的肿瘤进展和更差的预后。
Tumor‐associated macrophages (TAM) play a crucial role in promoting cancer progression. Upon cytokine stimulation, TAM preferentially polarize to the anti‐inflammatory and pro‐tumor M2 subtype. The mechanism underlying such preferential polarization remains elusive. Here, we report that macrophage‐specific deletion of the SUMO‐specific protease Sentrin/SUMO‐specific protease 3 promotes macrophage polarization towards M2 in bone marrow‐derived macrophage (BMDM) induced by interleukin 4 (IL‐4)/IL‐13 and in an ex vivo model (murine Py8119 cell line), as well as in a mouse orthotopic tumor model. Notably, Sentrin/SUMO‐specific protease 3 (SENP3) loss in macrophages accelerated breast cancer malignancy in ex vivo and in vivo models. Mechanistically, we identified Akt Serine/threonine kinase 1 (Akt1) as the substrate of SENP3 and found that the enhanced Akt1 SUMOylation upon SENP3 loss resulted in Akt1 hyper‐phosphorylation and activation, which facilitates M2 polarization. Analysis of clinical data showed that a lower level of SENP3 in TAM has a strong negative correlation with the level of the M2 marker CD206, as well as with a worse clinical outcome. Thus, increased Akt1 SUMOylation as a result of SENP3 deficiency modulates polarization of macrophages to the M2 subtype within a breast cancer microenvironment, which in turn promotes tumor progression. Cytokine induced polarization of tumor‐associated macrophages are crucial for cancer progression. Here we investigated the role of SUMO specific peptidase 3 (SENP3) in macrophage polarization. Loss of SENP3 resulted in SUMOylation and hyper‐phosphorylation of Akt1 that in turn facilitated M2 polarization by the cytokines like IL‐4. Altogether, loss of SENP3 contributed to tumor progression and worse prognosis in patients with breast cancer.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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82.9
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