Intracellular IL-37b interacts with Smad3 to suppress multiple signaling pathways and the metastatic phenotype of tumor cells
Intracellular IL-37b interacts with Smad3 to suppress multiple signaling pathways and the metastatic phenotype of tumor cells
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细胞内IL-37b与Smad3相互作用抑制多种信号通路和肿瘤细胞的转移表型
DOI：
10.1038/onc.2016.444
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发表时间：
2017-05-18
期刊：
影响因子：
8
通讯作者：
Feng, Z-H
中科院分区：
文献类型：
--
作者：
Luo, C.;Shu, Y.;Feng, Z-H
促进肿瘤细胞转移的多种信号通路在低/非转移性和转移性肿瘤细胞中被差异激活，导致转移相关基因的差异表达。其机制可能与肿瘤细胞内固有的负调控改变有关。本文报道了肿瘤细胞中白细胞介素-37 b（IL-37 b）的差异表达改变了信号通路的内在负调控，从而导致肿瘤细胞转移能力的差异。IL-37 b可与Smad 3结合，通过干扰Smad 2/3/4复合物的形成和核转位，抑制Smad 3通路。反过来，Smad 3可以作为一种辅助调节因子，使IL-37 b能够抑制多种非Smad途径。IL-37 b-Smad 3通过上调非受体蛋白酪氨酸磷酸酶（PTPNs）的表达进入细胞核，促进细胞脱磷酸化，抑制ERK、p38 MAPK、JNK、PI 3 K、NF-κB和STAT 3等酪氨酸磷酸化依赖的信号通路的激活。有趣的是，17个PTPN中的13个，其中大部分是转移抑制因子，由于IL-37 b的低表达，在转移性肿瘤细胞中下调。细胞内IL-37 b的显著降低减弱了肿瘤细胞内在的负性调节，导致多种信号通路的激活以及侵袭和转移定植能力的增强。IL-37 b在肿瘤组织中的低表达与肿瘤患者的不良预后显著相关。总之，这些发现揭示了细胞内IL-37 b是调节转移相关基因表达的多种信号传导途径的负调节的关键因素，并表明肿瘤细胞中IL-37 b的表达可能是癌症患者的组织病理学预后参数和预防肿瘤转移的治疗靶点。
Multiple signaling pathways that promote tumor cell metastasis are differentially activated in low/non-metastatic and metastatic tumor cells, resulting in the differential expression of metastasis-related genes. The underlying mechanism may involve the alterations of the intrinsic negative regulation in tumor cells. Here we report that the differential expression of interleukin-37b (IL-37b) in tumor cells alters the intrinsic negative regulation of signaling pathways, resulting in the difference of metastatic capacity. IL-37b could bind Smad3 and suppress Smad pathway by interfering with the formation and nuclear translocation of Smad2/3/4 complex. In turn, Smad3 could function as a co-regulator, enabling IL-37b to suppress multiple non-Smad pathways. IL-37b-Smad3 translocated into nucleus to upregulate the expression of non-receptor protein tyrosine phosphatases (PTPNs), thus promoting dephosphorylation to suppress the activation of tyrosine phosphorylation-dependent signaling pathways such as ERK, p38 MAPK, JNK, PI3K, NF-κB, and STAT3 pathways. Intriguingly, 13 of 17 PTPNs, most of which are metastasis suppressors, were downregulated in metastatic tumor cells because of the low expression of IL-37b. The marked decrease of intracellular IL-37b attenuated the intrinsic negative regulation in tumor cells, resulting in the enhanced activation of multiple signaling pathways and the increased capacity of invasiveness and metastatic colonization. Consistently, low expression of IL-37b in tumors was significantly associated with poor prognosis of cancer patients. Taken together, these findings reveal that intracellular IL-37b is a critical factor in the negative regulation of multiple signaling pathways that modulate the expression of metastasis-related genes, and suggest that IL-37b expression in tumor cells can potentially be a histopathological prognostic parameter for cancer patients and a therapeutic target for preventing tumor metastasis.