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首页> 外文期刊>Journal of experimental & clinical cancer research : >NLRP7 deubiquitination by USP10 promotes tumor progression and tumor-associated macrophage polarization in colorectal cancer
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NLRP7 deubiquitination by USP10 promotes tumor progression and tumor-associated macrophage polarization in colorectal cancer

机译：NLRP7通过USP10脱硫酸化促进结直肠癌中的肿瘤进展和肿瘤相关的巨噬细胞极化

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NOD-like receptors affect multiple stages of cancer progression in many malignancies. NACHT, LRR, and PYD domain-containing protein 7 (NLRP7) is a member of the NOD-like receptor family, although its role in tumorigenesis remains unclear. By analyzing clinical samples, we found that NLRP7 protein levels were upregulated in colorectal cancer (CRC). We proposed the hypothesis that a high level of NLRP7 in CRC may promote tumor progression. Here, we further investigated the role of NLRP7 in CRC and the underlying mechanism. NLRP7 expression in human CRC and adjacent non-tumorous tissues was examined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. The effect of NLRP7 in CRC progression was investigated in vitro and in vivo. Proteins interacting with NLRP7 were identified by immunoprecipitation and mass spectrometry analysis while immunofluorescence staining revealed the cellular location of the proteins. Cellular ubiquitination and protein stability assays were applied to demonstrate the ubiquitination effect on NLRP7. Cloning and mutagenesis were used to identify a lysine acceptor site that mediates NLRP7 ubiquitination. Cytokines/chemokines affected by NLRP7 were identified by RNA sequencing, qRT-PCR, and enzyme-linked immunosorbent assay. Macrophage phenotypes were determined using qRT-PCR, flow cytometry, and immunohistochemistry. NLRP7 protein levels, but not mRNA levels, were upregulated in CRC, and increased NLRP7 protein expression was associated with poor survival. NLRP7 promoted tumor cell proliferation and metastasis in vivo and in vitro and interacted with ubiquitin-specific protease 10, which catalyzed its deubiquitination in CRC cells. NLRP7 stability and protein levels in CRC cells were modulated by ubiquitination and deubiquitination, and NLRP7 was involved in the ubiquitin-specific protease 10 promotion of tumor progression and metastasis in CRC. K379 was an important lysine acceptor site that mediates NLRP7 ubiquitination in CRC cells. In CRC, NLRP7 promoted the polarization of pro-tumor M2-like macrophages by inducing the secretion of C-C motif chemokine ligand 2. Furthermore, NLRP7 promoted NF-κB nuclear translocation and activation of C-C motif chemokine ligand 2 transcription. We showed that NLRP7 promotes CRC progression and revealed an as-yet-unidentified mechanism by which NLRP7 induces the polarization of pro-tumor M2-like macrophages. These results suggest that NLRP7 could serve as a biomarker and novel therapeutic target for the treatment of CRC.
机译：点燃的受体在许多恶性肿瘤中影响癌症进展的多个阶段。含有NACHT，LRR和含PYD域的蛋白质7（NLRP7）是NOD样受体家族的成员，尽管其在肿瘤发生中的作用仍不清楚。通过分析临床样本，我们发现在结肠直肠癌（CRC）中令人上调NLRP7蛋白水平。我们提出了CRC中高水平NLRP7的假设可以促进肿瘤进展。在这里，我们进一步调查了NLRP7在CRC和潜在机制中的作用。通过定量的实时聚合酶链反应（QRT-PCR），Western印迹和免疫组化，检查人CRC和相邻非肿瘤组织中的NLRP7表达。体外和体内研究了NLRP7在CRC进展中的影响。通过免疫沉淀和质谱分析鉴定与NLRP7相互作用的蛋白质，同时免疫荧光染色显示蛋白质的细胞位置。施用细胞泛素化和蛋白质稳定性测定以证明对NLRP7的普发效应。使用克隆和诱变用于鉴定介导NLRP7泛素化的赖氨酸受体位点。通过RNA测序，QRT-PCR和酶联免疫吸附测定鉴定受NLRP7影响的细胞因子/趋化因子。使用QRT-PCR，流式细胞术和免疫组化测定巨噬细胞表型。在CRC中，NLRP7蛋白水平但不是mRNA水平，并且增加的NLRP7蛋白表达与存活率不良有关。 NLRP7促进体内和体外肿瘤细胞增殖和转移，并与泛素特异性蛋白酶10相互作用，其催化其在CRC细胞中的脱水。通过泛素化和脱氮调节CRC细胞中的NLRP7稳定性和蛋白质水平，并且NLRP7参与遍在蛋白特异性蛋白酶10促进CRC中的肿瘤进展和转移。 K379是一个重要的赖氨酸受体位点，其在CRC细胞中介导NLRP7泛素化。在CRC中，NLRP7通过诱导C-C基序趋化因子配体2的分泌来促进Pro-Tumor M2样巨噬细胞的极化。此外，NLRP7促进了NF-κB核转位和C-C基序趋化因子配体2转录的活化。我们表明，NLRP7促进了CRC进展，并揭示了NLRP7诱导Pro-Tumor M2样巨噬细胞的极化的尚未认定的机制。这些结果表明NLRP7可以作为治疗CRC的生物标志物和新的治疗靶标。

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