PLOD2-driven IL-6/STAT3 signaling promotes the invasion and metastasis of oral squamous cell carcinoma via activation of integrin β1
PLOD2-driven IL-6/STAT3 signaling promotes the invasion and metastasis of oral squamous cell carcinoma via activation of integrin β1
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DOI：
10.3892/ijo.2021.5209
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发表时间：
2021-06-01
影响因子：
5.2
通讯作者：
Kondo, Eisaku
中科院分区：
文献类型：
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作者：
Saito, Ken;Mitsui, Ayaka;Kondo, Eisaku
我们以前报道过，高表达的前胶原-赖氨酸2-酮戊二酸5-双加氧酶2（PLOD 2）导致整合素β 1的稳定和质膜易位，以促进口腔鳞状细胞癌（SCC）的侵袭和转移。本研究旨在进一步了解PLOD 2-整合素β 1信号转导与肿瘤微环境之间的关系。这项研究提供了进一步的深入见解，表明肿瘤微环境中升高的白细胞介素（IL）-6是触发PLOD 2-整合素β 1轴衍生的肿瘤侵袭和转移加速的关键分子。使用双荧光素酶报告基因测定系统发现，IL-6激活信号转导子和转录激活子3（STAT 3）对于通过直接激活口腔SCC中的PLOD 2启动子来增加PLOD 2的表达水平是必不可少的，而IL-6刺激并不有助于整合素β 1表达或随后的质膜上朝向功能形式的成熟过程。IL-6在口腔鳞癌组织中的表达主要分布在肿瘤间质中。免疫荧光双标法显示，IL-6在肿瘤巢周围分布的CD 163阳性M2巨噬细胞中表达。这些结果与我们先前的结果相结合表明，由于IL-6显著增加STAT 3介导的PLOD 2启动子活性，因此M2型肿瘤相关巨噬细胞释放的IL-6是促进PLOD 2-整合素β 1轴增强口腔SCC细胞侵袭和转移的关键因素。
We previously reported that high expression of procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2) leads to stabilization and plasma membrane translocation of integrin beta 1 to promote the invasion and metastasis of oral squamous cell carcinoma (SCC). The present study aimed to further understand the relationship between PLOD2-integrin beta 1 signaling and the tumor microenvironment. This study provided further advanced insights indicating that elevated interleukin (IL)-6 in the tumor microenvironment acts as a key molecule that triggers PLOD2-integrin beta 1 axis-derived acceleration of tumor invasion and metastasis. It was found using the dual-luciferase reporter assay system that signal transducer and activator of transcription 3 (STAT3) activation by IL-6 was essential for increasing the expression levels of PLOD2 through direct activation of the PLOD2 promoter in oral SCC, whereas IL-6 stimulation did not contribute to integrin beta 1 expression or the subsequent maturation process towards a functional form on the plasma membrane. Furthermore, the expression of IL-6 in oral SCC tissues was mainly observed in the tumor stroma. Finally, with double immunofluorescence staining, it was found that IL-6 expression occurred in CD163-positive M2 macrophages distributed around the tumor nest. These results combined with our previous results indicate that as IL-6 significantly increases STAT3-mediated PLOD2 promoter activity, IL-6 released by M2-type tumor-associated macrophages is a crucial factor that promotes PLOD2-integrin beta 1 axis-enhanced invasion and metastasis of oral SCC cells.