The Third Affiliated Hospital of Suzhou University, Jiangsu Changzhou 213003, People's Republic of China.
Anticancer Res. 2009 Nov;29(11):4497-501.
We previously reported that matrix metalloproteinase (MMP)-10 mRNA levels were significantly lower in tumor tissues than in adjacent normal tissues in human non-small cell lung cancer (NSCLC), whereas protein levels of MMP-10 were higher in the tumor tissues than the adjacent tissues. The mechanism of this divergence is still unknown. In the present study the role of Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) on interleukin (IL)-6 mediated regulation of MMP-10 expression was investigated in a human lung adenocarcinoma cell line (A549 cells) and the molecular regulatory mechanism of MMP-10 expression was explored. A549 cells were stimulated by different concentrations of IL-6 with or without AG490, a specific JAK2 inhibitor. It was demonstrated that IL-6 moderately reduced the MMP-10 mRNA levels, whereas it significantly enhanced the MMP-10 protein mass in the A549 cells. This phenomenon mimicked the divergence of mRNA level and protein mass of MMP-10 in human NSCLC. Moreover, the present study indicated that IL-6 regulation of MMP-10 expression was via the JAK2/STAT3 pathway. STAT3 mRNA levels were significantly increased when the cells were treated with IL-6, whereas when AG490 (50 muM) was added to the cell cultures, IL-6-induced increase of STAT3 mRNA levels was abolished. Meanwhile, AG490 blocked the IL-6-induced inhibition of MMP-10 mRNA as well as blocking the IL-6-induced increase of MMP-10 protein mass in the A549 cells. Neither IL-6 nor AG490 influenced JAK2 mRNA levels in the A549 cell cultures. It is concluded that the JAK2/STAT3 pathway is involved in the IL-6-mediated regulation of MMP-10, and IL-6 can moderately reduce MMP-10 mRNA levels and strongly increase MMP-10 protein mass in human lung adenocarcinoma A549 cells. Contrasting effects of IL-6 on MMP-10 mRNA level and protein concentration in A549 cells may partially explain the divergence of MMP-10 mRNA level and protein mass in human NSCLC.
我们之前报道称，在人类非小细胞肺癌（NSCLC）中，肿瘤组织中基质金属蛋白酶（MMP）-10mRNA 水平明显低于相邻正常组织，而肿瘤组织中 MMP-10 蛋白水平高于相邻组织。这种差异的机制尚不清楚。在本研究中，我们研究了在人肺腺癌细胞系（A549 细胞）中，Janus 激酶 2/信号转导和转录激活因子 3（JAK2/STAT3）在白细胞介素（IL）-6 介导的 MMP-10 表达调控中的作用，并探讨了 MMP-10 表达的分子调控机制。用不同浓度的 IL-6 刺激 A549 细胞，同时或不使用特定的 JAK2 抑制剂 AG490。结果表明，IL-6 适度降低 MMP-10mRNA 水平，而显著增强 A549 细胞中 MMP-10 蛋白质量。这种现象模拟了人类 NSCLC 中 MMP-10mRNA 水平和蛋白质量的差异。此外，本研究表明，IL-6 调节 MMP-10 表达是通过 JAK2/STAT3 途径。当细胞用 IL-6 处理时，STAT3mRNA 水平显著增加，而当将 AG490（50μM）加入细胞培养物中时，IL-6 诱导的 STAT3mRNA 水平增加被消除。同时，AG490 阻断了 IL-6 诱导的 MMP-10mRNA 减少以及阻断了 IL-6 诱导的 A549 细胞中 MMP-10 蛋白质量增加。IL-6 或 AG490 均不影响 A549 细胞培养物中的 JAK2mRNA 水平。结论：JAK2/STAT3 途径参与了 IL-6 介导的 MMP-10 调节，IL-6 可适度降低人肺腺癌 A549 细胞中 MMP-10mRNA 水平，并强烈增加 MMP-10 蛋白质量。IL-6 对 A549 细胞中 MMP-10mRNA 水平和蛋白浓度的相反作用部分解释了人类 NSCLC 中 MMP-10mRNA 水平和蛋白质量的差异。
