a Department of Neurology , Hebei Chest Hospital , Shijiazhuang , Hebei , China.
b Department of Urology , Hebei Chest Hospital , Shijiazhuang , Hebei , China.
Cell Adh Migr. 2018 Jan 2;12(1):28-36. doi: 10.1080/19336918.2017.1307482. Epub 2017 Jun 19.
Various survival factors such as the pleiotropic cytokine interleukin-6 (IL-6), a major mediator of inflammation and activator of signal transducer and activator of transcription 3 (STAT3), serve to block apoptosis in cancer cells. Our present study revealed that the expression of IL-6, while not other IL-2, IL-4, IL-8, or IL-10, was significantly elevated in resistance of renal carcinoma cells (RCC) when compared with human renal proximal tubule epithelial cell line HK-2. The inhibition of IL-6 by siRNA can suppress the proliferation, migration and invasion of RCC cells and increase the doxorubicin (Dox) sensitivity. While recombination IL-6 can attenuate the inhibition effects of Dox on proliferation of RCC cells. Further studies indicated that inhibition of IL-6 by siRNA can decrease the phosphorylation of STAT3 in RCC cells. Over expression of STAT3 increased the proliferation, migration and invasion of RCC cells and reversed si-IL-6 induced increase of Dox sensitivity of ACHN and A498 cells. In addition, IL-6 treatment can activate ERK1/2 via increasing its phosphorylation. PD98059, the ERK1/2 inhibitor, attenuated IL-6 induced proliferation and synergistically increased the Dox sensitivity of si-IL-6 transfected ACHN cells. Collectively, our data suggested that IL-6 plays an important role in malignancy and Dox sensitivity of RCC. The targeted inhibition of IL-6 signals might be a promising therapeutic strategy for the treatment of renal cancer.
多种生存因子，如多效细胞因子白细胞介素-6（IL-6），炎症的主要介质和信号转导子和转录激活子 3（STAT3）的激活剂，可阻止癌细胞凋亡。我们的研究表明，与人类肾近端小管上皮细胞系 HK-2 相比，肾癌细胞（RCC）中 IL-6 的表达明显升高，而其他白细胞介素（IL）-2、IL-4、IL-8 或 IL-10 的表达则没有升高。用 siRNA 抑制 IL-6 可抑制 RCC 细胞的增殖、迁移和侵袭，并增加阿霉素（Dox）的敏感性。而重组 IL-6 可以减弱 Dox 对 RCC 细胞增殖的抑制作用。进一步的研究表明，siRNA 抑制 IL-6 可以降低 RCC 细胞中 STAT3 的磷酸化。STAT3 的过表达增加了 RCC 细胞的增殖、迁移和侵袭，并逆转了 si-IL-6 诱导的 ACHN 和 A498 细胞对 Dox 敏感性的增加。此外，IL-6 处理可以通过增加其磷酸化来激活 ERK1/2。ERK1/2 抑制剂 PD98059 减弱了 IL-6 诱导的增殖，并协同增加了转染 si-IL-6 的 ACHN 细胞对 Dox 的敏感性。总之，我们的数据表明，IL-6 在 RCC 的恶性程度和 Dox 敏感性中发挥重要作用。靶向抑制 IL-6 信号可能是治疗肾癌的一种有前途的治疗策略。
