白细胞介素7及其受体在非小细胞肺癌中调控细胞增殖和促进淋巴管形成  

Interleukin 7 and its receptor promote cell proliferation and induce lymphangiogenesis in non-small cell lung cancer

作　　者：明健[1] 张清富[1] 姜彦多[2] 姜国成[2] 邱雪杉[1] 

机构地区：[1]中国医科大学基础医学院病理学教研室,沈阳110001 [2]解放军第二O二医院

出　　处：《中华病理学杂志》2012年第8期511-518,共8页Chinese Journal of Pathology

基　　金：国家自然科学基金（30972967）;国家教育部博士点专项基金（20092104110018）

摘　　要：目的应用体内外实验研究非小细胞肺癌（NSCLC）中白细胞介素7及其受体（IL-7／IL-7R）对调控细胞增殖和促进淋巴管形成的作用机制。方法应用免疫组织化学SP法观察95例NSCLC组织中IL-7、IL-7R、cyclin D1和血管内皮生长因子（VEGF）-D的表达，分析IL-7／IL-7R与各因素的关系。然后应用四甲基偶氮唑盐法、流式细胞术、逆转录-聚合酶链反应（RT—PCR）、Western blot法、染色质免疫沉淀法、免疫共沉淀法及裸鼠体内移植实验研究肺癌中IL-7／IL-7R调控细胞增殖和促进淋巴管形成的作用机制。结果IL-7（63．2％，60／95）、IL-7R（61．1％，58／95）、cyclin D1（52．6％，50／95）和VEGF—D（58．9％，56／95）在NSCLC中高表达。IL-7／IL-7R的表达与cyclin D1（P〈0．01，P〈0．01）、VEGF—D（P〈0．01，P〈0．01）、淋巴管密度（P=0．005，P=0．013）和肿瘤临床分期（P=0．008，P=0．005）、转移（P〈0．01，P〈0．01）相关。IL-7／IL-7R能促进A549细胞生长；同时能增加cyclin D1和VEGF—D的表达；同时能促进c—Fos／c—Jun的表达和磷酸化及c—Fos／c—Jun形成异二聚体并促使c—Fos／c—Jnn与cyclin D1和VEGF—D的启动子结合调控其转录；还能促进肺癌移植瘤生长及移植瘤淋巴管形成。结论在NSCLC中，ILG／IL-7R通过调控c—Fos／c—Jun的表达及活性进一步调控cyclin D1促进肿瘤细胞生长，调控VEGF—D促进淋巴管形成。Objective To study the mechanism of interleukin 7/interleukin 7 receptor （IL-7/IL-TR） in promoting cell proliferation and inducing lymphangiogenesis of non-small cell lung cancer （NSCLC） in vivo and in vitro. Methods Immunohistochemical study for IL-7, IL-TR, cyclin D1 and vascular endothelial growth factor-D （VEGF-D） was carried out in NSCLC tissues from 95 patients. The relationship between IL-7/IL-7R expression and various parameters was analyzed. The mechanism of IL-7/IL-7R in promoting cell proliferation and inducing lymphangiogenesis was studied by methyhhiazolyldiphenyl-tetrazolium bromide, fluorescence-activated cell sorting, reverse transeriptase-PCR, Western blot, co-immunopreeipitation, chromatin immunoprecipitation and nude mice experiments with xenograft tumors. Results IL-7 （ 63.2%, 60/95 ）, IL-7R （ 61.1%, 58/95 ）, cyclin D1 （ 52. 6%, 50/95） and VEGF-D （58.9%, 56/95） showed that high level of expression in NSCLC. IL-7/IL-7R over-expression correlated with eyclin D1 expression （P 〈 0. 01, P 〈 0. 01 ）, VEGF-D expression （ P 〈 0. 01, P 〈 0. 01 ）, increased lymphovascular density （ P = 0. 005, P = 0. 013 ）, advanced clinical stage （P =0. 008, P =0. 005） and presence of lymph node metastasis （P 〈0. 01, P 〈0. 01 ）. IL-7/IL-7R could promote proliferation of A549 cell, increase cyclin D1 and VEGF-D expression, and enhance c-Fos/c-Jun expression and phosphorylation, resulting in formation of heterodimer. Furthermore, IL-7/IL-7R could induce binding of c-Fos/c-Jun to cyclin D1/VEGF-D promoters and regulate their transcription. IL-7/IL-7R could also promote proliferation and lymphangiogenesis of lung cancer xenograft tumors. Conclusions IL-7/IL-7R promotes c-Fos/c-Jun expression and activity in NSCLC. This further facilitates expression and accelerates proliferation of cells and VEGF-D-induced lymphovascular formation.

关 键 词：白细胞介素7 受体 白细胞介素 癌 非小细胞肺 

分 类 号：R734.2[医药卫生—肿瘤]