Yang Zhiyong, Bach Leon A
Department of Medicine (Alfred), Monash University , Prahran, VIC , Australia.
Department of Medicine (Alfred), Monash University , Prahran, VIC , Australia ; Department of Endocrinology and Diabetes, Alfred Hospital , Melbourne, VIC , Australia.
Front Endocrinol (Lausanne). 2015 Jan 5;5:231. doi: 10.3389/fendo.2014.00231. eCollection 2014.
IGFBP-6 inhibits angiogenesis as well as proliferation and survival of rhabdomyosarcoma cells. However, it promotes migration of these cells in an IGF-independent manner. The IGF system is implicated in ovarian cancer, so we studied the effects of IGFBP-6 in ovarian cancer cells.
The effects of wild type (wt) and a non-IGF-binding mutant (m) of IGFBP-6 on migration of HEY and SKOV3 ovarian cancer cells, which, respectively, represent aggressive and transitional cancers, were studied. ERK and JNK phosphorylation were measured by Western blotting.
IGF-II, wt-, and mIGFBP-6 each promoted SKOV3 cell migration by 77-98% (p < 0.01). In contrast, IGF-II also increased HEY cell migration to 155 ± 13% of control (p < 0.001), but wt-IGFBP-6 and mIGFBP-6 decreased migration to 62 ± 5 and 66 ± 3%, respectively (p < 0.001). In these cells, coincubation of IGF-II with wt but not mIGFBP-6 increased migration. MAP kinase pathways are involved in IGFBP-6-induced rhabdomyosarcoma cell migration, so activation of these pathways was studied in HEY and SKOV3 cells. Wt and mIGFBP-6 increased ERK phosphorylation by 62-99% in both cell lines (p < 0.05). Wt-IGFBP-6 also increased JNK phosphorylation by 139-153% in both cell lines (p < 0.05), but the effect of mIGFBP-6 was less clear. ERK and JNK inhibitors partially inhibited the migratory effects of wt and mIGFBP-6 in SKOV3 cells, whereas the ERK inhibitor partially restored wt and mIGFBP-6-induced inhibition of HEY cell migration. The JNK inhibitor had a lesser effect on the actions of wtIGFBP-6 and no effect on the actions of mIGFBP-6 in HEY cells.
IGFBP-6 has opposing effects on migration of HEY and SKOV3 ovarian cancer cells, but activates MAP kinase pathways in both. Delineating the pathways underlying the differential effects on migration will increase our understanding of ovarian cancer metastasis and shed new light on the IGF-independent effects of IGFBP-6.
胰岛素样生长因子结合蛋白6（IGFBP - 6）可抑制血管生成以及横纹肌肉瘤细胞的增殖和存活。然而，它以不依赖IGF的方式促进这些细胞的迁移。IGF系统与卵巢癌有关，因此我们研究了IGFBP - 6在卵巢癌细胞中的作用。
研究了野生型（wt）和IGF结合缺陷型突变体（m）的IGFBP - 6对分别代表侵袭性癌和过渡性癌的HEY和SKOV3卵巢癌细胞迁移的影响。通过蛋白质免疫印迹法检测ERK和JNK磷酸化水平。
IGF - II、wt - IGFBP - 6和mIGFBP - 6均可使SKOV3细胞迁移增加77 - 98%（p < 0.01）。相比之下，IGF - II也使HEY细胞迁移增加至对照的155 ± 13%（p < 0.001），但wt - IGFBP - 6和mIGFBP - 6分别使迁移减少至62 ± 5%和66 ± 3%（p < 0.001）。在这些细胞中，IGF - II与wt - IGFBP - 6而非mIGFBP - 6共同孵育可增加迁移。MAP激酶途径参与IGFBP - 6诱导的横纹肌肉瘤细胞迁移，因此在HEY和SKOV3细胞中研究了这些途径的激活情况。wt - IGFBP - 6和mIGFBP - 6均可使两种细胞系中的ERK磷酸化增加62 - 99%（p < 0.05）。wt - IGFBP - 6还可使两种细胞系中的JNK磷酸化增加139 - 153%（p < 0.05），但mIGFBP - 6的作用不太明确。ERK和JNK抑制剂部分抑制了wt - IGFBP - 6和mIGFBP - 6对SKOV3细胞的迁移作用，而ERK抑制剂部分恢复了wt - IGFBP - 6和mIGFBP - 6对HEY细胞迁移的抑制作用。JNK抑制剂对wt - IGFBP - 6在HEY细胞中的作用影响较小，对mIGFBP - 6在HEY细胞中的作用无影响。
IGFBP - 6对HEY和SKOV3卵巢癌细胞的迁移具有相反的作用，但在两种细胞中均激活MAP激酶途径。阐明对迁移产生不同影响的潜在途径将增进我们对卵巢癌转移的理解，并为IGFBP - 6不依赖IGF的作用提供新的线索。
