Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration.
Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration.
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DOI：
10.1038/bjc.2011.133
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发表时间：
2011-05-10
影响因子：
8.8
通讯作者：
Williams, K. P.
中科院分区：
文献类型：
--
作者：
Thomas, Z. I.;Gibson, W.;Sexton, J. Z.;Aird, K. M.;Ingram, S. M.;Aldrich, A.;Lyerly, H. K.;Devi, G. R.;Williams, K. P.
炎症性乳腺癌(IBC)是乳腺癌的一种侵袭性亚型，具有不同的分子特征。基因表达谱以前发现sonic hedgehog(SHH)是IBC患者差异调控的基因信号的一部分。采用免疫印迹法、四甲基偶氮唑盐比色法、Annexin-V/PI法、常规细胞迁移实验和自动细胞迁移实验检测GLI1对细胞蛋白表达、细胞增殖、细胞凋亡和迁移的影响。对一组乳腺癌细胞株的评估显示，在对ErbB1/2靶向策略产生抗药性的三阴性、高侵袭性IBC细胞系SUM149及其同基因衍生的rSUM149中，GLI1表达升高，这通常是刺激性信号通路激活的标志。用小干扰RNA或小分子GLI1抑制剂下调SUM149和rSUM149细胞中GLI1的表达，可抑制细胞增殖，促进细胞凋亡。此外，与低GLI1表达的非侵袭性细胞株MCF-7相比，这些细胞系中GLI1的抑制显著抑制了细胞的迁移，这一点通过伤口愈合试验进行了评估。一种新的高含量迁移试验使我们能够量化GLI1沉默的多种影响，包括显着减少细胞移动距离和运动的线性。我们的数据揭示了GLI1在IBC细胞的增殖、存活和迁移中的作用，这支持了将GLI1作为IBC患者的一种新的治疗策略的可行性。
Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer with distinct molecular profiles. Gene expression profiling previously identified sonic hedgehog (SHH) as part of a gene signature that is differentially regulated in IBC patients. The effects of reducing GLI1 levels on protein expression, cell proliferation, apoptosis and migration were determined by immunoblots, MTT assay, Annexin-V/PI assay and conventional and automated cell migration assays. Evaluation of a panel of breast cancer cell lines revealed elevated GLI1 expression, typically a marker for hedgehog-pathway activation, in a triple-negative, highly invasive IBC cell line, SUM149 and its isogenic-derived counterpart rSUM149 that has acquired resistance to ErbB1/2 targeting strategies. Downregulation of GLI1 expression in SUM149 and rSUM149 by small interfering RNA or a small molecule GLI1 inhibitor resulted in decreased proliferation and increased apoptosis. Further, GLI1 suppression in these cell lines significantly inhibited cell migration as assessed by a wound-healing assay compared with MCF-7, a non-invasive cell line with low GLI1 expression. A novel high-content migration assay allowed us to quantify multiple effects of GLI1 silencing including significant decreases in cell distance travelled and linearity of movement. Our data reveal a role for GLI1 in IBC cell proliferation, survival and migration, which supports the feasibility of targeting GLI1 as a novel therapeutic strategy for IBC patients.
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影响因子：
5.7
作者：
Aird, Katherine M.;Ding, Xiuyun;Devi, Gayathri R.
通讯作者：
Devi, Gayathri R.
影响因子：
8.8
作者：
Forozan, F;Veldman, R;Ammerman, CA;Parsa, NZ;Kallioniemi, A;Kallioniemi, OP;Ethier, SP
通讯作者：
Ethier, SP
影响因子：
4.8
作者：
Das, Shamik;Harris, Lillianne G.;Shevde, Lalita A.
通讯作者：
Shevde, Lalita A.
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
11.2
作者：
Dennler, Sylviane;Andre, Jocelyne;Mauviel, Alain
通讯作者：
Mauviel, Alain