Receptor-interacting protein kinase 2 promotes triple-negative breast cancer cell migration and invasion via activation of nuclear factor-kappaB and c-Jun N-terminal kinase pathways.
Receptor-interacting protein kinase 2 promotes triple-negative breast cancer cell migration and invasion via activation of nuclear factor-kappaB and c-Jun N-terminal kinase pathways.
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DOI：
10.1186/bcr3629
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发表时间：
2014-03-19
期刊：
影响因子：
--
通讯作者：
Shay JW
中科院分区：
文献类型：
--
作者：
Singel SM;Batten K;Cornelius C;Jia G;Fasciani G;Barron SL;Wright WE;Shay JW
转移是乳腺癌发病和死亡的主要原因。允许肿瘤细胞迁移和侵袭的过程是重要的治疗靶点。在这里，我们证明了受体相互作用蛋白激酶2（RIP 2），一种已知参与炎症过程的激酶，在癌细胞迁移和侵袭中也具有新的作用。总共六个乳腺癌表达数据库，包括癌症基因组图谱，评估了RIP 2在各种临床亚型中的表达及其作为预后生物标志物的作用。对17例III期乳腺癌进行RIP 2的mRNA荧光原位杂交（FISH），以确定RIP 2表达与淋巴结受累之间是否存在相关性。RNA干扰用于敲低MDA-MB-231、Htb 126、SUM 149 PT、MCF 7、T47 D和HCC 1428细胞中的RIP 2表达。通过划痕/伤口愈合和transwell迁移试验在体外测量细胞迁移和侵袭。使用异种移植小鼠模型来评估在有和没有RIP 2小发夹RNA敲低的情况下MDA-MB-231细胞中的肿瘤生长和对多西他赛的体内化学敏感性。Western blot和免疫荧光成像检测蛋白表达。表达数据库的查询显示，与其他临床亚型相比，RIP 2表达在三阴性乳腺癌（TNBC：雌激素受体（ER）阴性、孕酮受体（PR）阴性、Her 2/neu-（Her 2）阴性）中显著过表达。使用由946名患者组成的联合乳腺癌表达阵列数据集，RIP 2高表达与无进展生存率较差相关。多变量分析显示RIP 2是独立的预后生物标志物。在MDA-MB-231、Htb 126、SUM 149 PT、MCF 7和T47 D细胞中，RIP 2的敲低显著降低划痕/伤口愈合和transwell迁移测定中的迁移，并且与核因子-κ B和c-Jun N-末端激酶（JNK）活化的降低相关。最后，在异种移植小鼠模型中，RIP 2敲低导致对多西他赛的敏感性增加，肿瘤质量和肺转移减少。这些结果突出了RIP 2作为晚期乳腺癌患者的促转移激酶。这些结果还说明了这种激酶除了在炎症中的已知作用外，还具有新的作用，并表明靶向RIP 2可能会改善其过表达的晚期乳腺癌患者的预后。
Metastasis is the main cause of breast cancer morbidity and mortality. Processes that allow for tumor cell migration and invasion are important therapeutic targets. Here we demonstrate that receptor-interacting protein kinase 2 (RIP2), a kinase known to be involved in inflammatory processes, also has novel roles in cancer cell migration and invasion. A total of six breast cancer expression databases, including The Cancer Genome Atlas, were assessed for RIP2 expression among various clinical subtypes and its role as a prognostic biomarker. mRNA fluorescence in situ hybridization (FISH) for RIP2 was performed on 17 stage III breast cancers to determine if there was a correlation between RIP2 expression and lymph node involvement. RNA-interference was used to knock-down RIP2 expression in MDA-MB-231, Htb126, SUM149PT, MCF7, T47D, and HCC1428 cells. Cell migration and invasion were measured in vitro by scratch/wound healing and transwell migration assays. A xenograft mouse model was used to assess tumor growth and chemosensitivity to docetaxel in vivo in MDA-MB-231 cells with and without RIP2 small hairpin RNA knockdown. Western blot and immunofluorescence imaging were used to evaluate protein expressions. Interrogation of expression databases showed that RIP2 expression is significantly over-expressed in triple-negative breast cancers (TNBC: estrogen-receptor (ER) negative, progesterone-receptor (PR) negative, Her2/neu- (Her2) negative), compared to other clinical subtypes. High RIP2 expression correlates with worse progression-free survival using a combined breast cancer expression array dataset consisting of 946 patients. Multivariate analysis shows RIP2 as an independent prognostic biomarker. Knock-down of RIP2 significantly decreases migration in both scratch/wound healing and transwell migration assays in MDA-MB-231, Htb126, SUM149PT, MCF7, and T47D cells and is correlated with decreased Nuclear Factor-kappaB and c-Jun N-terminal kinase (JNK) activation. Finally, RIP2 knock-down leads to increased sensitivity to docetaxel and decreased tumor mass and lung metastases in a xenograft mouse model. These results highlight RIP2 as a pro-metastasis kinase in patients with advanced breast cancer. These results also illustrate a novel role for this kinase in addition to its known role in inflammation, and suggest that targeting RIP2 may improve outcomes in advanced breast cancer patients, in which it is overexpressed.
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DOI：
10.1083/jcb.200511061
发表时间：
2006-01-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gruneberg U;Neef R;Li X;Chan EH;Chalamalasetty RB;Nigg EA;Barr FA
通讯作者：
Barr FA
影响因子：
6.4
作者：
Moreau, Marie;Mourah, Samia;Dosquet, Christine
通讯作者：
Dosquet, Christine
影响因子：
11.2
作者：
Hartman ZC;Poage GM;den Hollander P;Tsimelzon A;Hill J;Panupinthu N;Zhang Y;Mazumdar A;Hilsenbeck SG;Mills GB;Brown PH
通讯作者：
Brown PH
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
4.8
作者：
Helbig, G;Christopherson, KW;Nakshatri, H
通讯作者：
Nakshatri, H