Subtype of Neuroblastoma Cells with High KIT Expression Are Dependent on KIT and Its Knockdown Induces Compensatory Activation of Pro-Survival Signaling.
Subtype of Neuroblastoma Cells with High KIT Expression Are Dependent on KIT and Its Knockdown Induces Compensatory Activation of Pro-Survival Signaling.
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DOI：
10.3390/ijms23147724
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发表时间：
2022-07-13
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
神经母细胞瘤（NB）是一种具有高度临床和分子异质性的儿科癌症，高危肿瘤患者的治疗选择有限。受体酪氨酸激酶KIT已被确定为一个潜在的标记物，高风险的NB和一个有前途的目标，NB的治疗。我们研究了20种癌症类型的19，145种肿瘤RNA表达和分子途径激活谱，并检测到NB中相对高水平的KIT表达。KIT表达的增加与细胞存活途径的激活、凋亡诱导下调和细胞周期检查点控制途径相关。在SH-SY 5 Y细胞中用慢病毒载体编码的shRNA敲低KIT导致细胞增殖和凋亡诱导降低高达50%。我们的数据表明，细胞凋亡诱导是由有丝分裂灾难引起的，并且KIT敲除后G2-M细胞周期阶段的百分比减少了2倍。我们发现NB细胞中的KIT敲低导致其他促存活生长因子信号级联如EPO、NGF、IL-6和IGF-1通路的强烈上调。NGF、IGF-1和EPO能够以ERK 1/2依赖性方式增加KIT耗竭细胞中的细胞增殖。总体而言，我们表明，KIT是一个有前途的治疗目标，在NB，虽然这种治疗效率可能会受到阻碍的生长因子信号转导激活。
Neuroblastoma (NB) is a pediatric cancer with high clinical and molecular heterogeneity, and patients with high-risk tumors have limited treatment options. Receptor tyrosine kinase KIT has been identified as a potential marker of high-risk NB and a promising target for NB treatment. We investigated 19,145 tumor RNA expression and molecular pathway activation profiles for 20 cancer types and detected relatively high levels of KIT expression in NB. Increased KIT expression was associated with activation of cell survival pathways, downregulated apoptosis induction, and cell cycle checkpoint control pathways. KIT knockdown with shRNA encoded by lentiviral vectors in SH-SY5Y cells led to reduced cell proliferation and apoptosis induction up to 50%. Our data suggest that apoptosis induction was caused by mitotic catastrophe, and there was a 2-fold decrease in percentage of G2-M cell cycle phase after KIT knockdown. We found that KIT knockdown in NB cells leads to strong upregulation of other pro-survival growth factor signaling cascades such as EPO, NGF, IL-6, and IGF-1 pathways. NGF, IGF-1 and EPO were able to increase cell proliferation in KIT-depleted cells in an ERK1/2-dependent manner. Overall, we show that KIT is a promising therapeutic target in NB, although such therapy efficiency could be impeded by growth factor signaling activation.
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
8
作者：
Lebedev T;Vagapova E;Spirin P;Rubtsov P;Astashkova O;Mikheeva A;Sorokin M;Vladimirova U;Suntsova M;Konovalov D;Roumiantsev A;Stocking C;Buzdin A;Prassolov V
通讯作者：
Prassolov V
影响因子：
5
作者：
Chilamakuri R;Rouse DC;Yu Y;Kabir AS;Muth A;Yang J;Lipton JM;Agarwal S
通讯作者：
Agarwal S
影响因子：
2.8
作者：
Ergun, Sercan;Altay, Diler Us;Abur, Ummet
通讯作者：
Abur, Ummet
DOI：
10.2147/dddt.s89114
发表时间：
2016
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Abbaspour Babaei M;Kamalidehghan B;Saleem M;Huri HZ;Ahmadipour F
通讯作者：
Ahmadipour F