An E3 ubiquitin ligase: c-Cbl: a new therapeutic target of lung cancer.
An E3 ubiquitin ligase: c-Cbl: a new therapeutic target of lung cancer.
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作者：
Lo FY;Tan YH;Cheng HC;Salgia R;Wang YC
C-Cbl是多种酪氨酸激酶受体的E3泛素连接酶。我们先前在非小细胞肺癌(NSCLC)中检测到c-Cbl突变和低蛋白表达。因此，我们推测c-Cbl野生型(WT)的过表达可能具有肿瘤抑制作用。通过伤口愈合实验和Transwell实验检测c-Cbl WT在非小细胞肺癌细胞系中的细胞运动能力。流式细胞仪检测细胞周期。采用A549和H1299-Luc c-Cbl WT异种移植瘤和实验性转移模型，观察体内肿瘤生长和转移抑制情况。伤口愈合和Transwell检测显示，4-24小时后，A549和H226br细胞的迁移受到抑制。异位c-Cbl WT表达可抑制A549细胞48小时的增殖。重要的是，异位表达c-Cbl WT的A549和H1299-Luc细胞在体内显示出对肿瘤生长的抑制作用。高表达c-Cbl WT的A549细胞在动物模型中抑制肿瘤转移。我们的研究首次证明了c-Cbl WT蛋白过表达抑制了肺癌移植瘤模型中的肿瘤转移和肿瘤生长。我们的结果为异位表达c-Cbl WT蛋白提供了证据，可以作为肺癌治疗的靶向治疗。
c-Cbl is an E3 ubiquitin ligase of many tyrosine kinase receptors. We previously detected c-Cbl mutation and low protein expression in non-small cell lung cancer (NSCLC). Therefore, we hypothesized that the overexpression of c-Cbl wild type (WT) may exhibit tumor inhibition. Wound healing and transwell assays were conducted to examine cell motility after c-Cbl WT transfection in NSCLC cell lines. Cell cycle was investigated by flow cytometry. A549 and H1299-luc c-Cbl WT xenograft and experimental metastasis model were performed to investigate tumor growth and metastasis inhibition in vivo. Wound healing and transwell assays showed inhibition of migration in A549 and H226br cells 4-24 hr post-transfection. Ectopic c-Cbl WT expression reduced cell proliferation at 48 hr in A549 cells. Importantly, A549 and H1299-luc cells with ectopic c-Cbl WT expression showed inhibition of tumor growth in vivo. A549 cells overexpressing c-Cbl WT inhibited tumor metastasis in animal models. Our study demonstrates for the first time that c-Cbl WT protein overexpression inhibits tumor metastasis and tumor growth in lung cancer xenograft models. Our results provide evidence that ectopic expression of c-Cbl WT protein can be potentially applied as targeted therapy for lung cancer treatment.
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