Targeting Src in endometriosis-associated ovarian cancer
Targeting Src in endometriosis-associated ovarian cancer
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DOI：
10.1038/oncsis.2016.54
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发表时间：
2016-08-01
期刊：
影响因子：
6.2
通讯作者：
Lawrenson, K.
中科院分区：
文献类型：
--
作者：
Manek, R.;Pakzamir, E.;Lawrenson, K.
SRC原癌基因通常在癌症发展过程中过度表达或被激活。Src家族激酶抑制剂已被批准用于治疗某些白血病，并且正在进行治疗实体瘤的临床试验。Src信号在子宫内膜异位症中被激活，子宫内膜异位症是上皮性卵巢癌（OCs）透明细胞和子宫内膜样亚型的前体。我们检测了磷酸化Src （Src- py416）在381例原发性OC组织中的表达。36%的oc表达Src-pY416。Src-pY416表达在子宫内膜异位症相关的OCs （EAOCs）中最为常见（P=0.011），特别是在透明细胞OCs中，58.5%的病例表达Src-pY416。Src-pY416表达与较短的总生存期相关（log rank P=0.002）。使用4-氨基-5-（4-氯苯基）-7-（二甲基乙基）吡唑啉[3,4-d]嘧啶（PP2）体外抑制Src信号传导导致锚定非依赖性和依赖性生长减少，在三维细胞培养模型中，PP2破坏了Src- py416阳性细胞株的聚集形成，而在Src- py416阴性细胞株中没有。这些数据表明，靶向活性Src信号可能是EAOCs的一种新的治疗机会，并支持Src家族激酶抑制剂治疗表达Src- py416的OCs的进一步临床前研究。
The SRC proto-oncogene is commonly overexpressed or activated during cancer development. Src family kinase inhibitors are approved for the treatment of certain leukemias, and are in clinical trials for the treatment of solid tumors. Src signaling is activated in endometriosis, a precursor of clear cell and endometrioid subtypes of epithelial ovarian cancers (OCs). We examined the expression of phosphorylated Src (Src-pY416) in 381 primary OC tissues. Thirty-six percent of OCs expressed Src-pY416. Src-pY416 expression was most common in endometriosis-associated OCs (EAOCs) (P=0.011), particularly in clear cell OCs where 58.5% of cases expressed Src-pY416. Src-pY416 expression was associated with shorter overall survival (log rank P=0.002). In vitro inhibition of Src signaling using 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl) pyrazolo[3,4-d] pyrimidine (PP2) resulted in reduced anchorage-independent and dependent growth, and in three-dimensional cell culture models PP2 disrupted aggregate formation in Src-pY416-positive but not in Src-pY416-negative cell lines. These data suggest that targeting active Src signaling could be a novel therapeutic opportunity for EAOCs, and support the further pre-clinical investigation of Src family kinase inhibitors for treating OCs expressing Src-pY416.