Functional proteomic analysis of advanced serous ovarian cancer using reverse phase protein array: TGF-beta pathway signaling indicates response to primary chemotherapy.
Functional proteomic analysis of advanced serous ovarian cancer using reverse phase protein array: TGF-beta pathway signaling indicates response to primary chemotherapy.
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DOI：
10.1158/1078-0432.ccr-09-2502
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发表时间：
2010-05-15
期刊：
影响因子：
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通讯作者：
Hennessy BT
中科院分区：
文献类型：
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作者：
Carey MS;Agarwal R;Gilks B;Swenerton K;Kalloger S;Santos J;Ju Z;Lu Y;Zhang F;Coombes KR;Miller D;Huntsman D;Mills GB;Hennessy BT
我们使用反相蛋白质阵列技术(RPPA)检测了晚期高级别浆液性卵巢癌患者对初次化疗的反应相关蛋白的表达。肿瘤样本来自不列颠哥伦比亚省癌症机构妇科肿瘤库的45名晚期高级别浆液性癌症患者。治疗包括去髓核手术后以铂为基础的化疗。从新鲜的冷冻肿瘤样本中制备蛋白质裂解物，并用RPPA检测与卵巢癌发生有关的信号通路中的80种有效蛋白质。将化疗第3周期的Ca-125正常化作为评价化疗疗效的主要指标。用Logistic回归分析确定Ca-125正常化的蛋白预测因素，用COX回归检验蛋白表达与PFS之间的关系。采用显著性水平p≤0.0 5。平均确诊年龄为56.8岁。单因素检验显示，EGFR、YKL-40和几种转化生长因子β途径蛋白(c-jun氨基末端激酶JNK、第183位和185位磷酸化的JNK、PAI-1、Smad3、TAZ)与Ca-125的正常化显著相关。在多变量分析中，EGFR(p<；0.02)、JNK(p<；0.01)和Smad3(p<；0.04)与Ca-125正常化显著相关。对途径分类蛋白的列联表分析显示，由于错误发现，不太可能选择转化生长因子β途径蛋白(p<；0.007，Bonferroni调整)。转化生长因子β信号通路可能作为晚期浆液性卵巢癌化疗耐药的标志物或介体发挥重要作用。在此基础上，进一步研究开发和验证治疗失败的有用预测指标是有必要的。
Using Reverse Phase Protein Array (RPPA) we measured protein expression associated with response to primary chemotherapy in patients with advanced-stage high-grade serous ovarian cancer. Tumor samples were obtained from forty-five patients with advanced high-grade serous cancers from the Gynecology Tumor Bank at the British Columbia Cancer Agency. Treatment consisted of platinum-based chemotherapy following debulking surgery. Protein lysates were prepared from fresh frozen tumor samples and 80 validated proteins from signaling pathways implicated in ovarian carcinogenesis were measured by RPPA. Normalization of Ca-125 by the 3rd cycle of chemotherapy was chosen as the primary outcome measure of chemotherapy response. Logistic regression was used for multivariate analysis to identify protein predictors of Ca-125 normalization, and Cox regression to test for the association between protein expression and PFS. A significance level of p ≤ 0.05 was used. The mean age at diagnosis was 56.8 years. EGFR, YKL-40 and several TGFβ pathway proteins (c-Jun N-terminal kinase JNK, JNK phosphorylated at residues 183 and 185, PAI-1, Smad3, TAZ) showed significant associations with Ca-125 normalization on univariate testing. On multivariate analysis, EGFR (p < 0.02), JNK (p < 0.01), and Smad3 (p < 0.04) were significantly associated with normalization of Ca-125. Contingency table analysis of pathway-classified proteins revealed that the selection of TGFβ pathway proteins was unlikely due to false discovery (p < 0.007, Bonferroni-adjusted). TGFβ pathway signaling likely plays an important role as a marker or mediator of chemoresistance in advanced serous ovarian cancer. On this basis, future studies to develop and validate a useful predictor of treatment failure are warranted.