Gene expression signatures modulated by epidermal growth factor receptor activation and their relationship to cetuximab resistance in head and neck squamous cell carcinoma.
Gene expression signatures modulated by epidermal growth factor receptor activation and their relationship to cetuximab resistance in head and neck squamous cell carcinoma.
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DOI：
10.1186/1471-2164-13-160
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发表时间：
2012-05-01
期刊：
影响因子：
4.4
通讯作者：
Chung CH
中科院分区：
文献类型：
--
作者：
Fertig EJ;Ren Q;Cheng H;Hatakeyama H;Dicker AP;Rodeck U;Considine M;Ochs MF;Chung CH
表皮生长因子受体（EGFR）下游信号通路的异常激活被认为是头颈部鳞状细胞癌（HNSCC）对西妥昔单抗（EGFR单克隆抗体）耐药的机制之一。为了从HNSCC中的基因表达推断EGFR下游的相关和特异性途径激活，我们使用经受配体刺激并转染EGFR、RELA/p65或HRASVal 12 D的永生化角质形成细胞（HaCaT）产生基因表达特征。区分HaCaT变体和条件的基因表达模式使用马尔可夫链蒙特卡罗（MCMC）矩阵因子分解算法模式集中协调基因活性（CoGAPS）来推断。这种方法推断出的基因表达特征与细胞信号传导途径活化的相关性比用标准线性模型推断出的表达特征更大。此外，使用HaCaT-HRASVal 12 D产生的途径特征进一步与同基因西妥昔单抗敏感（UMSCC 1）和耐药（1CC 8）细胞系中的西妥昔单抗治疗反应相关。我们的数据表明，CoGAPS算法可以生成与受体信号通路激活的下游效应相关的基因表达特征，并可能用于对靶向治疗的耐药机制建模。
Aberrant activation of signaling pathways downstream of epidermal growth factor receptor (EGFR) has been hypothesized to be one of the mechanisms of cetuximab (a monoclonal antibody against EGFR) resistance in head and neck squamous cell carcinoma (HNSCC). To infer relevant and specific pathway activation downstream of EGFR from gene expression in HNSCC, we generated gene expression signatures using immortalized keratinocytes (HaCaT) subjected to ligand stimulation and transfected with EGFR, RELA/p65, or HRASVal12D. The gene expression patterns that distinguished the HaCaT variants and conditions were inferred using the Markov chain Monte Carlo (MCMC) matrix factorization algorithm Coordinated Gene Activity in Pattern Sets (CoGAPS). This approach inferred gene expression signatures with greater relevance to cell signaling pathway activation than the expression signatures inferred with standard linear models. Furthermore, the pathway signature generated using HaCaT-HRASVal12D further associated with the cetuximab treatment response in isogenic cetuximab-sensitive (UMSCC1) and -resistant (1CC8) cell lines. Our data suggest that the CoGAPS algorithm can generate gene expression signatures that are pertinent to downstream effects of receptor signaling pathway activation and potentially be useful in modeling resistance mechanisms to targeted therapies.
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影响因子：
3.7
作者：
Hatakeyama H;Cheng H;Wirth P;Counsell A;Marcrom SR;Wood CB;Pohlmann PR;Gilbert J;Murphy B;Yarbrough WG;Wheeler DL;Harari PM;Guo Y;Shyr Y;Slebos RJ;Chung CH
通讯作者：
Chung CH
影响因子：
3
作者：
Bidaut G;Suhre K;Claverie JM;Ochs MF
通讯作者：
Ochs MF
影响因子：
5.8
作者：
Fertig, Elana J.;Ding, Jie;Ochs, Michael F.
通讯作者：
Ochs, Michael F.
DOI：
10.1073/pnas.97.18.10101
发表时间：
2000-08-29
影响因子：
11.1
作者：
Alter, O;Brown, PO;Botstein, D
通讯作者：
Botstein, D
影响因子：
158.5
作者：
Bonner, JA;Harari, PM;Ang, KK
通讯作者：
Ang, KK