Inhibitor of differentiation 1 contributes to head and neck squamous cell carcinoma survival via the NF-kappaB/survivin and phosphoinositide 3-kinase/Akt signaling pathways.
Inhibitor of differentiation 1 contributes to head and neck squamous cell carcinoma survival via the NF-kappaB/survivin and phosphoinositide 3-kinase/Akt signaling pathways.
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DOI：
10.1158/1078-0432.ccr-08-2362
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发表时间：
2010-01-01
期刊：
影响因子：
--
通讯作者：
Ondrey FG
中科院分区：
文献类型：
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作者：
Lin J;Guan Z;Wang C;Feng L;Zheng Y;Caicedo E;Bearth E;Peng JR;Gaffney P;Ondrey FG
癌症的一个关键问题是细胞凋亡抗性。然而，对头颈部鳞状细胞癌（HNSCC）细胞存活的转录因子知之甚少。使用三批（54、64和38）HNSCC标本进行细胞和分子分析，以确定HNSCC中细胞存活的主要分子信号传导途径。采用动物模型（细胞培养和异种移植）来验证细胞凋亡抵抗在HNSCC中的重要性。分化抑制因子（Id）家族成员Id 1在临床HNSCC标本中显著上调，并起保护角质形成细胞免于凋亡的作用。Id 1转染HNSCC细胞后，可通过磷酸肌醇激酶3（PI 3 K）诱导Akt磷酸化（p-Akt），并通过核因子κ B（NF-κB）诱导Survivin表达增加。通过特异性抑制剂（分别为LY 294002和IκBαM）阻断这两种途径可消除Id 1诱导的角质形成细胞的细胞存活。体内研究表明，Id 1的表达增加允许非致瘤性角质形成细胞（Rhek-1A）通过增加存活基因（如p-Akt和生存素）的表达而在裸鼠中成为致瘤性的。更重要的是，在异种移植研究中，Id 1的短干扰RNA（siRNA）显著减少了HNSCC的肿瘤体积。临床数据分析证实了Id 1下游分子生存素在HNSCC患者预后中的重要性。以上数据综合起来表明，Id 1及其下游效应物是治疗HNSCC的潜在靶点，因为它们有助于细胞凋亡抗性。
A key issue in cancer is apoptosis resistance. However, little is known about the transcription factors which contribute to cellular survival of head and neck squamous cell carcinoma (HNSCC). Three batches (54, 64, and 38) of HNSCC specimens were used for cellular and molecular analyses in order to determine the major molecular signaling pathways for cellular survival in HNSCC. Animal models (cell culture and xenografts) were employed to verify the importance of apoptosis resistance in HNSCC. Inhibitor of differentiation (Id) family member, Id1, was significantly up-regulated in clinical HNSCC specimens and acted to protect keratinocytes from apoptosis. Transfection of HNSCC cells with Id1 in vitro induced the phosphorylation of Akt (p-Akt) via phosphoinositide kinase-3 (PI3K) and increased the expression of survivin via nuclear factor kappa B (NF-κB). Blockage of the both pathways by specific inhibitors (LY294002 and IκBαM, respectively) abrogated Id1-induced cell survival of keratinocytes. In vivo studies demonstrated that increased expression of Id1 allowed non-tumorigenic keratinocytes (Rhek-1A) to become tumorigenic in nude mice by increased expression of survival genes such as p-Akt and survivin. More importantly, short interfering RNA (siRNA) for Id1 significantly reduced HNSCC tumorvolume of HNSCC in xenograft studies. Analysis of clinical data verified the importance of the Id1 downstream molecule, survivin, in the prognosis of HNSCC patients. The above data, taken together, suggest that Id1 and its downstream effectors are potential targets for treatment of HNSCC because of their contribution to apoptosis resistance.