Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma.
Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma.
复制标题
DOI：
10.1371/journal.pone.0012702
复制
发表时间：
2010-09-13
期刊：
影响因子：
3.7
通讯作者：
Chung CH
中科院分区：
文献类型：
--
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
我们假设西妥昔单抗（一种单克隆抗 EGFR 抗体）对表皮生长因子受体 (EGFR) 的长期抑制会诱导其配体上调，从而导致耐药性，并且 microRNA (miR) 在头颈鳞状细胞癌 (HNSCC) 的配体调节中发挥重要作用。使用 DNA 微阵列和 RT-PCR 确定西妥昔单抗敏感细胞系 SCC1 及其耐药衍生物 1Cc8 中基因和 miR 表达的全基因组变化。通过 MTS、集落形成、ELISA 和蛋白质印迹分析检查差异表达 EGFR 配体和 miR 的影响。当比较 SCC1 和 1Cc8 的基因和 miR 表达时，肝素结合 EGF 样生长因子 (HB-EGF) 及其调节因子 miR-212 的差异表达具有统计学意义。 HB-EGF 刺激可诱导敏感细胞系对西妥昔单抗产生耐药性。抑制 HB-EGF 和添加 miR-212 模拟物可诱导耐药细胞系中的西妥昔单抗敏感性。在另外 33 个 HNSCC 和角质形成细胞系中，MicroRNA-212 和 HB-EGF 表达呈负相关。检查了来自 HNSCC 患者的 6 个肿瘤和 46 个血浆样本的 HB-EGF 水平。与复发疾病的患者相比，新诊断的 HNSCC 患者的 HB-EGF 血浆水平较低。由于 miR-212 下调而导致 HB-EGF 表达增加是西妥昔单抗耐药的可能机制。 EGFR配体抑制剂或miR调节剂与西妥昔单抗的组合可以改善西妥昔单抗治疗HNSCC的临床结果。
We hypothesized that chronic inhibition of epidermal growth factor receptor (EGFR) by cetuximab, a monoclonal anti-EGFR antibody, induces up-regulation of its ligands resulting in resistance and that microRNAs (miRs) play an important role in the ligand regulation in head and neck squamous cell carcinoma (HNSCC). Genome-wide changes in gene and miR expression were determined in cetuximab-sensitive cell line, SCC1, and its resistant derivative 1Cc8 using DNA microarrays and RT-PCR. The effects of differentially expressed EGFR ligands and miRs were examined by MTS, colony formation, ELISA, and western blot assays. Heparin-binding EGF-like growth factor (HB-EGF) and its regulator, miR-212, were differentially expressed with statistical significance when SCC1 and 1Cc8 were compared for gene and miR expression. Stimulation with HB-EGF induced cetuximab resistance in sensitive cell lines. Inhibition of HB-EGF and the addition of miR-212 mimic induced cetuximab sensitivity in resistant cell lines. MicroRNA-212 and HB-EGF expression were inversely correlated in an additional 33 HNSCC and keratinocyte cell lines. Six tumors and 46 plasma samples from HNSCC patients were examined for HB-EGF levels. HB-EGF plasma levels were lower in newly diagnosed HNSCC patients when compared to patients with recurrent disease. Increased expression of HB-EGF due to down-regulation of miR-212 is a possible mechanism of cetuximab resistance. The combination of EGFR ligand inhibitors or miR modulators with cetuximab may improve the clinical outcome of cetuximab therapy in HNSCC.
登录
查看更多内容
影响因子：
45.3
作者：
Khambata-Ford, Shirin;Garrett, Christopher R.;Mauro, David J.
通讯作者：
Mauro, David J.
影响因子：
158.5
作者：
Bonner, JA;Harari, PM;Ang, KK
通讯作者：
Ang, KK
影响因子：
4.8
作者：
Iwamoto, R;Handa, K;Mekada, E
通讯作者：
Mekada, E
影响因子：
45.3
作者：
Cohen, EEW;Rosen, F;Vokes, EE
通讯作者：
Vokes, EE
影响因子：
56.9
作者：
Engelman, Jeffrey A.;Zejnullahu, Kreshnik;Janne, Pasi A.
通讯作者：
Janne, Pasi A.