Progressive tumor formation in mice with conditional deletion of TGF-beta signaling in head and neck epithelia is associated with activation of the PI3K/Akt pathway.
Progressive tumor formation in mice with conditional deletion of TGF-beta signaling in head and neck epithelia is associated with activation of the PI3K/Akt pathway.
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DOI：
10.1158/0008-5472.can-08-4623
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发表时间：
2009-07-15
期刊：
影响因子：
11.2
通讯作者：
Kulkarni AB
中科院分区：
文献类型：
--
作者：
Bian Y;Terse A;Du J;Hall B;Molinolo A;Zhang P;Chen W;Flanders KC;Gutkind JS;Wakefield LM;Kulkarni AB
TGF-β信号转导在头颈部鳞状细胞癌（HNSCC）中的确切作用尚未完全了解。在这里，我们报告了通过将TGF-β受体I（Tgfbr 1）floxed小鼠与K14-CreERtam小鼠杂交来产生可诱导的头部和颈部特异性敲除小鼠模型。通过将他莫昔芬（TM）应用于小鼠口腔以诱导Cre表达，我们能够有条件地删除小鼠头颈部上皮中的Tgfbr 1。在用7，12-二甲基苯并蒽（DMBA）诱导肿瘤后，45%的Tgfbr 1条件性敲除（cKO）小鼠（n=42）从治疗后16周开始在头部和颈部区域发展鳞状细胞癌（SCC）。然而，在对照同窝仔中未观察到肿瘤。分子分析显示，TM和DMBA治疗4周后，Tgfbr 1 cKO小鼠头颈上皮基底层增殖增强，细胞凋亡消失。我们研究中最值得注意的发现是，磷酸肌醇3-激酶（PI 3 K）/Akt通路在SCC中被激活，SCC在Tgfbr 1 cKO小鼠中发展，通过Smad 2/3和DMBA处理使TGF-β信号转导失活。这些观察结果表明，Smad非依赖性途径的激活可能有助于协同与Smad依赖性途径的失活，以促进这些小鼠的头颈部癌变。我们的研究结果揭示了TGF-β信号通路及其与PI 3 K/Akt通路的相互作用在抑制头颈癌发生中的关键作用。
The precise role of TGF-β signaling in head and neck squamous cell carcinoma (HNSCC) is not yet fully understood. Here we report generation of an inducible head- and neck-specific knockout mouse model by crossing TGF-β receptor I (Tgfbr1) floxed mice with K14-CreERtam mice. By applying tamoxifen (TM) to oral cavity of the mouse to induce Cre expression, we were able to conditionally delete Tgfbr1 in the mouse head and neck epithelia. Upon tumor induction with 7, 12-dimethylbenzanthracene (DMBA), 45% of Tgfbr1 conditional knockout (cKO) mice (n=42) developed squamous cell carcinomas (SCCs) in the head and neck area starting from 16 weeks after treatment. However, no tumors were observed in the control littermates. A molecular analysis revealed an enhanced proliferation and loss of apoptosis in the basal layer of the head and neck epithelia of Tgfbr1 cKO mice 4 weeks after TM and DMBA treatment. The most notable finding of our study is that the phosphoinositide 3-kinase (PI3K)/Akt pathway was activated in SCCs that developed in the Tgfbr1 cKO mice upon inactivation of TGF-β signaling through Smad2/3 and DMBA treatment. These observations suggest that activation of Smad-independent pathways may contribute cooperatively with inactivation of Smad-dependent pathways to promote head and neck carcinogenesis in these mice. Our results revealed the critical role of the TGF-β signaling pathway and its crosstalk with the PI3K/Akt pathway in suppressing head and neck carcinogenesis.