A role for p38 MAPK in head and neck cancer cell growth and tumor-induced angiogenesis and lymphangiogenesis.
A role for p38 MAPK in head and neck cancer cell growth and tumor-induced angiogenesis and lymphangiogenesis.
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DOI：
10.1016/j.molonc.2013.10.003
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发表时间：
2014-02
影响因子：
6.6
通讯作者：
Gutkind, J. Silvio
中科院分区：
文献类型：
--
作者：
Leelahavanichkul, Kantima;Amornphimoltham, Panomwat;Molinolo, Alfredo A.;Basile, John R.;Koontongkaew, Sittichai;Gutkind, J. Silvio
我们最近获得了一个显着的了解突变景观的头颈部鳞状细胞癌（HNSCC）。然而，导致HNSCC进展的失调信号网络的性质仍然不清楚。在此，我们重点研究了丝裂原活化激酶（MAPK）家族、细胞外调节激酶（ERK）、c-Jun末端激酶（JNK）和p38 MAPK在HNSCC中的作用。对大量人类HNSCC组织的免疫组织化学分析显示，磷酸化的ERK 1/2和JNK活性形式的水平分别在不到33%和16%的病例中升高。然而，引人注目的是，在分析的数百个组织中的大多数（79%）中观察到高水平的活性磷酸化p38。我们使用三种独立的方法探索了p38在HNSCC细胞系中的生物学作用：用特异性p38抑制剂SB-203580处理;包括使用SB-203580与p38α的不敏感突变形式的表达相结合的逆转录抑制策略;以及靶向p38α的短发夹RNA（shRNAs）。我们发现，特异性阻断p38信号转导显着抑制HNSCC细胞在体外和体内的增殖。事实上，我们观察到HNSCC癌细胞中的p38抑制减少了肿瘤异种移植物中的癌症生长，并且显著减少了肿瘤内血管和淋巴管。我们的结论是p38α在肿瘤微环境中作为HNSCC的正性调节因子发挥作用，控制癌细胞生长以及肿瘤诱导的血管生成和淋巴管生成。
We have recently gained a remarkable understanding of the mutational landscape of head and neck squamous cell carcinoma (HNSCC). However, the nature of the dysregulated signaling networks contributing to HNSCC progression is still poorly defined. Here, we have focused on the role of the family of mitogen activated kinases (MAPKs), extracellular regulated kinase (ERK), c-Jun terminal kinase (JNK) and p38 MAPK in HNSCC. Immunohistochemical analysis of a large collection of human HNSCC tissues revealed that the levels of the phosphorylated active form of ERK1/2 and JNK were elevated in less than 33% and 16% of the cases, respectively. Strikingly, however, high levels of active phospho-p38 were observed in most (79%) of hundreds of tissues analyzed. We explored the biological role of p38 in HNSCC cell lines using three independent approaches: treatment with a specific p38 inhibitor, SB-203580; a retro-inhibition strategy consisting in the use of SB-203580 combined with the expression of an inhibitor-insensitive mutant form of p38α; and short-hairpin RNAs (shRNAs) targeting p38α. We found that specific blockade of p38 signaling significantly inhibited the proliferation of HNSCC cells both in vitro and in vivo. Indeed, we observed that p38 inhibition in HNSCC cancer cells reduces cancer growth in tumor xenografts and a remarkable decrease in intratumoral blood and lymphatic vessels. We conclude that p38α functions as a positive regulator of HNSCC in the context of the tumor microenvironment, controlling cancer cell growth as well as tumor-induced angiogenesis and lymphangiogenesis.
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影响因子：
11.2
作者：
Chen L;Mayer JA;Krisko TI;Speers CW;Wang T;Hilsenbeck SG;Brown PH
通讯作者：
Brown PH
DOI：
10.1165/ajrcmb.26.5.4689
发表时间：
2002-05-01
影响因子：
6.4
作者：
Greenberg, AK;Basu, S;Lee, TC
通讯作者：
Lee, TC
影响因子：
30.8
作者：
Hui, Lijian;Bakiri, Latifa;Wagner, Erwin F.
通讯作者：
Wagner, Erwin F.
影响因子：
4.3
作者：
Hui, Lijian;Bakiri, Latifa;Wagner, Erwin F.
通讯作者：
Wagner, Erwin F.
DOI：
10.1155/2012/169170
发表时间：
2012
期刊：
Journal of signal transduction
影响因子：
--
作者：
Rodríguez-Berriguete G;Fraile B;Martínez-Onsurbe P;Olmedilla G;Paniagua R;Royuela M
通讯作者：
Royuela M