VEGFR3 inhibition chemosensitizes lung adenocarcinoma A549 cells in the tumor-associated macrophage microenvironment through upregulation of p53 and PTEN.
VEGFR3 inhibition chemosensitizes lung adenocarcinoma A549 cells in the tumor-associated macrophage microenvironment through upregulation of p53 and PTEN.
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VEGFR3 抑制通过上调 p53 和 PTEN 使肿瘤相关巨噬细胞微环境中的肺腺癌 A549 细胞变得化学敏感
DOI：
10.3892/or.2017.5969
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发表时间：
2017-11
期刊：
影响因子：
4.2
通讯作者：
Shi Q
中科院分区：
文献类型：
--
作者：
Li Y;Weng Y;Zhong L;Chong H;Chen S;Sun Y;Li W;Shi Q
在肺腺癌中，肿瘤中p53和PTEN的缺失与对化疗的反应降低和存活率降低相关。通过上调p53和PTEN蛋白表达可以改善p53和PTEN缺陷型肿瘤患者的预后。在本研究中，我们揭示了肺腺癌细胞中血管内皮生长因子受体3（VEGFR 3）的抑制与肿瘤相关巨噬细胞（TAM）微环境中p53和PTEN表达水平的提高有关。肺腺癌细胞中VEGFR 3的抑制与生长停滞以及迁移和侵袭减少相关。在共培养的A549细胞中，VEGFR 3抑制后p53和PTEN蛋白表达的上调降低了化疗耐药性并提高了化疗敏感性，其中p53和PTEN表达降低。最后，我们证明TAM促进VEGF-C及其受体VEGFR 3的表达。蛋白质印迹分析显示，与TAM共培养的A549细胞是肿瘤微环境中VEGF-C和VEGFR 3的主要来源。我们的研究表明，VEGFR 3抑制可能是上调p53和PTEN蛋白表达并改善p53和PTEN缺陷型肿瘤患者预后的药理学手段。
In lung adenocarcinoma, loss of p53 and PTEN in tumors are associated with decreased response to chemotherapy and decreased survival. A means to pharmacologically upregulate p53 and PTEN protein expression could improve the prognosis of patients with p53- and PTEN-deficient tumors. In the present study we revealed that vascular endothelial growth factor receptor 3 (VEGFR3) inhibition in lung adenocarcinoma cells was associated with improved expression levels of both p53 and PTEN in the tumor-associated macrophage (TAM) microenvironment. Inhibition of VEGFR3 in lung adenocarcinoma cells was associated with growth arrest and decreased migration and invasion. The upregulation of p53 and PTEN protein expression after VEGFR3 inhibition decreased chemotherapy resistance and improved chemosensitivity in co-cultured A549 cells in which p53 and PTEN expression were decreased. Finally, we demonstrated that TAMs promoted the expression of VEGF-C and its receptor VEGFR3. Western blot analysis revealed the co-cultured A549 cells with TAMs are a primary source of VEGF-C and VEGFR3 in the tumor microenvironment. Our studies revealed that VEGFR3 inhibition may be a pharmacological means to upregulate p53 and PTEN protein expression and improve the outcome of patients with p53- and PTEN-deficient tumors.
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影响因子：
4.4
作者：
Martinez, Fernando O.;Gordon, Siamon;Mantovani, Alberto
通讯作者：
Mantovani, Alberto
影响因子：
1.3
作者：
Mills, Charles D.
通讯作者：
Mills, Charles D.
DOI：
10.1084/jem.20111424
发表时间：
2012-03-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hamerlik P;Lathia JD;Rasmussen R;Wu Q;Bartkova J;Lee M;Moudry P;Bartek J Jr;Fischer W;Lukas J;Rich JN;Bartek J
通讯作者：
Bartek J
影响因子：
4.8
作者：
Mayo, LD;Dixon, JE;Donner, DB
通讯作者：
Donner, DB
影响因子：
82.9
作者：
Beer, DG;Kardia, SLR;Hanash, S
通讯作者：
Hanash, S