Map2k4 Functions as a Tumor Suppressor in Lung Adenocarcinoma and Inhibits Tumor Cell Invasion by Decreasing Peroxisome Proliferator-Activated Receptor γ2 Expression
Map2k4 Functions as a Tumor Suppressor in Lung Adenocarcinoma and Inhibits Tumor Cell Invasion by Decreasing Peroxisome Proliferator-Activated Receptor γ2 Expression
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DOI：
10.1128/mcb.05562-11
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发表时间：
2011-11-01
影响因子：
5.3
通讯作者：
Kurie, Jonathan M.
中科院分区：
文献类型：
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作者：
Ahn, Young-Ho;Yang, Yanan;Kurie, Jonathan M.
MAP 2K 4编码在多种人类恶性肿瘤中突变的双特异性激酶（丝裂原活化蛋白激酶激酶4，或MKK 4），但是突变激酶的生化特性及其在肿瘤发生中的作用尚未完全阐明。在这里，我们发现11个癌症相关的MAP 2K 4突变中有8个降低了MKK 4蛋白的稳定性或损害了其激酶活性。基于对具有纯合MAP 2K 4缺失的人癌细胞系的生物信息学研究的发现，我们假设MKK 4在小鼠中由于突变型Kras和Tp 53的表达而发展的肺腺癌中作为肿瘤抑制因子起作用。小鼠支气管上皮中的条件性Map 2k 4失活没有单独的明显影响，但增加了致癌Kras诱导的早期肺肿瘤的多样性并加速了其生长。MKK 4抑制Kras-Tp 53突变肺腺癌细胞的侵袭和转移。MKK 4缺陷通过非经典MKK 4底物增加过氧化物酶体增殖物激活受体γ 2（PPAR γ 2）表达，并且PPAR γ 2增强肿瘤细胞侵袭。我们的结论是，Map 2k 4作为一种肿瘤抑制因子在肺腺癌中发挥作用，并通过降低PPAR γ 2水平来抑制肿瘤细胞的侵袭。
MAP2K4 encodes a dual-specificity kinase (mitogen-activated protein kinase kinase 4, or MKK4) that is mutated in a variety of human malignancies, but the biochemical properties of the mutant kinases and their roles in tumorigenesis have not been fully elucidated. Here we showed that 8 out of 11 cancer-associated MAP2K4 mutations reduce MKK4 protein stability or impair its kinase activity. On the basis of findings from bioinformatic studies on human cancer cell lines with homozygous MAP2K4 loss, we posited that MKK4 functions as a tumor suppressor in lung adenocarcinomas that develop in mice owing to expression of mutant Kras and Tp53. Conditional Map2k4 inactivation in the bronchial epithelium of mice had no discernible effect alone but increased the multiplicity and accelerated the growth of incipient lung neoplasias induced by oncogenic Kras. MKK4 suppressed the invasion and metastasis of Kras-Tp53-mutant lung adenocarcinoma cells. MKK4 deficiency increased peroxisomal proliferator-activated receptor gamma 2 (PPAR gamma 2) expression through noncanonical MKK4 substrates, and PPAR gamma 2 enhanced tumor cell invasion. We conclude that Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing PPAR gamma 2 levels.