Growth regulation via insulin-like growth factor binding protein-4 and -2 in association with mutant K-ras in lung epithelia.
Growth regulation via insulin-like growth factor binding protein-4 and -2 in association with mutant K-ras in lung epithelia.
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DOI：
10.2353/ajpath.2006.051068
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发表时间：
2006-11
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通讯作者：
Hanako Sato;T. Yazawa;Takehisa Suzuki;H. Shimoyamada;K. Okudela;Masaichi Ikeda;K. Hamada;H. Yamada‐Okabe;Masayuki Yao;Y. Kubota;Takashi Takahashi;H. Kamma;H. Kitamura
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文献类型：
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作者：
Hanako Sato;T. Yazawa;Takehisa Suzuki;H. Shimoyamada;K. Okudela;Masaichi Ikeda;K. Hamada;H. Yamada‐Okabe;Masayuki Yao;Y. Kubota;Takashi Takahashi;H. Kamma;H. Kitamura
K-ras功能获得性点突变影响肺细支气管肺泡癌的早期事件我们使用寡核苷酸微阵列研究了人外周肺上皮细胞（HPL 1A）中K-Ras激活的mRNA表达改变。在HPL 1A中稳定表达的突变K-Ras加速细胞生长并诱导胰岛素样生长因子（IGF）结合蛋白（IGFBP）-4和IGFBP-2的表达，其通过IGF调节细胞生长。其他肺上皮细胞系（NHBE和HPL 1D）通过突变的K-ras转基因显示与HPL 1A相同的现象。突变的K-ras基因转导也加速了肺癌细胞的生长，而IGFBP-4/2的诱导作用比表达突变的K-ras的肺上皮细胞弱。为了解K-Ras激活的IGFBP-4/2信号通路在非肿瘤性肺上皮和肺癌中的差异，我们探讨了IGFBP-4/2转录激活的机制。我们的研究结果表明，Egr-1，这是诱导激活Ras-丝裂原活化蛋白激酶信号，是至关重要的IGFBP-4/2的反式激活。此外，IGFBP-4和IGFBP-2启动子在肺癌中经常高甲基化，产生IGFBP-4/2的低基础表达/弱诱导。这些发现表明，持续的K-Ras激活加速细胞生长，并通过IGFBP-4/2引发反馈系统，以防止过度生长。此外，由于IGFBP-4/2基因的启动子超甲基化，这种生长调节在肺癌中被破坏。
Gain-of-function point mutations in K-ras affect early events in pulmonary bronchioloalveolar carcinoma. We investigated altered mRNA expression on K-Ras activation in human peripheral lung epithelial cells (HPL1A) using oligonucleotide microarrays. Mutated K-Ras stably expressed in HPL1A accelerated cell growth and induced the expression of insulin-like growth factor (IGF)-binding protein (IGFBP)-4 and IGFBP-2, which modulate cell growth via IGF. Other lung epithelial cell lines (NHBE and HPL1D) revealed the same phenomena as HPL1A by mutated K-ras transgene. Lung cancer cell growth was also accelerated by mutated K-ras gene transduction, whereas IGFBP-4/2 induction was weaker compared with mutated K-Ras-expressing lung epithelial cells. To understand the differences in IGFBP-4/2 inducibility via K-Ras-activated signaling between nonneoplastic lung epithelia and lung carcinoma, we addressed the mechanisms of IGFBP-4/2 transcriptional activation. Our results revealed that Egr-1, which is induced on activation of Ras-mitogen-activated protein kinase signaling, is crucial for transactivation of IGFBP-4/2. Furthermore, IGFBP-4 and IGFBP-2 promoters were often hypermethylated in lung carcinoma, yielding low basal expression/weak induction of IGFBP-4/2. These findings suggest that continuous K-Ras activation accelerates cell growth and evokes a feedback system through IGFBP-4/2 to prevent excessive growth. Moreover, this growth regulation is disrupted in lung cancers because of promoter hypermethylation of IGFBP-4/2 genes.