Ho Ming-Yi, Liang Chi-Ming, Liang Shu-Mei
Genomics Research Center, Academia Sinica, Taipei, Taiwan, ROC.
Genomics Research Center, Academia Sinica, Taipei, Taiwan, ROC. Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC.
Oncotarget. 2015 Jan 1;6(1):381-93. doi: 10.18632/oncotarget.2804.
Growth factors and COX-2/PGE2 enhance lung cancer invasion/metastasis via PI3K/Akt and RAS/Raf. Here, we explored their mechanism of action further. We found first that higher levels of migration inducting gene-7 protein (MIG-7) and PHB phosphorylated at threonine 258 (phospho-PHBT258) are positively correlated with advanced stages of human lung cancer in tissue microarray. PGE2 or growth factors such as EGF, HGF and IGF-1 increased complex formation of phospho-PHBT258 with Ras, phospho-AktS473, phospho-Raf-1S338, MEKK1 and IKKα/βS176/180 in the raft domain transiently within 1 hour and MIG-7 in the cytosol 12-24 hours later. Association of phospho-PHBT258 with MEKK1 but not MEKK3 activates IKK/IκB/NF-κB and MEK/ERK to increase cellular COX-2/PGE2 and an E-cadherin suppressor Snail leading to enhancement of epithelial-mesenchymal transition (EMT) and lung cancer migration/invasion. MIG-7, on the other hand, was induced by growth factors and PGE2 via Akt/GSK-3β in a phospho-PHBT258 independent manner. MIG-7 increased two E-cadherin suppressors ZEB-1 and Twist to enhance EMT and cancer migration/invasion. Downregulating phospho-PHBT258 and MIG-7 had an additive effect on attenuating lung cancer invasion/metastasis and prolonging the survival of xenograft mice. Phospho-PHBT258 and MIG-7 may thus play complementary roles in the initiation and sustainment of the effects of growth factors and COX-2/PGE2 on cancer invasion/metastasis.
生长因子和COX-2/PGE2通过PI3K/Akt和RAS/Raf增强肺癌的侵袭/转移。在此，我们进一步探究了它们的作用机制。我们首先发现，在组织芯片中，迁移诱导基因-7蛋白（MIG-7）和苏氨酸258位点磷酸化的PHB（磷酸化-PHBT258）水平升高与人类肺癌的晚期阶段呈正相关。PGE2或生长因子如表皮生长因子（EGF）、肝细胞生长因子（HGF）和胰岛素样生长因子-1（IGF-1）在1小时内可使磷酸化-PHBT258与Ras、磷酸化-AktS473、磷酸化-Raf-1S338、丝裂原活化蛋白激酶激酶激酶1（MEKK1）和IκB激酶α/β（IKKα/βS176/180）在脂筏结构域的复合物形成短暂增加，12 - 24小时后使细胞溶质中的MIG-7增加。磷酸化-PHBT258与MEKK1而非MEKK3的结合激活IKK/IκB/NF-κB和MEK/ERK，从而增加细胞内COX-2/PGE2以及一种E-钙黏蛋白抑制因子Snail，导致上皮-间质转化（EMT）增强以及肺癌迁移/侵袭增加。另一方面，生长因子和PGE2通过Akt/糖原合成酶激酶-3β以磷酸化-PHBT258非依赖的方式诱导MIG-7。MIG-7增加两种E-钙黏蛋白抑制因子锌指蛋白E盒结合因子-1（ZEB-1）和Twist，以增强EMT和癌症迁移/侵袭。下调磷酸化-PHBT258和MIG-7对减弱肺癌侵袭/转移以及延长异种移植小鼠的生存期具有累加效应。因此，磷酸化-PHBT258和MIG-7可能在生长因子和COX-2/PGE2对癌症侵袭/转移的起始和维持作用中发挥互补作用。
