title: MIG-7 and phosphorylated prohibitin coordinately regulate lung cancer invasion/metastasis.
abstract: 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.
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Ming-Yi
authors.initials: MY
authors.lastname: Ho
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Liang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan, ROC. Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Shu-Mei
authors.initials: SM
authors.lastname: Liang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D000091402:Prohibitins; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D046888:Tissue Array Analysis; D014162:Transfection
chemical_list: D009363:Neoplasm Proteins; C000717328:PHB protein, human; D000091402:Prohibitins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C482285:TOX4 protein, human