title: Extracellular signal-regulated kinase and Akt activation play a critical             role in the process of hepatocyte growth factor-induced epithelial-mesenchymal             transition.
abstract: Epithelial-mesenchymal transition (EMT) has recently been studied to elucidate mechanisms of the liver metastatic process. We investigated EMT in the process of liver metastasis and the effects of chemotherapy on EMT cells as therapeutic strategy for colorectal liver metastasis. We used the CT26 murine colorectal carcinoma cell line to create an in vivo mouse liver metastasis model. Liver tumors were stained immuno-histochemically. Expression of proteins associated with TGF-β/Smad and hepatocyte growth factor (HGF)/c-Met pathways were investigated by western blotting. Cells with c-Met mRNA knockdown by siRNA techniques showed clearly reduced liver metastases compared with regular cells at 21 days. TGF-β and HGF induced EMT expression, but signal transduction was quite different. TGF-β induced ERK, but not Akt phosphory-lation. HGF mediated both ERK and Akt phosphorylation. Akt inhibitor blocked Akt phosphorylation but did not affect TGF-β-induced activation of ERK, Snail and Slug. U-0126 did not reduce Snail activity by TGF-β at a concentration to block ERK phosphorylation. However, Akt inhibitor and U-0126 completely inhibited HGF-induced Slug activation. 5-FU mediated cell death in the EMT process induced by TGF-β more effectively than HGF. ERK/Akt signaling, but not the Smad pathway, may be one of the main processes in HGF-induced EMT, despite the Smad pathway, but not ERK/Akt, being critical for TGF-β-induced EMT. The MAPK/Akt pathway is indispensable in HGF/c-Met signaling. The ERK/Akt pathway particularly may be critical in the HGF-induced EMT process. However, long-term use of chemotherapeutic agents may induce drug resistance and distant metastases through EMT-related signaling pathway activation.
authors.affiliation: Department of Surgical Oncology, Gifu University Graduate School                     of Medicine, Gifu, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tanahashi
authors.forename: Shinji
authors.initials: S
authors.lastname: Osada
authors.forename: Atsuko
authors.initials: A
authors.lastname: Yamada
authors.forename: Junko
authors.initials: J
authors.lastname: Kato
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yawata
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Mori
authors.forename: Hisashi
authors.initials: H
authors.lastname: Imai
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Shiro
authors.initials: S
authors.lastname: Saito
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nonaka
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000235:genetics* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D051058:Oncogene Protein v-akt; D048052:Mitogen-Activated Protein Kinase 3