scholarly journals Down-regulation of CMTM8 Induces Epithelial-to-Mesenchymal Transition-like Changes via c-MET/Extracellular Signal-regulated Kinase (ERK) Signaling

2012 ◽  
Vol 287 (15) ◽  
pp. 11850-11858 ◽  
Author(s):  
Wenjuan Zhang ◽  
Michelle C. Mendoza ◽  
Xiaolei Pei ◽  
Didem Ilter ◽  
Sarah J. Mahoney ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Tumor Cell ◽  
Hepg2 Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Mapk Pathway ◽  
Cellular Transformation ◽  
Down Regulation ◽  
Mesenchymal Transition ◽  
Hepatocyte Growth

The acquisition of an invasive phenotype is a critical turning point for malignant tumor cells. CMTM8, a potential tumor suppressor, is frequently down-regulated in solid tumors, and its overexpression induces tumor cell apoptosis. Here, we identify a new role for CMTM8 in regulating tumor cell migration. Reducing CMTM8 expression in HepG2 hepatocellular carcinoma cells results in the acquisition of epithelial-to-mesenchymal transition (EMT) features, including a morphological change from organized epithelial sheets to scattered fibroblast-like shapes, reduction of the epithelial marker E-cadherin, and an increased invasive and migratory ability. These phenotypic changes are mediated in large part by the ERK-MAPK pathway, as the MEK inhibitor U0126 and shRNA-mediated knockdown of ERK2 significantly reversed these phenotypes. Hepatocyte growth factor binding to the c-MET receptor is known to induce EMT in HepG2 cells. We found that CMTM8 knockdown in HepG2 cells induced c-MET signaling and ERK activation. Inhibition of c-MET signaling with the small molecule inhibitor SU11274 or c-MET RNAi blocked the EMT-like changes following CMTM8 knockdown. CMTM8 overexpression in HepG2 cells inhibited hepatocyte growth factor-induced EMT-like morphological changes and cell motility. Down-regulation of CMTM8 also promoted an EMT-like change in MCF-10A cells, indicating a broader role for CMTM8 in regulating cellular transformation.

Estradiol-mediated hepatocyte growth factor is involved in the implantation of endometriotic cells via the mesothelial-to-mesenchymal transition in the peritoneum

2015 ◽  
Vol 308 (11) ◽  
pp. E950-E959 ◽  
Author(s):  
Yoshihiro J. Ono ◽  
Masami Hayashi ◽  
Akiko Tanabe ◽  
Atsushi Hayashi ◽  
Masanori Kanemura ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Conditioned Medium ◽  
Epithelial To Mesenchymal Transition ◽  
Estrogen Receptor Α ◽  
Mesothelial Cells ◽  
Mesenchymal Transition ◽  
Endometrial Cells ◽  
Invasion And Migration ◽  
Hepatocyte Growth

The pathogenesis of endometriosis, a chronic painful gynecological disease characterized by the presence of endometrial tissue located outside of the uterus and often adhering to the peritoneum, is known to be estrogen dependent. However, the precise pathophysiology of endometriosis remains elusive. Recent studies indicate that the epithelial-to-mesenchymal transition (EMT) of human endometrial cells is important for the progression of endometriosis, and another previous study has implicated hepatocyte growth factor (HGF) in endometriosis progression. The aim of the present study was to examine the role of estradiol in the regulation of HGF production and progression of peritoneal endometriosis, focusing on the interactions between the peritoneum and endometriotic cells. Consequently, estradiol was found to promote the proliferation, invasion, and migration of immortalized human endometrial epithelial cells (hEECs) via HGF upregulation, and the estradiol-induced direct binding of estrogen receptor-α to the HGF promoter was confirmed on a chromatin immunoprecipitation (ChIP) assay. Estradiol also induced the EMT in hEECs by promoting HGF production. Furthermore, human mesothelial cells underwent the mesothelial-to-mesenchymal transition (MMT) during culture with estradiol-stimulated hEEC conditioned medium. Importantly, estradiol itself did not induce the MMT, and the estradiol-stimulated hEEC-conditioned medium in the presence of HGF antibodies reversed the MMT process. These results, which were obtained using immortalized hEECs, indicate that estradiol-induced HGF production may play a crucial role in the peritoneal implantation of human endometriotic cells by exerting proliferative and invasive effects via the EMT in hEECs and promoting the MMT in mesothelial cells.

Prostaglandin E2 is a potent inhibitor of epithelial-to-mesenchymal transition: interaction with hepatocyte growth factor

2006 ◽  
Vol 291 (6) ◽  
pp. F1323-F1331 ◽  
Author(s):  
Aihua Zhang ◽  
Mong-Heng Wang ◽  
Zheng Dong ◽  
Tianxin Yang
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Epithelial To Mesenchymal Transition ◽  
Mdck Cells ◽  
Specific Inhibitor ◽  
Intracellular Camp ◽  
Mesenchymal Transition ◽  
Cox 2 ◽  
Oxidant Production ◽  
Hepatocyte Growth

Epithelial-to-mesenchymal transition (EMT) has emerged as a critical event in the pathogenesis of tubulointerstitial fibrosis. EMT is typically induced by transforming growth factor-β1 (TGF-β1) and inhibited by hepatocyte growth factor (HGF). The present study was undertaken to evaluate the potential role of cyclooxygenase (COX)-2-derived PGE2 in regulation of EMT in cultured Madin-Darby canine kidney (MDCK) cells, in the setting of HGF treatment. Exposure to 50 ng/ml HGF significantly induced COX-2 protein expression and PGE2 release, whereas other growth factors, including epidermal growth factor, the insulin-like growth factor I protein, platelet-derived growth factor-BB, and TGF-β1, had no effects on COX-2 expression or PGE2 release. COX-2 induction by HGF was preceded by activation of ERK1/2, and an ERK1/2-specific inhibitor, U-0126 (10 μM), completely abolished HGF-induced COX-2 expression. Exposure of MDCK cells to 10 ng/ml TGF-β1 for 72 h induced EMT as evidenced by conversion to the spindle-like morphology, loss of E-cadherin, and activation of α-smooth muscle actin. In contrast, treatment with 1 μM PGE2 completely blocked EMT, associated with a significant elevation of intracellular cAMP and complete blockade of TGF-β1-induced oxidant production. cAMP-elevating agents, including 8-Br-cAMP, forskolin, and IBMX, inhibited EMT and associated oxidative stress induced by TGF-β1, but inhibition of cAMP pathway with Rp-cAMP, the cAMP analog, and H89, the protein kinase A (PKA) inhibitor, did not block the effect of PGE2. The effect of HGF on EMT was inhibited by ∼50% in the presence of a COX-2 inhibitor SC-58635 (10 μM). Therefore, our data suggest that PGE2 inhibits EMT via inhibition of oxidant production and COX-2-derived PGE2 partially accounts for the antifibrotic effect of HGF.

scholarly journals Cbl-transforming Variants Trigger a Cascade of Molecular Alterations That Lead to Epithelial Mesenchymal Conversion

2000 ◽  
Vol 11 (10) ◽  
pp. 3397-3410 ◽  
Author(s):  
Tanya M. Fournier ◽  
Louie Lamorte ◽  
Christiane R. Maroun ◽  
Mark Lupher ◽  
Hamid Band ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Hepatocyte Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Morphological Changes ◽  
Cell Spreading ◽  
Mesenchymal Transition ◽  
Amino Terminal ◽  
Src Homology ◽  
Hepatocyte Growth

Dispersal of epithelial cells is an important aspect of tumorigenesis, and invasion. Factors such as hepatocyte growth factor induce the breakdown of cell junctions and promote cell spreading and the dispersal of colonies of epithelial cells, providing a model system to investigate the biochemical signals that regulate these events. Multiple signaling proteins are phosphorylated in epithelial cells during hepatocyte growth factor–induced cell dispersal, including c-Cbl, a protooncogene docking protein with ubiquitin ligase activity. We have examined the role of c-Cbl and a transforming variant (70z-Cbl) in epithelial cell dispersal. We show that the expression of 70z-Cbl in Madin-Darby canine kidney epithelial cells resulted in the breakdown of cell–cell contacts and alterations in cell morphology characteristic of epithelial–mesenchymal transition. Structure–function studies revealed that the amino-terminal portion of c-Cbl, which corresponds to the Cbl phosphotyrosine-binding/Src homology domain 2 , is sufficient to promote the morphological changes in cell shape. Moreover, a point mutation at Gly-306 abrogates the ability of the Cbl Src homology domain 2 to induce these morphological changes. Our results identify a role for Cbl in the regulation of epithelial–mesenchymal transition, including loss of adherens junctions, cell spreading, and the initiation of cell dispersal.

Hepatocyte growth factor suppresses the anticancer effect of irinotecan by decreasing the level of active metabolite in HepG2 cells

2011 ◽  
Vol 82 (11) ◽  
pp. 1720-1730 ◽  
Author(s):  
Manabu Okumura ◽  
Tomomi Iwakiri ◽  
Akinori Takagi ◽  
Yasutoshi Hirabara ◽  
Yohei Kawano ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Hepg2 Cells ◽  
Active Metabolite ◽  
Anticancer Effect ◽  
Hepatocyte Growth

Internalization and degradation of hepatocyte growth factor in hepatocytes with down-regulation of the receptor/c-Met

FEBS Letters ◽  
1993 ◽  
Vol 329 (1-2) ◽  
pp. 147-152 ◽  
Author(s):  
Daiji Naka ◽  
Takeshi Shimomura ◽  
Yoshiko Yoshiyama ◽  
Maki Sato ◽  
Mutsumi Sato ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Down Regulation ◽  
Hepatocyte Growth

scholarly journals Enhancement of Hepatocyte Growth Factor-Induced Cell Scattering in N-Acetylglucosaminyltransferase III-transfected HepG2 Cells

2004 ◽  
Vol 27 (6) ◽  
pp. 781-785 ◽  
Author(s):  
Masashi Hyuga ◽  
Sumiko Hyuga ◽  
Nana Kawasaki ◽  
Miyako Ohta ◽  
Satsuki Itoh ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Hepg2 Cells ◽  
Cell Scattering ◽  
Hepatocyte Growth
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