Role of CXCR4/SDF-1 alpha in the migratory phenotype of hepatoma cells that have undergone epithelial-mesenchymal transition in response to the transforming growth factor-beta.
Treatment of FaO rat hepatoma cells with TGF-beta selects cells that survive to its apoptotic effect and undergo epithelial-mesenchymal transitions (EMT). We have established a cell line (T beta T-FaO, from TGF-beta-treated FaO) that shows a mesenchymal, de-differentiated, phenotype in the presence of TGF-beta and is refractory to its suppressor effects. In the absence of this cytokine, cells revert to an epithelial phenotype in 3-4 weeks and recover the response to TGF-beta. T beta T-FaO show higher capacity to migrate than that observed in the parental FaO cells. We found that FaO cells express low levels of CXCR4 and do not respond to SDF-1 alpha. However, TGF-beta up-regulates CXCR4, through a NF kappaB-dependent mechanism, and T beta T-FaO cells show elevated levels of CXCR4, which is located in the presumptive migration front. A specific CXCR4 antagonist (AMD3100) attenuates the migratory capacity of T beta T-FaO cells on collagen gels. Extracellular SDF-1 alpha activates the ERKs pathway in T beta T-FaO, but not in FaO cells, increasing cell scattering and protecting cells from apoptosis induced by serum deprivation. Targeted knock-down of CXCR4 with specific siRNA blocks the T beta T-FaO response to SDF-1 alpha. Thus, the SDF-1/CXCR4 axis might play an important role in mediating cell migration and survival after a TGF-beta-induced EMT in hepatoma cells.
Bertran
Esther
E
Laboratori d'Oncologia Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Spain. ebertran@idibell.org
Caja
Laia
L
Navarro
Estanis
E
Sancho
Patricia
P
Mainez
Jèssica
J
Murillo
Miguel M
MM
Vinyals
Antonia
A
Fabra
Angels
A
Fabregat
Isabel
I
D000818:Animals; D017209:Apoptosis; D001596:Benzylamines; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism / Q000502:physiology*; D000080027:Cyclams; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006571:Heterocyclic Compounds / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008648:Mesoderm / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D001596:Benzylamines; D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D000080027:Cyclams; D006571:Heterocyclic Compounds; D016328:NF-kappa B; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D016212:Transforming Growth Factor beta; D048049:Extracellular Signal-Regulated MAP Kinases; C088327:plerixafor