PMID- 16651427
OWN - NLM
STAT- MEDLINE
DCOM- 20060705
LR  - 20161128
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 66
IP  - 9
DP  - 2006 May 1
TI  - Validation of met as a therapeutic target in alveolar and embryonal 
      rhabdomyosarcoma.
PG  - 4742-9
AB  - Rhabdomyosarcoma (RMS) is a highly malignant soft-tissue tumor of childhood 
      deriving from skeletal muscle cells. RMS can be classified in two major 
      histologic subtypes: embryonal (ERMS) and alveolar (ARMS), the latter being 
      characterized by the PAX3/7-FKHR translocation. Here we first investigated 
      whether the Met receptor, a transcriptional target of PAX3 and PAX7, has a role 
      in PAX3-FKHR-mediated transformation. Following PAX3-FKHR transduction, Met was 
      up-regulated in mouse embryonal fibroblasts (MEF), NIH 3T3 and C2C12 cells, and 
      they all acquired anchorage independence. This property was lost in low serum but 
      addition of hepatocyte growth factor/scatter factor (HGF/SF) rescued soft-agar 
      growth. Genetic proof that Met is necessary for this PAX3-FKHR-mediated effect 
      was obtained by transducing with PAX3-FKHR MEFs derived from Met mutant 
      (Met(D/D)) and wild-type (Met(+/+)) embryos. Only Met(+/+) MEFs acquired 
      anchorage-independent growth whereas PAX3-FKHR-transduced Met(D/D) cells were 
      unable to form colonies in soft agar. To verify if Met had a role in RMS 
      maintenance, we silenced the receptor by transducing ERMS and ARMS cell lines 
      with an inducible lentivirus expressing an anti-Met short hairpin RNA (shRNA). 
      Met down-regulation significantly affected RMS cells proliferation, survival, 
      invasiveness, and anchorage-independent growth. Finally, induction of the 
      Met-directed shRNA promoted a dramatic reduction of tumor mass in a xenograft 
      model of RMS. Our data show that both ARMS- and ERMS-derived cell lines, in spite 
      of the genetic drift which may have occurred in years of culture, seem to have 
      retained an "addiction" to the Met oncogene and suggest that Met may represent a 
      target of choice to develop novel therapeutic strategies for ARMS.
FAU - Taulli, Riccardo
AU  - Taulli R
AD  - Center for Experimental Research and Medical Studies (CERMS), University of 
      Turin, Turin, Italy.
FAU - Scuoppo, Claudio
AU  - Scuoppo C
FAU - Bersani, Francesca
AU  - Bersani F
FAU - Accornero, Paolo
AU  - Accornero P
FAU - Forni, Paolo E
AU  - Forni PE
FAU - Miretti, Silvia
AU  - Miretti S
FAU - Grinza, Alberto
AU  - Grinza A
FAU - Allegra, Paola
AU  - Allegra P
FAU - Schmitt-Ney, Michel
AU  - Schmitt-Ney M
FAU - Crepaldi, Tiziana
AU  - Crepaldi T
FAU - Ponzetto, Carola
AU  - Ponzetto C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (FOXO1 protein, human)
RN  - 0 (Forkhead Box Protein O1)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Oncogene Proteins, Fusion)
RN  - 0 (PAX3 Transcription Factor)
RN  - 0 (PAX3 protein, human)
RN  - 0 (Paired Box Transcription Factors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, Growth Factor)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.10.1 (MET protein, human)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Animals
MH  - Apoptosis/genetics
MH  - Cell Growth Processes/genetics
MH  - Cell Transformation, Neoplastic/genetics/pathology
MH  - Female
MH  - Forkhead Box Protein O1
MH  - Forkhead Transcription Factors/genetics
MH  - Gene Silencing
MH  - HeLa Cells
MH  - Hepatocyte Growth Factor
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - NIH 3T3 Cells
MH  - Neoplasm Invasiveness
MH  - Oncogene Proteins, Fusion/genetics
MH  - PAX3 Transcription Factor
MH  - Paired Box Transcription Factors/genetics
MH  - Proto-Oncogene Proteins/*antagonists & inhibitors/genetics/*physiology
MH  - Proto-Oncogene Proteins c-met
MH  - RNA Interference
MH  - RNA, Small Interfering/biosynthesis/genetics
MH  - Receptors, Growth Factor/*antagonists & inhibitors/genetics/*physiology
MH  - Rhabdomyosarcoma, Alveolar/genetics/metabolism/pathology/*therapy
MH  - Rhabdomyosarcoma, Embryonal/genetics/metabolism/pathology/*therapy
MH  - Transduction, Genetic
MH  - Up-Regulation
EDAT- 2006/05/03 09:00
MHDA- 2006/07/06 09:00
CRDT- 2006/05/03 09:00
PHST- 2006/05/03 09:00 [pubmed]
PHST- 2006/07/06 09:00 [medline]
PHST- 2006/05/03 09:00 [entrez]
AID - 66/9/4742 [pii]
AID - 10.1158/0008-5472.CAN-05-4292 [doi]
PST - ppublish
SO  - Cancer Res. 2006 May 1;66(9):4742-9. doi: 10.1158/0008-5472.CAN-05-4292.