PAX6 is expressed in pancreatic cancer and actively participates in cancer progression through activation of the MET tyrosine kinase receptor gene.
Tumors of the exocrine pancreas have a poor prognosis. Several proteins are overexpressed in this cancer type, including the MET tyrosine kinase receptor and the transcription factor PAX6. In this report, we find that PAX6(5a), an alternately spliced variant form of PAX6, is expressed in pancreatic carcinoma cell lines at higher levels than the canonical PAX6 protein. Both protein forms of PAX6 bind directly to an enhancer element in the MET promoter and activate the expression of the MET gene. In addition, inhibition of PAX6 transcripts leads to a decline in cell growth and survival, differentiation, and a concurrent reduction of MET protein expression. These data support a model for a neoplastic pathway, where expression of a transcription factor from development activates the MET receptor, a protein that has been directly linked to protumorigenic processes of resisting apoptosis, tumor growth, invasion, and metastasis.
Mascarenhas
Joseph B
JB
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Young
Kacey P
KP
Littlejohn
Erica L
EL
Yoo
Brian K
BK
Salgia
Ravi
R
Lang
Deborah
D
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D018450:Disease Progression; D005136:Eye Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000172:deficiency / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D015533:Transcriptional Activation
D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D012097:Repressor Proteins; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met