Expression of connective tissue growth factor in pancreatic cancer cell lines.
Connective tissue growth factor (CTGF/CCN2) is thought to play a role in normal wound repair and bone remodeling, but also promotes fibrosis in several disease processes including diabetic nephropathy, sclerodoma and pancreatitis. A contribution to desmoplasia associated with pancreatic cancer progression has also been proposed. CTGF is induced by TGFbeta in diverse cell types, but TGFbeta receptor mediated signaling is impaired in pancreatic cancers and cell lines, usually due to DPC4/Smad4 mutations which arise during the later stages of intraepithelial neoplastic progression. Therefore, in order to define signaling pathways that mediate basal and TGFbeta-induced CTGF expression in normal and transformed cells, we compared CTGF gene regulation in pancreatic cancer cells and fibroblasts by measuring the effects of small molecule inhibitors and dominant negative mutants of signaling proteins on CTGF promoter reporter activity, message, and protein expression. We determined that the previously identified TEF-1 cis element is essential for CTGF promoter reporter activity in pancreatic cancer cell lines. Whereas p38 mediated CTGF induction by TGFbeta in fibroblasts, MEK/ERK signaling mediated TGFbeta-induced CTGF expression in pancreatic cancer cells and was also responsible for basal CTGF expression in pancreatic cancer cell lines with defective Smad signaling. Since activating Ras mutations occur in the earliest stages of pancreatic cancer, CTGF may be induced independent of Smad4 in pancreatic cancer cells.
Kwon
Sungwon
S
Gastrointestinal Research Laboratory, Veterans Affairs Medical Center, San Francisco, CA 94132, USA.
Munroe
Xander
X
Crawley
Suzanne C
SC
Lee
Hwa Young
HY
Spong
Suzanne
S
Bradham
Douglass
D
Gum
James R
JR
Sleisenger
Marvin H
MH
Kim
Young S
YS
D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D004268:DNA-Binding Proteins / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism