title: SMURF1 amplification promotes invasiveness in pancreatic cancer.
abstract: Pancreatic cancer is a deadly disease, and new therapeutic targets are urgently needed. We previously identified DNA amplification at 7q21-q22 in pancreatic cancer cell lines. Now, by high-resolution genomic profiling of human pancreatic cancer cell lines and human tumors (engrafted in immunodeficient mice to enrich the cancer epithelial fraction), we define a 325 Kb minimal amplicon spanning SMURF1, an E3 ubiquitin ligase and known negative regulator of transforming growth factor β (TGFβ) growth inhibitory signaling. SMURF1 amplification was confirmed in primary human pancreatic cancers by fluorescence in situ hybridization (FISH), where 4 of 95 cases (4.2%) exhibited amplification. By RNA interference (RNAi), knockdown of SMURF1 in a human pancreatic cancer line with focal amplification (AsPC-1) did not alter cell growth, but led to reduced cell invasion and anchorage-independent growth. Interestingly, this effect was not mediated through altered TGFβ signaling, assayed by transcriptional reporter. Finally, overexpression of SMURF1 (but not a catalytic mutant) led to loss of contact inhibition in NIH-3T3 mouse embryo fibroblast cells. Together, these findings identify SMURF1 as an amplified oncogene driving multiple tumorigenic phenotypes in pancreatic cancer, and provide a new druggable target for molecularly directed therapy.
authors: Department of Pathology, Stanford University, Stanford, California, United States of America.
authors: Kevin A
authors: KA
authors: Kwei
authors: A Hunter
authors: AH
authors: Shain
authors: Ryan
authors: R
authors: Bair
authors: Kelli
authors: K
authors: Montgomery
authors: Collins A
authors: CA
authors: Karikari
authors: Matt
authors: M
authors: van de Rijn
authors: Manuel
authors: M
authors: Hidalgo
authors: Anirban
authors: A
authors: Maitra
authors: Murali D
authors: MD
authors: Bashyam
authors: Jonathan R
authors: JR
authors: Pollack
mesh_terms: D000818:Animals; D002450:Cell Communication; D002460:Cell Line; D045744:Cell Line, Tumor; D005784:Gene Amplification / Q000502:physiology*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D009361:Neoplasm Invasiveness; D009857:Oncogenes; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases