PLoS ONE (Jan 2011)

SMURF1 amplification promotes invasiveness in pancreatic cancer.

  • Kevin A Kwei,
  • A Hunter Shain,
  • Ryan Bair,
  • Kelli Montgomery,
  • Collins A Karikari,
  • Matt van de Rijn,
  • Manuel Hidalgo,
  • Anirban Maitra,
  • Murali D Bashyam,
  • Jonathan R Pollack

DOI
https://doi.org/10.1371/journal.pone.0023924
Journal volume & issue
Vol. 6, no. 8
p. e23924

Abstract

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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.