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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere23924
JournalPLoS One
Volume6
Issue number8
DOIs
StatePublished - 2011

Fingerprint

pancreatic neoplasms
Pancreatic Neoplasms
Amplification
Cells
Transforming Growth Factors
transforming growth factors
Ubiquitin-Protein Ligases
Cell growth
Fibroblasts
Growth
cell lines
Contact Inhibition
Tumors
therapeutics
ubiquitin-protein ligase
neoplasms
cell invasion
oncogenes
Fluorescence
mice

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Kwei, K. A., Shain, A. H., Bair, R., Montgomery, K., Karikari, C. A., van de Rijn, M., ... Pollack, J. R. (2011). SMURF1 amplification promotes invasiveness in pancreatic cancer. PLoS One, 6(8), [e23924]. https://doi.org/10.1371/journal.pone.0023924

SMURF1 amplification promotes invasiveness in pancreatic cancer. / Kwei, Kevin A.; Shain, A. Hunter; Bair, Ryan; Montgomery, Kelli; Karikari, Collins A.; van de Rijn, Matt; Hidalgo, Manuel; Maitra, Anirban; Bashyam, Murali D.; Pollack, Jonathan R.

In: PLoS One, Vol. 6, No. 8, e23924, 2011.

Research output: Contribution to journalArticle

Kwei, KA, Shain, AH, Bair, R, Montgomery, K, Karikari, CA, van de Rijn, M, Hidalgo, M, Maitra, A, Bashyam, MD & Pollack, JR 2011, 'SMURF1 amplification promotes invasiveness in pancreatic cancer', PLoS One, vol. 6, no. 8, e23924. https://doi.org/10.1371/journal.pone.0023924
Kwei KA, Shain AH, Bair R, Montgomery K, Karikari CA, van de Rijn M et al. SMURF1 amplification promotes invasiveness in pancreatic cancer. PLoS One. 2011;6(8). e23924. https://doi.org/10.1371/journal.pone.0023924
Kwei, Kevin A. ; Shain, A. Hunter ; Bair, Ryan ; Montgomery, Kelli ; Karikari, Collins A. ; van de Rijn, Matt ; Hidalgo, Manuel ; Maitra, Anirban ; Bashyam, Murali D. ; Pollack, Jonathan R. / SMURF1 amplification promotes invasiveness in pancreatic cancer. In: PLoS One. 2011 ; Vol. 6, No. 8.
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