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Tumor Biology

, Volume 36, Issue 1, pp 399–408 | Cite as

Stathmin in pancreatic neuroendocrine neoplasms: a marker of proliferation and PI3K signaling

  • Simon Schimmack
  • Andrew Taylor
  • Ben Lawrence
  • Hubertus Schmitz-Winnenthal
  • Lars Fischer
  • Markus W Büchler
  • Irvin M Modlin
  • Mark Kidd
  • Laura H Tang
Research Article

Abstract

Chromosome 1p35-36, which encodes tumor suppressors and mitotic checkpoint control genes, is commonly altered in human malignancies. One gene at this locus, stathmin 1 (STMN1), is involved in cell cycle progression and metastasis. We hypothesized that increased STMN1 expression may play a role in pancreatic neuroendocrine neoplasm (pNEN) malignancy. We investigated stathmin copy number variation, mRNA, and protein expression using PCR-Taqman Copy Number Assays, Q-PCR, Western blot, and immunohistochemistry. A mechanistic role for stathmin in proliferation was assessed in the BON cell line under growth-restrictive conditions and siRNA silencing. Furthermore, its role in PI3K signaling pathway activation was evaluated using pharmacological inhibitors. mRNA (p = 0.0001) and protein (p < 0.05) were overexpressed in pNENs. Expression was associated with pNEN tumor extension (p < 0.05), size (p < 0.01), and Ki67 expression (p < 0.01). Serum depletion decreased Ki67 expression (p < 0.01) as well as Ser38 phosphorylation (p < 0.05) in BON cells. STMN1 knockdown (siRNA) decreased proliferation (p < 0.05), and PI3K inhibitors directly inhibited proliferation via stathmin inactivation (dephosphorylation p < 0.01). We identified that stathmin was overexpressed and associated with pathological parameters in pancreatic NENs. We postulate that STMN1 overexpression and phosphorylation result in a loss of cell cycle mitotic checkpoint control and may render tumors amenable to PI3K inhibitory therapy.

Keywords

Pancreatic neuroendocrine neoplasms Stathmin Loss of heterozygosity Metastasis NET Phosphorylation 

Notes

Acknowledgments

Funding support for SS was provided by the Deutsche Forschungsgemeinschaft SCHI 1177/1-1. BL was partially supported by the Murray Jackson Clinical Fellowship from the Genesis Oncology Trust, Auckland, New Zealand.

Conflicts of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Simon Schimmack
    • 1
    • 2
  • Andrew Taylor
    • 1
  • Ben Lawrence
    • 1
    • 3
  • Hubertus Schmitz-Winnenthal
    • 2
  • Lars Fischer
    • 2
  • Markus W Büchler
    • 2
  • Irvin M Modlin
    • 1
  • Mark Kidd
    • 1
  • Laura H Tang
    • 4
  1. 1.Gastrointestinal Pathobiology Research GroupDepartment of Surgery, Yale University School of MedicineNew HavenUSA
  2. 2.General, Visceral and Transplantation SurgeryUniversity Hospital of HeidelbergHeidelbergGermany
  3. 3.Discipline of OncologyUniversity of AucklandAucklandNew Zealand
  4. 4.Department of PathologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA

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