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

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Tumor Biology

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.

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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.

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Authors and Affiliations

  1. Gastrointestinal Pathobiology Research Group, Department of Surgery, Yale University School of Medicine, PO Box 208602, New Haven, CT, USA

    Simon Schimmack, Andrew Taylor, Ben Lawrence, Irvin M Modlin & Mark Kidd

  2. General, Visceral and Transplantation Surgery, University Hospital of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

    Simon Schimmack, Hubertus Schmitz-Winnenthal, Lars Fischer & Markus W Büchler

  3. Discipline of Oncology, University of Auckland, Private Bag 92019, Auckland, New Zealand

    Ben Lawrence

  4. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Laura H Tang

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  1. Simon Schimmack
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  2. Andrew Taylor
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Schimmack, S., Taylor, A., Lawrence, B. et al. Stathmin in pancreatic neuroendocrine neoplasms: a marker of proliferation and PI3K signaling. Tumor Biol. 36, 399–408 (2015). https://doi.org/10.1007/s13277-014-2629-y

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