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

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.

• Authors: Simon Schimmack, Andrew Taylor, Ben Lawrence, Hubertus Schmitz-Winnenthal, Lars Fischer, Markus W Büchler, Irvin M Modlin, Mark Kidd, Laura H Tang
• Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine (Tumour Biol) Vol. 36 Issue 1 Pg. 399-408 (Jan 2015) ISSN: 1423-0380 [Electronic] Netherlands
• PMID: 25266798 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Imidazoles
• Phosphoinositide-3 Kinase Inhibitors
• Quinolines
• RNA, Messenger
• STMN1 protein, human
• Stathmin
• dactolisib

Topics

• Cell Line, Tumor
• Cell Proliferation
• DNA Copy Number Variations
• Gene Expression
• Humans
• Imidazoles (pharmacology)
• Liver Neoplasms (metabolism, secondary)
• Neuroendocrine Tumors (metabolism, secondary)
• Pancreas (metabolism, pathology)
• Pancreatic Neoplasms (metabolism, pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation
• Protein Processing, Post-Translational
• Quinolines (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Signal Transduction
• Stathmin (metabolism)