title: 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.affiliation: Gastrointestinal Pathobiology Research Group, Department of Surgery, Yale University School of Medicine, PO Box 208602, New Haven, CT, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Schimmack
authors.forename: Andrew
authors.initials: A
authors.lastname: Taylor
authors.forename: Ben
authors.initials: B
authors.lastname: Lawrence
authors.forename: Hubertus
authors.initials: H
authors.lastname: Schmitz-Winnenthal
authors.forename: Lars
authors.initials: L
authors.lastname: Fischer
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Irvin M
authors.initials: IM
authors.lastname: Modlin
authors.forename: Mark
authors.initials: M
authors.lastname: Kidd
authors.forename: Laura H
authors.initials: LH
authors.lastname: Tang
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056915:DNA Copy Number Variations; D015870:Gene Expression; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000556:secondary; D018358:Neuroendocrine Tumors / Q000378:metabolism* / Q000556:secondary; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D050777:Stathmin / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D012333:RNA, Messenger; D050777:Stathmin; C493995:STMN1 protein, human; C531198:dactolisib