Stathmin in pancreatic neuroendocrine neoplasms: a marker of proliferation and PI3K signaling
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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.
KeywordsPancreatic neuroendocrine neoplasms Stathmin Loss of heterozygosity Metastasis NET Phosphorylation
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
- 18.Sherbet G, Cajone F. Stathmin in cell proliferation and cancer progression. Cancer Genomics Proteomics. 2005;2:227–38.Google Scholar
- 26.Baquero MT, Hanna JA, Neumeister V, Cheng H, Molinaro AM, Harris LN, et al. Stathmin expression and its relationship to microtubule-associated protein tau and outcome in breast cancer. Cancer. 2012.Google Scholar
- 37.Tan HT, Wu W, Ng YZ, Zhang X, Yan B, Ong CW, et al. Proteomic analysis of colorectal cancer metastasis: stathmin-1 revealed as a player in cancer cell migration and prognostic marker. J Proteome Res. 2012;10:10.Google Scholar
- 39.Modlin I, Moss SF, Gustafsson BI, Lawrence B, Schimmack S, Kidd M. The archaic distinction between functioning and non-functioning neuroendocrine neoplasms is no longer clinically relevant. Langenbecks Arch Surg. 2011.Google Scholar
- 49.Wik E, Birkeland E, Trovik J, Werner HM, Hoivik EA, Mjos S, et al. High phospho-stathmin (Serine38) expression identifies aggressive endometrial cancer and suggests an association with PI3Kinase inhibition. Clin Cancer Res. 2013;28:28.Google Scholar
- 52.Saal LH, Johansson P, Holm K, Gruvberger-Saal SK, She QB, Maurer M, et al. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci U S A. 2007;104:7564–9. Epub 2007 Apr 7523.CrossRefPubMedPubMedCentralGoogle Scholar