Stathmin 1, a marker of PI3K pathway activation and regulator of microtubule dynamics, is expressed in early pelvic serous carcinomas

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Gynecologic Oncology (Impact Factor: 3.69). 06/2011; 123(1):5-12. DOI: 10.1016/j.ygyno.2011.05.021
Source: PubMed

ABSTRACT Most high-grade pelvic serous carcinomas (HGPSCs) arise from fallopian tube epithelium (FTE). To date, few markers have been shown to characterize FTE transformation. Stathmin 1 (STMN1) is a candidate oncogene whose activity is influenced by p53, p27Kip1 (p27), and PI3K/Akt pathway activation. As a microtubule destabilizing protein, STMN1 regulates cytoskeletal dynamics, cell cycle progression, mitosis, and cell migration. This study examines the expression of STMN1 and its negative regulator p27 along the morphologic continuum from normal FTE to invasive carcinoma.
STMN1 and p27 expression were examined by immunohistochemistry (IHC) in benign (n=12) and malignant (n=13) fallopian tubes containing normal epithelium, morphologically benign putative precursor lesions ("p53 signatures"), potential transitional precursor lesions ("proliferative p53 signatures"), tubal intraepithelial carcinoma (TIC), and/or invasive serous carcinoma. STMN1 expression was further assessed in 131 late-stage HGPSCs diagnosed as primary ovarian and in 6 ovarian cancer cell lines by IHC and Western blot, respectively.
STMN1 expression was absent in benign FTE and infrequently detected in p53 signatures. However, it was weakly expressed in proliferative p53 signatures and robustly induced upon progression to TIC and invasive carcinoma, typically accompanied by decreased p27 levels. STMN1 was expressed in >80% of high-grade serous ovarian carcinomas and cell lines.
STMN1 is a novel marker of early serous carcinoma that may play a role in FTE tumor initiation. Our data are consistent with a model by which STMN1 overexpression, resulting from loss of p27-mediated regulation, may potentiate aberrant cell proliferation, migration, and/or loss of polarity during early tumorigenesis.

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Available from: Michelle S Hirsch, Mar 25, 2014
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    • "Stathmin may also be essential for cancer cell survival [23]. More recently, stathmin has been shown to associate with PI3K activity in ovarian cancer [24], supporting the hypothesis that stathmin may be linked to the progression of ovarian cancer. In a previous study, we reported stathmin knockdown to inhibit the activation of Akt and HIF-1í µí»¼ in human endometrial and endothelial cells [25]; however, there is no study on the involvement of the PI3K/Akt/mTOR pathway and stathmin in HIF expression during hypoxia in cultured CCA cells. "
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    ABSTRACT: Stathmin, a microtubule-destabilizing phosphoprotein, is highly expressed in ovarian cancer, but the pathophysiological significance of this protein in ovarian carcinoma cells remains poorly understood. This study reports the involvement of stathmin in the mTOR/HIF-1 α /VEGF pathway in ovarian clear cell adenocarcinoma (CCA) during hypoxia. HIF-1 α protein and VEGF mRNA levels were markedly elevated in RMG-1 cells, a CCA cell line, cultured under hypoxic conditions. Rapamycin, an inhibitor of mTOR complex 1, reduced the level of HIF-1 α and blocked phosphorylation of ribosomal protein S6 kinase 1 (S6K), a transcriptional regulator of mTOR, demonstrating that hypoxia activates mTOR/S6K/HIF-1 α signaling in CCA. Furthermore, stathmin knockdown inhibited hypoxia-induced HIF-1 α and VEGF expression and S6K phosphorylation. The silencing of stathmin expression also reduced Akt phosphorylation, a critical event in the mTOR/HIF-1 α /VEGF signaling pathway. By contrast, stathmin overexpression upregulated hypoxia-induced HIF-1 α and VEGF expression in OVCAR-3 cells, another CCA cell line. In addition, suppression of Akt activation by wortmannin, a phosphoinositide 3-kinase (PI3K) inhibitor, decreased HIF-1 α and VEGF expression. These results illustrate that regulation of HIF-1 α through the PI3K/Akt/mTOR pathway is controlled by stathmin in CCA. Our findings point to a new mechanism of stathmin regulation during ovarian cancer.
    05/2013; 2013:279593. DOI:10.1155/2013/279593
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    • "The clinical relevance of this pathway in human EOC has been clearly demonstrated in three independent sets of EOC samples where high stathmin expression significantly correlated with mutant p53 (Supporting Information Tables S4 and S5 and Fig 8). This correlation has been independently confirmed by a recent report demonstrating that stathmin was overexpressed in 84% of 131 high-grade serous ovarian carcinomas and that its expression was already associated with the p53 proliferative signature, characteristic of premalignant type II EOC (Karst et al, 2011). Thus, while in several types of human cancer stathmin overexpression is typically found in advanced/metastatic disease (reviewed in Belletti & Baldassarre, 2011) and in mice is not required for the onset of sarcoma, skin and bladder carcinomas (D'Andrea et al, 2012), our and others' data pointed to type II HG-EOC as a neoplasia in which stathmin expression is required at early stages of tumour onset, downstream of p53 mutation. "
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    ABSTRACT: Stathmin is a p53-target gene, frequently overexpressed in late stages of human cancer progression. Type II High Grade Epithelial Ovarian Carcinomas (HG-EOC) represents the only clear exception to this observation. Here, we show that stathmin expression is necessary for the survival of HG-EOC cells carrying a p53 mutant (p53(MUT) ) gene. At molecular level, stathmin favours the binding and the phosphorylation of p53(MUT) by DNA-PKCS , eventually modulating p53(MUT) stability and transcriptional activity. Inhibition of stathmin or DNA-PKCS impaired p53(MUT) -dependent transcription of several M phase regulators, resulting in M phase failure and EOC cell death, both in vitro and in vivo. In primary human EOC a strong correlation exists between stathmin, DNA-PKCS , p53(MUT) overexpression and its transcriptional targets, further strengthening the relevance of the new pathway here described. Overall our data support the hypothesis that the expression of stathmin and p53 could be useful for the identification of high risk patients that will benefit from a therapy specifically acting on mitotic cancer cells.
    EMBO Molecular Medicine 05/2013; 5(5). DOI:10.1002/emmm.201201504 · 8.25 Impact Factor
  • Gynecologic Oncology 07/2011; 123(1):1-2. DOI:10.1016/j.ygyno.2011.07.015 · 3.69 Impact Factor
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