Downregulation of stathmin 1 in human gallbladder carcinoma inhibits tumor growth in vitro and in vivo

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Abstract

Gallbladder carcinoma (GBC) is a highly lethal malignancy of the gastrointestinal tract. Despite extensive research, the underlying molecular mechanism of GBC remains largely unclear. Stathmin 1 (STMN1) is an important cytosolic protein associated with microtubule stability that was reported to be involved in tumorigenesis. Up to our knowledge, its role in gallbladder carcinoma has not been analyzed. In this study, we found that STMN1 was significantly highly expressed in GBC by immunohistochemistry (IHC). Further research demonstrated that silencing of STMN1 inhibited cell growth in vitro. Moreover, knockdown of STMN1 induced apoptosis and delayed G2/M phase transformation in GBC cells. Our data support a rationale for further studies that the silencing of STMN1 may regulate the activity of p38 MAPK kinase and p53/p21 signal pathway. Besides, xenografted gallbladder carcinoma cells growth were significantly impaired after STMN1 was silenced in vivo. These results suggested that STMN1 played an important role in cell proliferation and migration. This provided a potential clue for investigating the therapeutic target in GBC.

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Stathmin: a protein with many tasks. New biomarker and potential target in cancer.

Barbara Belletti, Gustavo Baldassarre (2011)

Stathmin is a microtubule-destabilizing phosphoprotein, firstly identified as the downstream target of many signal transduction pathways. Several studies then indicated that stathmin is overexpressed in many types of human malignancies, thus deserving the name of Oncoprotein 18 (Op18). At molecular level, stathmin depolymerizes microtubules by either sequestering free tubulin dimers or directly inducing microtubule-catastrophe. A crucial role for stathmin in the control of mitosis has been proposed, since both its overexpression and its downregulation induce failure in the correct completion of cell division. Accordingly, stathmin is an important target of the main regulator of M phase, cyclin-dependent kinase 1. Recent evidences support a role for stathmin in the regulation of cell growth and motility, both in vitro and in vivo, and indicate its involvement in advanced, invasive and metastatic cancer more than in primary tumors. Many studies suggest that high stathmin expression levels in cancer negatively influence the response to microtubule-targeting drugs. These notions together with the fact that stathmin is expressed at very low levels in most adult tissues strongly support the use of stathmin as marker of prognosis and as target for novel anti-tumoral and anti-metastatic therapies.

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Stathmin 1: a novel therapeutic target for anticancer activity.

John Nemunaitis, Neil Senzer, Phillip Maples … (2008)

Stathmin 1 (STMN1), also known as p17, p18, p19, 19K, metablastin, oncoprotein 18, LAP 18 and Op18, is a 19 kDa cytosolic protein. It was the first discovered member of a family of phylogenetically related microtubule-destabilizing phosphoproteins critically involved in the construction and function of the mitotic spindle. A threshold level of STMN1 is required for orderly progression through mitosis in a variety of cell types. STMN1 is overexpressed across a broad range of human malignancies (leukemia, lymphoma, neuroblastoma; ovarian, prostatic, breast and lung cancers and mesothelioma). It is also upregulated in normally proliferating cell lines but is only rarely upregulated in nonproliferating cell lines with the exception of neurons, anterior pituitary cells and glial cells. Its expression is also upregulated in hepatocytes during regeneration and in lymphoid cells when they are signaled to proliferate. In this review, we summarize available data as rationale for the therapeutic manipulation of STMN1 in cancer patients.

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Gallbladder cancer: differences in presentation, surgical treatment, and survival in patients treated at centers in three countries.

Enrique Waugh, Peter J. Allen, Yuman Fong … (2010)

Gallbladder cancer (GBCA) is a rare malignancy with a variable incidence worldwide. This study analyzed GBCA patients treated at centers in 3 countries. The aim was to assess for location-specific differences in presentation and outcomes, which might suggest differences in pathogenesis or disease biology. Data for consecutive patients submitted to operation at Instituto Oncológico Fundación Arturo López Pérez (FALP, Chile), Yokohama City University (YCU, Japan), and Memorial Sloan-Kettering Cancer Center (MSKCC, USA) between 1999 and 2007 were studied retrospectively. Patient demographics, disease- and treatment-related variables and outcomes were analyzed by chi-square, Kruskal-Wallis, and log-rank test. Two hundred sixty-one patients (MSKCC, 130; FALP, 85; YCU, 46) underwent exploration, and 160 (MSKCC, 91; FALP, 33; YCU, 36) underwent R0 resection. Patients treated at FALP were younger (median 57 years, p < 0.001) and more often female (80%, p < 0.005); at YCU there were fewer patients with incidental tumors (19.5% compared with more than 60% at FALP and MSKCC, p < 0.001). En bloc liver and bile duct resections were performed more commonly at MSKCC and YCU (p < 0.001). Patients treated at FALP had more advanced tumor stage compared with those treated at MSKCC and YCU (p < 0.001). Disease-specific survival (DSS) was not different among the groups when patients submitted to an R0 resection were analyzed (p = 0.12). On multivariate analysis, T-stage, nodal involvement, and bile duct involvement were predictors of DSS; center was not significant. Despite some differences in presentation, disease extent, and surgical treatment, DSS after curative intent resection was similar among all 3 groups. The most important predictors of outcomes were related to tumor extent rather than country of origin. Copyright © 2011 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

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Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 28 June 2016

Publication date Collection: 2016

Volume: 6

Electronic Location Identifier: 28833

Affiliations

[1 ]Department of General Surgery, Zhongshan Hospital, General Surgery Institute, Fudan University , Shanghai 200030, China

[2 ]Glycobiology and Glycochemistry Lab, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China

[3 ]PET-CT Center, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College , Beijing 100021, China

[4 ]Beijing Key Laboratory for Genetic Research of Skeletal Deformity , Beijing, China

[5 ]Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College; Chinese Academy of Medical Sciences , Beijing 100730, China

[6 ]Department of Breast Surgical Oncology, Cancer Hospital of Chinese Academy of Medical Sciences , Beijing, 100021, P. R. China

[7 ]Department of General Surgery, The Fifth People’s Hospital of Shanghai, Fudan University , Shanghai 200240, China

Author notes

[a ] dingkan@ 123456simm.ac.cn

[b ] liuhbfdu@ 123456sina.com

[*]

These authors contributed equally to this work.

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Publisher Item ID: srep28833

DOI: 10.1038/srep28833

PMC ID: 4923895

PubMed ID: 27349455

SO-VID: d3d29596-db01-42cc-b309-199e655c2010

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Downregulation of stathmin 1 in human gallbladder carcinoma inhibits tumor growth in vitro and in vivo

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Most cited references 20

Stathmin: a protein with many tasks. New biomarker and potential target in cancer.

Stathmin 1: a novel therapeutic target for anticancer activity.

Gallbladder cancer: differences in presentation, surgical treatment, and survival in patients treated at centers in three countries.

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