Elevated nuclear maspin expression is associated with microsatellite instability and high tumour grade in colorectal cancer

Bettstetter, Marcus; Woenckhaus, Matthias; Wild, Peter J.; Rümmele, Petra; Blaszyk, Hagen; Hartmann, Arndt; Hofstädter, Ferdinand; Dietmaier, Wolfgang

doi:10.1002/path.1732

Cited by 73 publications

(104 citation statements)

References 41 publications

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“…Alternatively, it is possible that maspin exerts its role in the nucleus at the level of gene or chromatin regulation and thus indirectly affects the cell-matrix interaction or differentiation state. This would be consistent with previous reports of nuclear maspin (47)(48)(49)(50)(51)(52)(53)(54) and the redistribution of maspin from the nucleus to the cytoplasm on MCF10A differentiation shown in this study. It is also consistent with observations that maspin interacts with the transcription factor IRF6 (18) and that a related clade B serpin has chromatin remodeling capability (55).…”

Section: Discussionsupporting

confidence: 94%

Maspin (SERPINB5) Is an Obligate Intracellular Serpin

Teoh

Whisstock

Bird

2010

Journal of Biological Chemistry

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Maspin (SERPINB5) is a tumor suppressor lost in breast and prostate cancer whose molecular function is unknown. It is a non-inhibitory member of the clade B serpins suggested to play a role in a plethora of intracellular and extracellular settings, yet its normal cellular distribution has never been clarified. Here we investigate the distribution of maspin in non-transformed human epithelial cells. By indirect immunofluorescence, maspin has a nucleocytoplasmic distribution in breast (MCF10A) and prostate (RWPE-1) cells and, by immunoblotting and pulse-chase analyses, is neither glycosylated nor secreted. Cell surface biotinylation studies also show that maspin is not present at the cell surface. Differentiation of MCF10A cells into three-dimensional acini results in the redistribution of maspin from the nucleus to the cytoplasm but does not result in secretion. Addition of an efficient conventional signal peptide to maspin directs it into the secretory pathway and results in glycosylation but not secretion. We further show that maspin in the cytoplasm of MCF10A cells is a soluble monomeric protein that is not detectably associated with the cytoskeleton or other extractable components. Taken together, these results suggest that maspin is restricted to an intracellular, possibly nuclear, role in which it influences cell-matrix interactions indirectly. It is probably released only as a consequence of cell damage or necrosis.

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Section: Discussionsupporting

confidence: 94%

Maspin (SERPINB5) Is an Obligate Intracellular Serpin

Teoh

Whisstock

Bird

2010

Journal of Biological Chemistry

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“…In fact, maspin has been found to be able to inhibit tumor cell motility, invasion, and metastasis, [10][11][12][13] to act as an inhibitor of angiogenesis 14 and as a pro-apoptotic molecule in breast and prostate cancer cells [15][16][17][18] and in endothelial cells. 19 On the other hand, several clinical studies have questioned the tumor-suppressive activity of maspin, in colorectal, 20 pancreatic, 21 ovarian, 22 and even in breast cancer. 5,23 In this regards, it is important to underline that maspin can present as a nuclear, a cytoplasmic, a secreted, as well as a cell surfaceassociated protein.…”

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confidence: 99%

Maspin expression and melanoma progression: a matter of sub-cellular localization

et al. 2014

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Maspin, a member of the serpin family of protease inhibitors, is involved in key processes of cancer progression. Its biological activity seems to be cancer and compartment specific, with the protein acting either as a suppressor or as a tumor promoter in different cancer types. Characterization of maspin expression and its sub-cellular localization in melanoma is missing, hence, we aim to investigate its possible association with melanoma prognostic factors and disease progression. Nuclear and cytoplasmic maspin expression were evaluated on 60 nevi, 152 primary lesions, and 106 melanoma metastases using tissue microarrays and immunohistochemistry. The association between maspin immunoreactivity and patient's clinic-pathological features was evaluated. Multivariate logistic models and survival analyses were performed for maspin expression in primary melanomas. Nuclear maspin was detected in 8% nevi, 49% primary melanomas, and 28% metastases, whereas cytoplasmic maspin in 12% nevi, 18% primary lesions, and 9% metastases. In univariate analysis, nuclear maspin expression in primary melanomas was significantly associated with melanoma prognostic factors (nodular histotype, tumor thickness, mitotic rate, and ulceration) and disease stage, whereas cytoplasmic maspin was observed at higher frequency in thin superficial spreading melanomas, without mitosis. In multivariate analysis, nuclear maspin remained significantly associated with risk of developing a tumor prone to disease progression and, accordingly, with significantly shorter disease-free and overall survival. In this study, maspin was expressed at highest frequency in primary lesions and when expressed in the nuclei, was significantly associated with poor prognostic markers, melanoma recurrence, and worse survival. The present study suggests a tumor-suppressive effect of cytoplasmic maspin and a tumor-promoting effect of nuclear maspin, which open the discussion on its potential use in cancer therapy. Modern Pathology (2014) 27, 412-419; doi:10.1038/modpathol.2013.157; published online 13 September 2013Keywords: biomarker; maspin; melanoma; tissue microarrays Melanoma is a malignant neoplasm that originates from melanocytes and it is characterized by frequent local recurrence, early metastasis, and refractoriness to chemotherapy and biological treatment. 1 With early diagnosis and adequate surgical treatment of primary tumors (Stage I patients), the 5-year survival rate is 495%. 2 However, once melanoma has metastasized to distant sites, life expectancy dramatically declines, with 1-year survival rate of 33% for patients with Stage IV metastatic disease. 2 Primary tumor thickness, ulceration, and mitotic rate, together with the presence of lymph node and systemic metastases, are the histopathologic criteria used for melanoma staging to predict disease outcome in terms of life expectancy and survival rates. 2 However, a significant minority of melanomas contravenes these conventional parameters and displays unpredictable clinical behavior. Furthermore, lack of...

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“…Maspin seems to be of ambivalent nature, as positive maspin expression was found in cancer of colon (Bettstetter et al 2005, Dietmaier et al 2006) and pancreas (Maass et al 2001), and higher levels of maspin expression correlated with poor prognosis in some types of breast cancer (Sheng 2004).…”

Section: Discussionmentioning

confidence: 99%

The maspin expression in canine mammary tumors: an immunohistochemical and molecular study

et al. 2009

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RESUMO.-[A expressão do maspin nos tumores mamários caninos: um estudo imuno-histoquímico e molecular.] O serpin maspin, um supressor tumoral no câncer de mama foi descrito como inibidor de migração celular e indutor de adesão celular entre a membrana basal e a matriz extracelular resultando na inibição da metástase tumoral. Por outro lado, a alta expressão do maspin está relacionada com um mau prognóstico em outros tipos de câncer. Pouco se sabe sobre a expressão, regulação e função do maspin nos tumores mamários caninos. Neste estudo, foi demonstrada uma perda da expressão de maspin nas células mamárias malignas de cães quando comparadas com um pool de tecido mamário normal de cães, analisado por PCR quantitativa em tempo real. Houve uma expressão fraca maspin em preparações de tumores mamários malignos observadas por imuno-histoquímica. Também foi verificado que a expressão nuclear do maspin em tumores mamários caninos está relacionada a um bom prognóstico. Assim, o maspin pode ser utilizado como um marcador prognóstico nas neoplasias mamárias em cães. The serpin maspin, a tumor suppressor in breast cancer was described as an inhibitor of cell migration and inducer of cell adhesion between the basement membrane and extracellular matrix resulting in inhibition of tumor metastasis. In contrast, overexpression of maspin is correlated with poor prognosis in other types of cancer. Little is known about expression, regulation and function of maspin in canine mammary tumors. It was demonstrated in this study, a loss of maspin expression in malignant canine mammary cells compared with a pool of normal canine mammary tissue, analyzed by quantitative real-time PCR; weak maspin expression in malignant canine mammary tumors were observed by immunohistochemistry. It was also demonstrated that a correlation with nuclear maspin expression and a good prognosis. It is suggested that maspin could be used as a prognostic marker in canine mammary neoplasia.INDEX TERMS: Maspin, canine mammary tumor, immunohistochemistry, molecular biology, prognosis.1

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Elevated nuclear maspin expression is associated with microsatellite instability and high tumour grade in colorectal cancer

Cited by 73 publications

References 41 publications

Maspin (SERPINB5) Is an Obligate Intracellular Serpin

Maspin (SERPINB5) Is an Obligate Intracellular Serpin

Maspin expression and melanoma progression: a matter of sub-cellular localization

The maspin expression in canine mammary tumors: an immunohistochemical and molecular study

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