Role of maspin in cancer

Rossana Berardi 0 Francesca Morgese 0 Azzurra Onofri 0 Paola Mazzanti 0 Mirco Pistelli 0 Zelmira Ballatore 0 Agnese Savini 0 Mariagrazia De Lisa 0 Miriam Caramanti 0 Silvia Rinaldi 0 Silvia Pagliaretta 0 Matteo Santoni 0 Chiara Pierantoni 0 Stefano Cascinu 0 0 Medical Oncology Unit, Universit Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I , GM Lancisi, G Salesi di Ancona, Via Conca, Ancona 71-60126, Italy Maspin (mammary serine protease inhibitor), is a member of the serine protease inhibitor/non-inhibitor superfamily. Its expression is down-regulated in breast, prostate, gastric and melanoma cancers but over-expressed in pancreatic, gallbladder, colorectal, and thyroid cancers suggesting that maspin may play different activities in different cell types. However, maspin expression seems to be correlated with better prognosis in prostate, bladder, lung, gastric, colorectal, head and neck, thyroid and melanoma cancer. In breast and ovarian cancer maspin significance is associated with its subcellular localization: nucleus maspin expression correlates with a good prognosis, whilst in pancreatic cancer it predicts a poor prognosis. Since tumor metastasis requires the detachment and invasion of tumor cells through the basement membrane and stroma, a selectively increased adhesion by the presence of maspin may contribute to the inhibition of tumor metastasis. Furthermore the different position of maspin inside the cell or its epigenetic modifications may explain the different behavior of the expression of maspin between tumors. The expression of maspin might be useful as a prognostic and possibly predictive factor for patients with particular types of cancer and data can guide physicians in selecting therapy. Its expression in circulating tumor cells especially in breast cancer, could be also useful in clinical practice along with other factors, such as age, comorbidities, blood examinations in order to select the best therapy to be carried out. Focusing on the malignancies in which maspin showed a positive prognostic value, therapeutic approaches studied so far aimed to re-activate a dormant tumor suppressor gene by designed transcription factors, to hit the system that inhibits the expression of maspin, to identify natural substances that can determine the activation and the expression of maspin or possible molecules binds to introduce maspin in cancer cell and gene therapy capable of up-regulating the maspin in an attempt to reduce primarily the risk of metastasis. Further studies in these directions are necessary to better define the therapeutic implication of maspin. - Review Introduction Maspin (mammary serine protease inhibitor), is a member of the serine protease inhibitor/non-inhibitor superfamily (serpin), like plasminogen activator inhibitors 1 and 2 and 1-antitrypsin. Maspin gene is located on chromosome 18q21.3q23 and it was identified for the first time in 1994. Maspin expression is down-regulated in breast, prostate, gastric and melanoma cancers but over-expressed in pancreatic, gallbladder, colorectal, and thyroid cancers suggesting that maspin may play different activity in different cell types. These conflicting observations might be explained by distinct subcellular localization of maspin in cancer cells (cytoplasmic, nuclear or both cytoplasmicnuclear expression); by interactions with extracellular matrix and its structure and epigenetic modifications [1-4]. A characteristic feature of serpin structure, is a reactive center loop (RCL), a peptide stretch that is located 915 residues amino-terminal to the reactive site peptide bond. RCL allows the reactive site to present an optimal configuration for binding, and subsequent inhibiting target protease. The conformational change is known as the stressed-to -relaxed transition. Maspin, however, contains a relatively short, divergent, not highly conserved, hydrophobic RCL not capable of undergoing this transition. Collectively, these properties place maspin into the non-inhibitory category of the large serpin superfamily and shift the focus away from attempting to identify a target protease as explanation for the biological activities of maspin (Figure 1) [5-7]. Another interesting aspect of Maspin pertains to the G -helix (G-helix), an internal salt bridge or the P1 position of the reactive center loop. The Maspin G-helix is capable of an open and closed conformational change inducing redistribution of charged residues within the molecule. An intact G-helix is absolutely required for the effect of maspin on cell migration, and the effect of the maspin protein can be mimicked by a short peptide corresponding to this structural element. Maspin and the G-helix in isolation are reliant on 1 integrins for their effects on cell migration [8]. Furthermore the action of maspin on cell migration needed a 15-mer G-helix peptide right direct binding to the 1 integrin subunit resulting in the inactivation of 1 integrins (Figure 2) [9-11]. In fact several studies showed that Maspin elicits changes in the expression of proteins associated with the actin cytoskeleton that predict a less motile and Figure 1 The x-ray crystal structure of maspin. Figure 2 Maspin three-dimensional structure. invasive phenotype and reduced metastatic spread. Moreover, RCL appears to mediate binding to a cell surface receptor that promotes cell adhesion to type I collagen and fibronectin [12,13]. To confirm this maspin action time-lapse video microscopic studies showed that recombinant maspin dramatically also inhibited the lamellopodia extension and vectorial translation [14]. Since tumor metastasis requires the detachment and invasion of tumor cells through the basement membrane and stroma, selectively increased adhesion by the presence of maspin may contribute to the inhibition of tumor metastasis (Figure 3) [15-17]. During the process of metastasis, there are consistent changes in gene expression. Studies of genes that are reduced or silenced have yielded surprising insights into in vivo mechanisms of regulating tumor metastasis. This review describes a tumor suppressor gene, Maspin, which is often silenced in cancer cells and exhibits suppressing activity against tumor growth and metastasis. Maspin has been shown to be involved in processes that are important to both tumor growth and metastasis such as cell invasion, angiogenesis, and more recently apoptosis. Hence, many efforts have been devoted to deciphering the molecular mechanism of maspin. While some insights have come from the protease inhibitory effect of maspin, more perceptive results on how maspin may function in suppressing tumor metastasis have come from studies of gene manipulation, protein interactions and global protein profiling [18]. Recent evidence indicates, however, that nuclear localization of maspin in cancer cells is necessary for its tumor suppressor activity and nuclear-localized maspin binds to chromatin are (...truncated)