A role of novel serpin maspin in tumor progression: The divergence revealed through efforts to converge

Abstract

Maspin, a 42 kDa protein, belongs to the serine protease inhibitor (serpin) superfamily and is more closely related to the ovalbumin-like serpin subfamily (ov-serpins). More than a decade after the discovery of the maspin gene, our pursuit of the molecular mechanisms of maspin revealed a significant divergence of maspin from other serpins. This review article summarizes recent advances in the identification of maspin-binding proteins and the potential underlying molecular mechanisms of maspin in tumor progression. Specifically, the molecular interactions of maspin with the cell surface-associated pro-urokinase-type plasminogen activator (pro-uPA) and intracellular histone deacetylase 1 (HDAC1) are highlighted. Our new evidence suggests a new paradigm that maspin acts as a serpin-like molecule to inhibit serine protease-like targets. From an evolution point of view, the uniquely important function of maspin in development and tumor progression is likely due to its ancestral sequence code, and accordingly, its novel "meta"-serpin structure. It is reasonable to hypothesize that the conservation of a serine protease-like catalytic center in many molecules requires the co-existence of endogenous antagonists. The unique inhibitory interaction of maspin with both HDAC1 and pro-uPA might not be substituted by other serpins that have evolved to acquire higher target specificities. Thus, tumor suppressive maspin offers a unique therapeutic opportunity.

Identification of Biomarkers for Predicting Nasopharyngeal Carcinoma Response to Radiotherapy by Proteomics

“…Maspin is also an important apoptosis-sensitizing factor, making tumor sensitive to drug-induced apoptosis (27,28). It has been shown that Maspin expression was directly correlated with radiochemotherapy response in head and neck squamous cell carcinoma (13,29) and the use of Maspin as a therapeutic target against cancer through the reexpression of Maspin by pharmacologic intervention have been explored (30). In this study, Maspin was downregulated in the radioresistant NPC cells and tissues and its downregulation was associated with NPC radioresistance, which together with reporters suggests that the decrease of Maspin expression in NPC increased its radiation resistance and Maspin might be a biomarker for predicting NPC response to radiotherapy.…”

Candidate therapeutic agents for hepatocellular cancer can be identified from phenotype‐associated gene expression signatures

“…24 Loss of maspin can contribute to tumor invasion and metastasis in cancer cells. 25 In addition, maspin can block neovascularization and reduce the density of tumorassociated microvessels in vivo. 26 Thus, we speculated that the altered maspin activation could contribute to the ability of 17-AAG to reverse tumor cell invasion.…”

Proteomics Demonstration That Normal Breast Epithelial Cells Can Induce Apoptosis of Breast Cancer Cells through Insulin-like Growth Factor-binding Protein-3 and Maspin

“…Maspin (mammary serpin) is a serine protease inhibitor with tumor suppression activities. Since its discovery in 1994, maspin has been consistently shown to suppress the aggressive tumor phenotypes, inhibiting cell invasion and mobility in vitro and inhibiting tumor growth and metastasis in experimental animal models (32)(33)(34). Maspin is localized both in cytoplasmic and nuclear compartments but may also be secreted.…”