Maspin Reprograms the Gene Expression Profile of Prostate Carcinoma Cells for Differentiation

Qin

International Journal of Molecular Medicine

et al. 2015

Abstract. Mammary serine protease inhibitor (maspin) is a tumor suppressor gene that is silenced in the majority of cancer cells during metastatic progression by transcriptional and epigenetic mechanisms. The function of maspin in non-small cell lung cancer cells (NSCLC) has not been clearly defined. In the present study, the expression of maspin in NSCLC cell lines, in particular, the adenocarcinoma cell lines, was heterogeneous. While the expression levels of maspin in PC-9 and H460 cell lines were intact, the expression of maspin in the A549 and SPC-A1 cells was hardly detected. Ectopic expression of maspin in A549 cells carrying the K-ras gene point mutation significantly inhibited cell migration and invasion abilities, which was associated with downregulated expression of matrix metalloproteinase-2 and integrin β1. Ectopic expression of maspin in SPC-A1 cells harboring the wild-type K-ras gene predominantly affected cell growth via targeting the AKT signaling molecules. Maspin functions differently in lung adenocarcinoma cells, possibly due to the varied molecular characteristics. IntroductionLung cancer is a leading cause of cancer mortality worldwide. Lung cancer is generally divided into non-small cell lung cancer cells (NSCLC) and SCLC, in which the NSCLC constitutes 80-85% of lung cancers. The three major NSCLC subtypes are adenocarcinoma, squamous cell carcinoma and large cell carcinoma. NSCLC, which is characterized by slow tumor cell growth and dissemination, is refractory to chemotherapy and chest radiotherapy. Several driven genes have been identified in NSCLC, such as EGFR, c-MET and the ALK-EML4 fusion gene (1). Treatment for lung cancer is mainly based on tumor stage, tumor pathology and molecular pathology. Understanding thoroughly the molecular mechanism underlying the aberrant cellular events driving lung cancer progressions is crucial for developing novel treatments.Mammary serine protease inhibitor (maspin), also known as Serpin B5, was first identified in 1994 (2). Maspin belongs to the serine protease inhibitor superfamily, and is predominantly localized in the cytoplasm, but is also localized in the nucleus and membrane, and is secreted. The exact roles of maspin in cancer are far more complicated than initially thought due to the conflicting experimental and clinical data that have been reported. In prostate cancer, the expression of maspin is frequently absent (3). Overexpression of maspin is considered an independent factor in predicting a favorable prognosis in breast cancer and lung squamous cell cancer (4-6). However, it has been also reported that the increased nuclear maspin expression predicts a favorable prognosis, whereas the enhanced cytoplasmic expression is associated with early-relapsing and unfavorable prognosis in breast cancer (7). Enhanced expression of maspin is correlated with unfavorable prognosis in pancreatic, ovarian and colorectal cancer (8-10). High maspin expression correlates with an unfavorable outcome in colorectal cancer in stage III and IV, suggesting th...

Section: Discussionsupporting

confidence: 81%

Different maspin functions in the lung adenocarcinoma A549 and SPC-A1 cell lines

Qin

International Journal of Molecular Medicine

et al. 2015

“…We have previously shown that maspin, a 42 kDa tumor suppressive endogenous histone deacetylase (HDAC) 1 inhibitor (15, 16), plays a predominant role in the maintenance of the epigenetic program for differentiation (17, 18). Consistently, accumulated experimental evidence showed that maspin exerts multifaceted tumor suppressive effects including reduces tumor cell-associated uPA:uPAR activity (19, 20), blocks tumor cells detachment from established contacts with the extracellular matrix (21), inhibits tumor cell motility and invasion in vitro (17, 22) and inhibits tumor growth and metastasis in xenograft (18) or syngeneic tumor models (23-25).…”

Section: Introductionmentioning

confidence: 99%

Maspin Expression in Prostate Tumor Cells Averts Stemness and Stratifies Drug Sensitivity

et al. 2015

Future curative cancer chemotherapies have to overcome tumor cell heterogeneity and plasticity. To test the hypothesis that the tumor suppressor maspin may reduce microenvironment-dependent prostate tumor cell plasticity and thereby modulate drug sensitivity, we established a new schematic combination of 2D, 3D and suspension cultures to enrich prostate cancer cell subpopulations with distinct differentiation potentials. We report here that, depending on the level of maspin expression, tumor cells in suspension and 3D collagen I manifest the phenotypes of stem-like and dormant tumor cell populations, respectively. In suspension, the surviving maspin-expressing tumor cells lost the self-renewal capacity, underwent senescence, lost the ability to dedifferentiate in vitro and failed to generate tumors in vivo. Maspin-nonexpressing tumor cells that survived the suspension culture in compact tumorspheres, displayed a higher level of stem cell marker expression, maintained the self-renewal capacity, formed tumorspheres in 3D matrices in vitro and were tumorigenic in vivo. The drug sensitivities of the distinct cell subpopulations depend on the drug target and the differentiation state of the cells. In 2D, Docetaxel, MS275 and Salinomycin were all cytotoxic. In suspension, while MS275 and Salinomycin were toxic, Docetaxel showed no effect. Interestingly, cells adapted to 3D collagen I were only responsive to Salinomycin. Maspin expression correlated with higher sensitivity to MS275 in both 2D and suspension, and to Salinomycin in 2D and 3D collagen I. Our data suggest that maspin reduces prostate tumor cell plasticity, and enhances tumor sensitivity to Salinomycin which may hold promise in overcoming tumor cell heterogeneity and plasticity.

Prostate Cancer - Leading-Edge Diagnostic Procedures and Treatments

“…In normal breast and prostate epithelial cells, maspin is highly expressed and found to be localized mostly in the cytoplasm but has also been detected in the nucleus, secretory vesicles, and occasionally at the cell surface [6][7][8]. Maspin expression is almost completely suppressed in the human prostate cancer LNCaP, DU145, and PC-3 cell lines [9]. At the tissue level, maspin's function seems to be directly correlated with its localization.…”

Section: Expression Of Maspin In Normal Prostate and Cancermentioning

confidence: 81%

“…In benign prostate epithelium, maspin expression is uniformly noted in basal cells at high levels. In contrast, maspin expression is predominantly absent in benign secretory cells and elevated in secretory cells at the transition site between benign prostatic hyperplasia and high-grade PIN lesions [9,10]. Pierson et al noted higher expression of maspin in HGPIN lesions, particularly within secretory cells [11].…”

Section: Expression Of Maspin In Normal Prostate and Cancermentioning

confidence: 96%

“…Overexpression of maspin in DU145 cells leads to apoptosis by abrogating AKT activation induced by hypoxia. According to recent studies, it has been shown that maspin expression (endogenously) is able to sensitize prostate cancer LNCaP and DU145 cells to apoptosis [9]. Watanabe et al used adeno-associated virus (AAV, serotype 2) vector encoding maspin as a means for introducing in vivo gene therapy subcutaneously formed human prostate cancer LNCaP or DU145 tumors in nude mice [43].…”

Section: Biological Functions Of Maspinmentioning

confidence: 99%

See 1 more Smart Citation

Maspin Expression and its Metastasis Suppressing Function in Prostate Cancer

Shankar¹,

Candamo²,

MacLennan³

et al. 2016

Mammary Serine Protease Inhibitor (Maspin) is a unique member of the serpin family with tumor suppressive properties. Maspin is a secreted protein encoded by a class II tumor suppressor gene, expressed in normal prostate luminal and basal cells but reduced or absent in prostate cancer. Currently, there is a consensus that maspin expression in prostate cancer is an indicator of a better prognosis and is a predictive marker for therapeutic response in prostate cancer. Experimental evidence consistently indicates that maspin suppresses tumor growth, invasion, and metastasis and promotes apoptosis in cancer cells. In this chapter, we discuss regulation of maspin expression, binding partners of maspin, and pathways through which maspin exerts its tumor suppressive properties. In addition, we summarize the progress that investigators have made in clarifying the role of maspin in prostate cancer biology and in assessing its role as a diagnostic marker and therapeutic agent.