SERPINB5

Gene Summary

Gene:SERPINB5; serpin family B member 5
Aliases: PI5, maspin
Location:18q21.33
Summary:-
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:serpin B5
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SERPINB5 (cancer-related)

Strien L, Joensuu K, Heikkilä P, Leidenius MH
Different Expression Patterns of CXCR4, CCR7, Maspin and FOXP3 in Luminal Breast Cancers and Their Sentinel Node Metastases.
Anticancer Res. 2017; 37(1):175-182 [PubMed] Related Publications
AIM: Luminal A breast cancers (BC) represent low-risk tumors conferring better outcome than luminal B and human epidermal growth factor 2 (HER2)-positive or triple-negative tumors. One reason for the heterogeneous outcome among patients with luminal BC is the variation in cell proliferation. As chemokine receptors and tumor suppressors show potential for estimation of infiltration to regional lymph nodes, we aimed to compare differently sized sentinel node metastases with their primary tumors (PT).
MATERIALS AND METHODS: We compared 29 BCs of luminal subtype A and 23 of subtype B (Ki-67 cut off at 14%) by immunohistochemistry for the chemokine receptors C-X-C chemokine receptor 4 (CXCR4), C-C-chemokine receptor 7 (CCR7), the tumor suppressor Maspin and the regulatory T-cell immunosuppressor forkhead box protein 3 (FOXP3) between PTs and their metastases of different size.
RESULTS: Expression of CXCR4 was low in luminal A type tumors, and CCR7 and FOXP3 expression were high in luminal B type cancer. CXCR4 expression significantly positively correlated with CCR7 both in PTs and metastases. Most Maspin-positive PTs became negative in the metastases. The PTs for all Maspin-positive metastases were luminal B type.
CONCLUSION: High CXCR4 expression in PTs was found to be associated with luminal A type tumor, suggesting more favorable outcome. In contrast, CCR7 and FOXP3 expressions in PTs represented luminal B tumors, pointing to more aggressive tumor behavior. Maspin expression did not differ between luminal types.

Leopizzi M, Cocchiola R, Milanetti E, et al.
IKKα inibition by a glucosamine derivative enhances Maspin expression in osteosarcoma cell line.
Chem Biol Interact. 2017; 262:19-28 [PubMed] Related Publications
Chronic inflammation has been associated to cancer development by the alteration of several inflammatory pathways, such as Nuclear Factor-κB pathway. In particular, IκB kinase α (IKKα), one of two catalytic subunit of IKK complex, has been described to be associated to cancer progression and metastasis in a number of cancers. The molecular mechanism by which IKKα affects cancer progression is not yet completely clarified, anyway an association between IKKα and the expression of Maspin (Mammary Serine Protease Inhibitor or SerpinB5), a tumor suppressor protein, has been described. IKKα shuttles between cytoplasm and nucleus, and when is localized into the nuclei, IKKα regulates the expression of several genes, among them Maspin gene, whose expression is repressed by high amount of nuclear IKKα. Considering that high levels of Maspin have been associated with reduced metastatic progression, it could be hypothesized that the repression of IKKα nuclear translocation could be associated with the repression of metastatic phenotype. The present study is aimed to explore the ability of a glucosamine derivative, 2-(N-Carbobenzyloxy)l-phenylalanylamido-2-deoxy-β-d-glucose (NCPA), synthesized in our laboratory, to stimulate the production of Maspin in an osteosarcoma cell line, 143B. Immunofluorescence and Western blotting experiments showed that NCPA is able to inhibit IKKα nuclear translocation, and to stimulate Maspin production. Moreover, in association with stimulation of Maspin production we found the decrease of β1 Integrin expression, the down-regulation of metalloproteases MMP-9 and MMP-13 production and cell migration inhibition. Taking in account that β1 Integrin and MMP-9 and -13 have been correlated with the invasiveness of osteosarcoma, considering that NCPA affects the invasiveness of 143B cell line, we suggest that this molecule could affect the osteosarcoma metastatic ability.

Safadi RA, Quda BF, Hammad HM
Immunohistochemical expression of K6, K8, K16, K17, K19, maspin, syndecan-1 (CD138), α-SMA, and Ki-67 in ameloblastoma and ameloblastic carcinoma: diagnostic and prognostic correlations.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2016; 121(4):402-11 [PubMed] Related Publications
OBJECTIVE: To identify cutoff values of markers that correlate with the histopathologic diagnosis of ameloblastic carcinoma (AC) and/or the increased recurrence potential of ameloblastoma (AB).
STUDY DESIGN: Immunohistochemical expression (IHCE) of 9 selected markers were investigated in 18 non-recurrent ameloblastomas (NRABs), 6 recurrent ameloblastomas (RABs), and 5 ACs.
RESULTS: No significant difference in IHCE of K6, K8, K16, K17, K18, K19, maspin, or syndecan-1 was observed among study groups. α Smooth muscle actin (α-SMA)-positive area in central epithelial cells significantly differentiated between AB and AC (P = .017; t -test). Ki-67 score significantly differentiated between AB and AC (P < .005; t -test) and between AC and RAB (P = .015; ANOVA/post hoc).
CONCLUSIONS: Ki-67 score of 75 cells/HPF (ROC curve) is a potential indicator of AC. Clinical recurrence of AB may be predicted by α-SMA expression pattern. Syndecan-1 and α-SMA may indicate a higher aggressive potential of AB when expressed in the stroma.

Yin R, Guo L, Zhang J, et al.
RGD and polyhistidine tumor homing peptides potentiates the action of human Maspin as an antineoplastic candidate.
Appl Microbiol Biotechnol. 2016; 100(14):6209-18 [PubMed] Related Publications
Maspin, a non-inhibitory member of serine protease family, acts as an effective tumor suppressor by inhibiting cell inhesion and mobility. We found that exogenous wild-type rMaspin had a low effect on tumor growth in vivo. However, when the peptide Arg-Gly-Asp-hexahistidine (RGD-6His) was introduced into rMaspin, the modified rMaspin showed significant inhibitory activity in angiogenic assays and tumor-bearing animal models. Overall, our data suggested that both the RGD and hexahistidine fragments contributed to improve the fusion protein activity and polyhistidine peptide could be considered as flexible linker to separate RGD and Maspin moieties to avoid function interference. Besides, it is an efficient tag to achieve purified recombinant proteins. Furthermore, rMaspin fusing with RGD and hexahistidine could be a viable anticancer candidate.

Tang Y, Zu X, Xiong Y, Zhang X
[Expression of Maspin in bladder carcinoma and the relationship between Maspin and lymph node metastasis].
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2015; 40(12):1306-12 [PubMed] Related Publications
OBJECTIVE: To examine the expression of Maspin in the bladder carcinoma, and to explore the relationship among Maspin expression, clinical pathology and lymph node metastasis.

METHODS: The expression of Maspin in 72 bladder cancer tissues and 12 normal bladder tissues were detected by immunohistochemistry. Preoperative pelvic CT images and postoperative pathological results of lymph node metastasis in 72 bladder cancer patients were analyzed retrospectively. The sensibility, specificity, positive predictive value and negative predictive value were calculated, and the advantage for diagnosis of lymph node metastasis was compared between Maspin examination and CT scan.

RESULTS: 1) The expression of Maspin in 72 bladder cancer tissues was significantly lower than that in the normal bladder tissues (P<0.05); 2) The expression of Maspin was obviously decreased with the progress in clinical stage, pathlogical grade and lymph node metastasis, with significant difference (all P<0.05); 3) There were 27 patients diagnosed as pelvic lymph node metastasis by CT scan, and the positive rate was 37.5% (27/72); there were 22 patients diagnosed as pelvic lymph node metastasis by pathological results, and the positive rate was 30.5% (22/72). The pathological diagnose for pelvic lymph node metastasis was the gold standard. The sensitivity, specificity, positive predictive value and negative predictive value for CT was 45.5%, 73.3%, 37.0%, and 66.7%, respectively; the sensibility, specificity, positive predictive value and negative predictive value was 81.8%, 50%, 41.8% and 86.2% in the diagnosis of lymph node metastasis for the 72 bladder cancer cases by Maspin examination; the sensitivity, specificity, positive predictive value and negative predictive was 90.9%, 78.0%, 64.5% and 95.0% in the diagnose of lymph node metastasis by Maspin examination combined with CT scan.

CONCLUSION: The expression of Maspin in bladder cancer is significantly lower than that in normal bladder cancer, and a statistically significant correlation is also observed between Maspin expression and lymph node metastasis. Maspin maybe a valuable biomarker in diagnose of bladder cancer with lymph node metastasis. Maspin examination combined with CT scan has more advantage in the evaluation of bladder cancer with lymph node metastasis than Maspin or CT alone.

Chen J, Wang L, Tang Y, et al.
Maspin enhances cisplatin chemosensitivity in bladder cancer T24 and 5637 cells and correlates with prognosis of muscle-invasive bladder cancer patients receiving cisplatin based neoadjuvant chemotherapy.
J Exp Clin Cancer Res. 2016; 35:2 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Maspin, a non-inhibitory member of the serine protease inhibitor superfamily, has been characterized as a tumor suppressor gene in multiple cancer types. Chemotherapeutic insensitivity is one of major obstacles to effectively treating muscle invasive bladder cancer (MIBC). This study was conducted to investigate the role and probable mechanism of Maspin enhancing cisplatin chemosensitivity of bladder cancer in vitro and MIBC patients.
METHODS: Maspin expression was quantified by qRT-PCR in two MIBC cell lines (T24 and 5637). After successful established Maspin overexpression model by lipidosome transfection, MTT and cell apoptosis assay were used to assess the MIBC's cisplatin sensitivity. Western blot method was used to test PI3K/ AKT/mTOR signal passway and apoptosis related molecules Caspase3 and Bcl-2. Additionally, we evaluated Maspin expression and prognosis in 62 MIBC cases who underwent cisplatin based neoadjuvant chemotherapy (NACT) using immunohistochemistry.
RESULT: Upregulate Maspin expression could enhance the chemosensitivity induced by cisplatin in T24 and 5637 cell lines. The cell viability, cloning ability and IC50 were reduced while apoptosis rate was upregulated when cells were transfected Maspin. Phospho(p)-AKT, PI3K, mTOR, and Bcl-2 expression were significantly decreased, whereas Caspase3 was greatly increased in the Maspin group. In the clinic study, there was significant correlation between Maspin expression and overall survival (OS) and progression-free survival (PFS) rate in MIBC patients who received cisplatin based NACT.
CONCLUSION: Maspin could enhance cisplatin chemosensitivity in T24 and 5637 cell lines. Its expression correlated with prognosis of MIBC patients who received cisplatin based neoadjuvant chemotherapy.

Mardin WA, Ntalos D, Mees ST, et al.
SERPINB5 Promoter Hypomethylation Differentiates Pancreatic Ductal Adenocarcinoma From Pancreatitis.
Pancreas. 2016 May-Jun; 45(5):743-7 [PubMed] Related Publications
OBJECTIVES: The diagnosis of pancreatic ductal adenocarcinoma (PDAC) is challenging in the setting of pancreatitis. We investigated SERPINB5 for its impact on PDAC tumor biology and its use as a diagnostic marker for PDAC in the setting of pancreatitis.
METHODS: Patient samples from PDAC primary tumors, PDAC lymph node metastases, and pancreatitis were investigated for SERPINB5 promoter methylation by methylation-specific polymerase chain reaction (PCR). Six PDAC cell lines were investigated in vitro and in vivo using an orthotopic mouse model to generate primary tumors and metastases. SERPINB5 mRNA expression, protein expression, and promoter methylation were determined by quantitative reverse transcriptase-PCR, methylation-specific PCR, and Western Blot.
RESULTS: In patient samples, detection of an unmethylated SERPINB5 promoter differentiated pancreatitis from PDAC with a sensitivity of 57% and a specificity of 95% (P < 0.001). SERPINB5 was not deregulated in primary tumors versus metastases, but primary tumors without SERPINB5 protein expression had significantly reduced viability (P = 0.02).
CONCLUSIONS: SERPINB5 seems to assume an oncogenic role in PDAC. In clinical samples, detection of unmethylated SERPINB5 was a specific marker for PDAC even in the context of pancreatitis and may provide the basis for a liquid biopsy option to detect PDAC.

Dzinic SH, Bernardo MM, Oliveira DS, et al.
Tumor suppressor maspin as a modulator of host immune response to cancer.
Bosn J Basic Med Sci. 2015; 15(4):1-6 [PubMed] Free Access to Full Article Related Publications
Despite the promising clinical outcome, the primary challenge of the curative cancer immunotherapy is to overcome the dichotomy of the immune response: tumor-evoked immunostimulatory versus tumor-induced immunosuppressive. The goal needs to be two-fold, to re-establish sustainable antitumor-cancer immunity and to eliminate immunosuppression. The successful elimination of cancer cells by immunosurveillance requires the antigenic presentation of the tumor cells or tumor-associated antigens and the expression of immunostimulatory cytokines and chemokines by cancer and immune cells. Tumors are heterogeneous and as such, some of the tumor cells are thought to have stem cell characteristics that enable them to suppress or desensitize the host immunity due to acquired epigenetic changes. A central mechanism underlying tumor epigenetic instability is the increased histone deacetylase (HDAC)-mediated repression of HDAC-target genes regulating homeostasis and differentiation. It was noted that pharmacological HDAC inhibitors are not effective in eliminating tumor cells partly because they may induce immunosuppression. We have shown that epithelial-specific tumor suppressor maspin, an ovalbumin-like non-inhibitory serine protease inhibitor, reprograms tumor cells toward better differentiated phenotypes by inhibiting HDAC1. Recently, we uncovered a novel function of maspin in directing host immunity towards tumor elimination. In this review, we discuss the maspin and maspin/HDAC1 interplay in tumor biology and immunology. We propose that maspin based therapies may eradicate cancer.

Hong F, Sun J, Li C, et al.
[Expressions of Maspin and Ki67 in extranodal nasal type NK/T-cell lymphoma and the significance].
Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2015; 29(13):1184-6 [PubMed] Related Publications
OBJECTIVE: To analyze the expression of Maspin and Ki67 in EN-NK/TCL and the significance.
METHOD: The expressions of Maspin and Ki67 were detected by immunohistochemistry in 34 cases of EN-NK/TCL and 11 cases of chronic sinusitis.
RESULT: Maspin was low expressed in EN-NK/TCL, Ki67 was highly expressed in EN-NK/TCL. Negative correlation was found between the expression of Maspin and Ki67 in EN-NK/TCL.
CONCLUSION: The combined examination of Maspin and Ki67 has important significance in the diagnosis in EN-NK/ TCL.

Hasby EA
Mammary serine protease inhibitor and CD138 immunohistochemical expression in ovarian serous and clear cell carcinomas.
Tumour Biol. 2016; 37(4):4889-900 [PubMed] Related Publications
This study aims to investigate the immunohistochemical expression of mammary serine protease inhibitor (maspin) and CD138 in primary ovarian high-grade serous carcinomas (HGSC) as compared to low-grade serous carcinomas (LGSC) and clear cell carcinomas and investigate if the studied markers have a correlation to International Federation of Gynaecology and Obstetrics (FIGO) stage, Ki67 proliferation index, and to each other. Maspin cellular location varied significantly between studied groups with only nuclear expression seen in 46.7 % of LGSC group, mixed nuclear and cytoplasmic in 13.3, 28.6, and 20 % of LGSC, HGSC, and clear cell carcinoma, respectively, and was only cytoplasmic in 26.7, 71.4, and 80 % of LGSC, HGSC, and clear cell carcinoma, respectively. Mean maspin and CD138 counts were significantly higher in HGSC and clear cell carcinoma compared to LGSC. Both maspin and CD138 scores varied significantly between studied groups and were positively correlated with adverse prognostic factors in studied carcinomas including FIGO stage and Ki67 proliferation index. Besides, both maspin and CD138 had significant correlation to each other. These findings suggest that epithelial cytoplasmic expression of maspin and CD138 may have a significant role in tumorigenesis in ovarian high-grade serous carcinomas and clear cell carcinomas; these markers may regulate tumor cell proliferation, and their significant correlation to each other may suggest that CD138 probably induces maspin expression to protect tumor growth factors from being lysed by proteolytic enzymes.

Liu ZQ, Zhao GQ, Meng W, et al.
Effect of biological behavior and clinical significance of maspin gene on cervical squamous carcinoma SiHa cell.
Eur J Gynaecol Oncol. 2015; 36(5):533-8 [PubMed] Related Publications
OBJECTIVE: This study was performed to evaluate the effect of mammary serine protease inhibitor (maspin) overexpression on human cervical squamous carcinoma (SCC) SiHa cell proliferation and apoptosis in vitro.
MATERIAL AND METHODS: Recombinant plasmid pcDNA3-maspin was stably transfected into human cervical SCC SiHa cell. Maspin mRNA was determined by RT-PCR, whereas maspin protein was detected by Western blot analysis and immunocytochemistry (IHC). Cell proliferation activity was measured by MTT method. Apoptosis rate and cell cycle distribution were detected by flow cytometry to understand the changes in the cell biological characteristics.
RESULTS: The strengthened expression of the maspin gene in the SiHa cell was confirmed by RT-PCR, Western blot, and immunocytochemistry (IHC) (p < 0.05). Suppressed proliferation activity and increased apoptosis rate of SiHa-m (maspin stable transfected) versus SiHa and SiHa-vector cell (SiHa-pc3) were shown by MTT and flow cytometry (p < 0.05). SiHa and SiHa-pc3-had no statistical significance (p > 0.05).
CONCLUSION: The results showed that maspin gene can significantly inhibit human cervical SCC SiHa cell proliferation and effectively slow cancer growth. Maspin may be a new molecular target in the gene therapy of human cervical SCC.

Al-Mamun MA, Farid DM, Ravenhil L, et al.
An in silico model to demonstrate the effects of Maspin on cancer cell dynamics.
J Theor Biol. 2016; 388:37-49 [PubMed] Related Publications
Most cancer treatments efficacy depends on tumor metastasis suppression, where tumor suppressor genes play an important role. Maspin (Mammary Serine Protease Inhibitor), an non-inhibitory serpin has been reported as a potential tumor suppressor to influence cell migration, adhesion, proliferation and apoptosis in in vitro and in vivo experiments in last two decades. Lack of computational investigations hinders its ability to go through clinical trials. Previously, we reported first computational model for maspin effects on tumor growth using artificial neural network and cellular automata paradigm with in vitro data support. This paper extends the previous in silico model by encompassing how maspin influences cell migration and the cell-extracellular matrix interaction in subcellular level. A feedforward neural network was used to define each cell behavior (proliferation, quiescence, apoptosis) which followed a cell-cycle algorithm to show the microenvironment impacts over tumor growth. Furthermore, the model concentrates how the in silico experiments results can further confirm the fact that maspin reduces cell migration using specific in vitro data verification method. The data collected from in vitro and in silico experiments formulates an unsupervised learning problem which can be solved by using different clustering algorithms. A density based clustering technique was developed to measure the similarity between two datasets based on the number of links between instances. Our proposed clustering algorithm first finds the nearest neighbors of each instance, and then redefines the similarity between pairs of instances in terms of how many nearest neighbors share the two instances. The number of links between two instances is defined as the number of common neighbors they have. The results showed significant resemblances with in vitro experimental data. The results also offer a new insight into the dynamics of maspin and establish as a metastasis suppressor gene for further molecular research.

Huang CY, Chang YJ, Luo SD, et al.
Maspin mediates the gemcitabine sensitivity of hormone-independent prostate cancer.
Tumour Biol. 2016; 37(3):4075-82 [PubMed] Related Publications
Androgen deprivation therapy has constituted the main treatment for prostate cancer; however, tumors ultimately progress to hormone-independent prostate cancer (HIPC), and suitable therapeutic strategies for HIPC are not available. Maspin, which is also known as mammary serine protease inhibitor, has been suggested to be a valuable focus for targeted cancer therapy. Specifically, maspin has been shown to be upregulated after androgen ablation therapy. Gemcitabine is used as a first-line therapy for metastatic castration-resistant prostate cancer, but its disease control rate is low. Furthermore, the role of maspin in the therapeutic efficacy of gemcitabine for HIPC remains unclear. The expression levels of maspin in PC-3 and DU145 cells were determined by real-time PCR and Western blotting. Furthermore, the expression of maspin was silenced using shRNA technology to generate maspin-KD cells. The cytotoxicity of gemcitabine to prostate cancer cells was assessed using 3-[4,5-dimethylthiazol-2-yl]-3,5-diphenyl tetrazolium bromide (MTT) assays, whereas flow cytometry analyses and annexin V-propidium iodide (PI) apoptosis assays were used to assess the ability of gemcitabine to induce apoptosis in maspin-KD and control cells. Additionally, the expression patterns of anti-apoptosis proteins (myeloid cell leukemia 1 (Mcl-1) and B cell lymphoma 2 (Bcl-2)) and pro-apoptosis proteins (Bcl-2-associated death promoter (Bad) and Bcl-2-associated X protein (Bax)) were determined by Western blotting. In this study, PC-3 cells were more resistant to gemcitabine administration than DU145 cells, which correlated with the higher expression levels of maspin observed in PC-3 cells. Furthermore, maspin knockdown enhanced gemcitabine-induced cell death, as evidenced by the increased number of apoptotic cells. Gemcitabine treatment upregulated the levels of anti-apoptosis proteins (Mcl-2 and Bcl-2) in both scrambled control and maspin-KD cells; however, the fold changes in Mcl-1 and Bcl-2 expression were larger in gemcitabine-treated scrambled control cells than in maspin-KD cells. Finally, our findings indicate for the first time that maspin may mediate the therapeutic efficacy of gemcitabine in HIPC. Our results demonstrate that maspin knockdown enhanced the sensitivity of androgen-independent prostate cancer cells to gemcitabine. Therefore, combining gemcitabine with a drug that targets maspin might constitute a valuable strategy for prostate cancer treatment.

Yaman B, Nart D, Ekren PK, et al.
Expression of p63, TTF-1 and Maspin in Non-Small Cell Lung Carcinoma and Their Effect on the Prognosis and Differential Diagnosis.
Turk Patoloji Derg. 2015; 31(3):163-74 [PubMed] Related Publications
OBJECTIVE: Lung cancer is still the leading cause of cancer mortality. Antiapoptotic genes and protease inhibitors play an important role in the development of lung cancer.
MATERIAL AND METHOD: p63, TTF-1 and maspin expression and their role in the differential diagnosis, overall survival, progression-free survival and other clinicopathological characteristics of the patients were investigated in 80 surgically-resected non-small cell lung carcinomas.
RESULTS: The maximal tumor diameter range was 1.5-11 cm (mean: 4.06±1.8 cm). Forty-five (56.3%) tumors were adenocarcinoma, 23 (28.8%) squamous cell carcinoma, four (5%) large cell carcinoma, six (7.5%) large cell neuroendocrine carcinoma, one (1.2%) sarcomatoid carcinoma while one was (1.2%) both adenocarcinoma and squamous cell carcinoma. The patients with advanced TNM stage and a tumor diameter more than 3 cm had markedly poor survival. Immunohistochemically, p63 staining was present in 87.5% of squamous cell carcinomas, 4.3% of adenocarcinomas, 25% of large cell carcinomas, and 16.7% of large cell neuroendocrine carcinomas. Similarly, maspin was positive in 66.7% of squamous cell carcinomas and 17.4% of adenocarcinomas. The TTF-1 staining rate was higher in adenocarcinomas (84.8%). There was no immunoreactivity in squamous cell carcinomas (p < 0.001). We found that p63 and TTF-1 had no significant effect on survival in either tumor group (p > 0.05) while maspin has a negative prognostic effect in adenocarcinoma (p=0.048).
CONCLUSION: This study suggests that p63 and TTF-1 are reliable markers in non-small cell lung carcinoma and can be used in differential diagnosis. Maspin has been identified as a prognostic marker in adenocarcinoma. However, more studies are required to elucidate the significance of maspin.

Ciortea CD, Jung I, Gurzu S, et al.
Correlation of angiogenesis with other immunohistochemical markers in cutaneous basal and squamous cell carcinomas.
Rom J Morphol Embryol. 2015; 56(2 Suppl):665-70 [PubMed] Related Publications
UNLABELLED: The aim of this study was to establish an immunoprofile of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), and to explore as first time in literature the possible correlation between maspin, DOG-1, p16 protein and angiogenesis in these tumors. For SCCs, the histological grade of differentiation was also taken into account. The angiogenesis was quantified in 38 randomly selected cases of SCCs and 17 BCCc, respectively, using the antibodies vascular endothelial growth factor (VEGF-A) and COX-2, while the microvessel density (MVD) was evaluated with the CD31.
RESULTS: In SCCs, maspin cytoplasm to nuclear shift was an indicator of a deeper tissue invasion and dedifferentiation in the invasion front. The poorly differentiated cases, compared to G1÷G2-SCCs, expressed more frequent the markers p16 (30.77% vs. 8%) and VEGF-A (53.85% vs. 32%), regardless the MVD. However, the p16 positivity was more frequent in BCCs than SCCs (52.94% vs. 15.79%). All of the p16-positive carcinomas were located in the head and neck area. DOG-1 marked 21.05% of SCCs and 5.88% of BCCs, being directly correlated with COX-2 positivity. Eccrine glands and hair follicles also expressed DOG-1.
CONCLUSIONS: In cutaneous SCCs located in the head and neck area, sun-dependent p16÷VEGF interaction seems to be responsible by tumor dedifferentiation, whereas maspin cytoplasm to nuclear shift might indicate a high degree of invasiveness. This is the first report about DOG-1 positivity in BCCs and eccrine glands, the significance of this pattern being unknown.

Yi HM, Yi H, Zhu JF, et al.
A five-variable signature predicts radioresistance and prognosis in nasopharyngeal carcinoma patients receiving radical radiotherapy.
Tumour Biol. 2016; 37(3):2941-9 [PubMed] Related Publications
Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment. Clinical tumor-node-metastasis (TNM) staging has limited accuracy in predicting NPC radioresponse and determining its therapeutic regimens. To construct a risk score model for predicting NPC radioresistance, immunohistochemistry was used to assess the expression of four proteins (14-3-3σ, Maspin, RKIP, and GRP78) in 149 NPC samples with different radiosensitivity. Sequentially, a logistic regression analysis was performed to identify independent predictors of NPC radioresistance and establish a risk score model. As a result, a risk score model, Z = -3.189 - 1.478 (14-3-3σ) - 1.082 (Maspin) - 1.666 (RKIP) + 2.499 (GRP78) + 2.597 (TNM stage), was constructed, and a patient's risk score was estimated by the formula: e (Z)/(e (Z) + 1) × 100, where "e" is the base of natural logarithm. High-risk score was closely associated with NPC radioresistance, and was observed more frequently in the radioresistant patients than that in the radiosensitive patients. The sensitivity, specificity, and accuracy of the risk score model for predicting NPC radioresistance was 88.00, 86.48, and 87.25 %, respectively, which was clearly superior to each individual protein and TNM stage. Furthermore, Kaplan-Meier survival analysis showed that high-risk score correlated with the markedly reduced overall survival (OS) and disease-free survival (DFS) of the patients, and Cox regression analysis showed that the risk score model was an independent predictor for OS and DFS. This study constructs a risk score model for predicting NPC radioresistance and patient survival, and it may serve as a complement to current radioresistance risk stratification approaches.

Chen L, Huang K, Himmelfarb EA, et al.
Diagnostic value of maspin in distinguishing adenocarcinoma from benign biliary epithelium on endoscopic bile duct biopsy.
Hum Pathol. 2015; 46(11):1647-54 [PubMed] Related Publications
Histopathologic distinction between benign and malignant epithelia on endoscopic bile duct biopsy can be extremely challenging due to small sample size, crush artifact, and a propensity for marked inflammatory and reactive changes after stent placement. Our previous studies have shown that the insulin-like growth factor II mRNA-binding protein 3, S100P, and the von Hippel-Lindau gene product (pVHL) can help the distinction. This study analyzed 134 endoscopic bile duct biopsy specimens (adenocarcinoma 45, atypical 31, and benign 58) by immunohistochemistry for the expression of maspin, a serine protease inhibitor. The results demonstrated that (1) maspin expression was more frequently detected in malignant than in benign biopsies; (2) malignant biopsies frequently showed diffuse, strong/intermediate, and combined nuclear/cytoplasmic staining patterns for maspin, which were much less commonly seen in benign biopsies; (3) the malignant staining patterns for maspin observed in atypical biopsies were consistent with follow-up data showing that 67% of these patients were subsequently diagnosed with adenocarcinoma; (4) a maspin+/S100P+/pVHL- staining profile was seen in 75% of malignant biopsies but in none of the benign cases. These observations demonstrate that maspin is a useful addition to the diagnostic immunohistochemical panel (S100P, pVHL, and insulin-like growth factor II mRNA-binding protein 3) to help distinguish malignant from benign epithelia on challenging bile duct biopsies.

Zhou J, Hualong Q, Zhou P, Guo F
Different maspin functions in the lung adenocarcinoma A549 and SPC-A1 cell lines.
Int J Mol Med. 2015; 36(5):1440-8 [PubMed] Related Publications
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.

Daltoe FP, Grando LJ, Meurer MI, et al.
A Rare Case of Mucoepidermoid Carcinoma ex Pleomorphic Adenoma arising in Minor Salivary Gland: Histopathological and Immunohistochemical Analysis.
J Contemp Dent Pract. 2015; 16(7):603-6 [PubMed] Related Publications
Mucoepidermoid carcinoma ex pleomorphic adenoma (MCxPA) is a rare salivary gland tumor predominantly found in major salivary glands. A case of MCxPA involving the soft tissue and bone of the retromolar region of a 26-year-old man is presented. The histopathological features revealed a neoplasm with predominance of pleomorphic adenoma (PA) elements, and presence of mucoepidermoid carcinoma malignant epithelial cells in several areas. Histochemical and immunohistochemical studies were positive for periodic acid Schiff, alcian blue, cytokeratins 7, 13, 14, and 19, Bcl-2, c-erbB-2, FGF-2 and maspin in the malignant areas. The patient underwent a partial resection of the left side of the mandible with neck dissection and MCxPA diagnosis was confirmed.

Chen WS, Yen CJ, Chen YJ, et al.
miRNA-7/21/107 contribute to HBx-induced hepatocellular carcinoma progression through suppression of maspin.
Oncotarget. 2015; 6(28):25962-74 [PubMed] Free Access to Full Article Related Publications
Maspin suppresses tumor progression by promoting cell adhesion and apoptosis and by inhibiting cell motility. However, its role in tumorigenesis of hepatocellular carcinoma (HCC) remains unclear. The gene regulation of maspin and its relationship with HCC patient prognosis were investigated in this study. Maspin expression was specifically reduced in HBV-associated patients and correlated with their poor prognosis. Maspin downregulation in HCC cells was induced by HBx to promote their motility and resistance to anoikis and chemotherapy. HBx-dependent induction of microRNA-7, -107, and -21 was further demonstrated to directly target maspin mRNA, leading to its protein downregulation. Higher expressions of these microRNAs also correlated with maspin downregulation in HBV-associated patients, and were associated with their poor overall survival. These data not only provided new insights into the molecular mechanisms of maspin deficiency by HBx, but also indicated that downregulation of maspin by microRNAs confers HBx-mediated aggressiveness and chemoresistance in HCC.

Carozzi F, Tamburrino L, Bisanzi S, et al.
Are biomarkers evaluated in biopsy specimens predictive of prostate cancer aggressiveness?
J Cancer Res Clin Oncol. 2016; 142(1):201-12 [PubMed] Related Publications
PURPOSE: To evaluate biomarkers involved in biological pathways for prostate cancer (PCa) progression, measured in biopsy specimens, in order to distinguish patients at higher risk for fatal PCa and thus improve the initial management of disease.
METHODS: Retrospective case-control study. In 129 PCa patients who underwent ultrasound-guided needle prostate biopsy and subsequent radical prostatectomy from 1987 to 1999 at the University Hospital of Careggi, we evaluated: (1) mRNA expression of the serine 2 (TMPRSS2): erythroblastosis virus E26 oncogene homolog (ERG); (2) expression of matrix metalloproteinases (MMP)-2 and 9 (epithelial and stromal); (3) expression of androgen receptor; (4) expression of prognostic marker Ki67 (MIB1); (5) presence and typing of human papilloma virus; (6) DNA methylation of CpG islands of several genes involved in PCa progression.
RESULTS: The cohort consists of 38 cases (patients with PCa and died of PCa within 10 years from diagnosis) and 91 controls (patients with PCa but alive 10 years after diagnosis). Gleason bioptic score, epithelial MMP expression and SERPINB5 methylation correlated with statistically significant increase in death risk OR. Compared with patients with high level of MMP, patients with low level of MMP had OR for specific death 4.78 times higher (p = 0.0066). After adjustment for age and Gleason score, none of the investigated biomarkers showed increased OR for PCa death.
CONCLUSIONS: Our preliminary results suggest that evaluation, in prostate biopsy specimens, of a panel of biomarkers known to be involved in PCa progression is poorly indicative of tumor outcome.

Bernardo MM, Kaplun A, Dzinic SH, et al.
Maspin Expression in Prostate Tumor Cells Averts Stemness and Stratifies Drug Sensitivity.
Cancer Res. 2015; 75(18):3970-9 [PubMed] Free Access to Full Article Related Publications
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 two-dimensional (2D), three-dimensional (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.

Rubio CA, Kaufeldt A, Björk J, Jaramillo E
Maspin, a Marker of Serrated Colorectal Polyps.
Anticancer Res. 2015; 35(7):4139-44 [PubMed] Related Publications
The serine proteinase inhibitor maspin is a tumor-suppressor protein that stimulates apoptosis and inhibits motility, invasion and cancer metastasis. Mutant maspin galvanises partial loss of tumor-suppressor function, reducing susceptibility to apoptosis and facilitating malignant progression. Mutant maspin has been reported in many tumor types. We recently analyzed maspin expression in 128 colorectal lesions: 39 hyperplastic polyps (HPs), 29 sessile serrated adenoma/polyps (SSA/Ps), three traditional serrated adenomas (TSAs), 20 conventional colorectal adenomas (CCRAs), 5 carcinomas evolving from CCRA, 12 active inflammatory bowel disease (IBD), 2 ulcerative colitis (UC) in remission, 4 solitary ulcers (rectum) and 12 normal colorectal mucosa. The topographic distribution of maspin in the cytoplasm was classified into i) extensive, ii) focal, or iii) negative. The intensity of maspin expression in the cytoplasm was classified into i) unquestionable or ii) negative. Cases with faint (questionable) maspin expression were also recorded as negative. Extensive maspin expression was recorded in 95% (39/41) of the HPs, in 100% (29/29) of the SSA/Ps (including one carcinoma arising in a SSA/P), in 66% (2/3) of the TSAs, but only in 10% (2/20) of the CCRAs. None of the specimens with carcinoma arising in CCRA, with UC in remission or with solitary ulcer exhibited extensive maspin expression. Importantly, maspin was not expressed in the normal mucosa (including that adjacent to HP, SSA/P, TSA and CCRA). It is submitted that extensive maspin expression might be a manifestation of mutant maspin in lesions central to the serrated pathway of colorectal carcinogenesis.

Toll A, Margalef P, Masferrer E, et al.
Active nuclear IKK correlates with metastatic risk in cutaneous squamous cell carcinoma.
Arch Dermatol Res. 2015; 307(8):721-9 [PubMed] Related Publications
About 5% of all cutaneous squamous cell carcinomas (cSCCs) metastasize, which is the principal cause of death by this type of cancer. However, to date there are no reliable biomarkers that categorize those SCC patients that will progress to metastasis. Nuclear active IKKα diminishes Maspin levels in prostate cancer facilitating its metastatic potential. In this paper, we describe the immunohistochemical analysis of active IKK and Maspin in 56 metastasizing and 51 non-metastasizing primary cSCC to measure their association with cancer behaviour. We also determined the effect of inhibiting IKK activity in SCC cell growth and migration in vitro. We found that high levels of nuclear active IKK in the primary tumour are predictive of cSCC metastatic capacity, in particular when combined with poor tumour differentiation and a history of tumour recurrence. Active IKK inversely correlated with Maspin levels in cSCC tumours, and samples negative for Maspin are exclusively found in the metastatic group. Mechanistically, IKK activity regulates cellular motility and SCC cell survival. Our results indicate that nuclear active IKK is a robust biomarker to predict cSCC outcome, and suggest the possibility of targeting IKK activity as a future therapy for treating metastatic cSCC.

Zhu H, Yun F, Shi X, Wang D
Inhibition of IGFBP-2 improves the sensitivity of bladder cancer cells to cisplatin via upregulating the expression of maspin.
Int J Mol Med. 2015; 36(2):595-601 [PubMed] Related Publications
The present study aimed to reveal the association between insulin-like growth factor binding protein-2 (IGFBP-2) and the sensitivity of bladder cancer cells to cisplatin, and determine the underlying mechanism involving maspin. A total of 32 bladder cancer tissue samples were collected for analysis. Cells of the BIU87 human bladder cancer cell line were cultured and a cisplatin-resistant subline (BIU87-CisR) was established by continuous exposure of the cells to cisplatin. Targeted inhibition of IGFBP-2 in the BIU87-CisR cells was performed using small interfering RNA technology. The expression levels of IGFBP-2 and maspin in the tissue samples and cells were analyzed using reverse transcription-quantitative polymerase chain reaction and western blot analyses. Cell viability following treatment in each group was evaluated using a Cell Counting Kit-8 assay subsequent to treatment with 3 μM cisplatin. The cell cycle and apoptotic rate of the BIU87-CisR cells were analyzed using flow cytometry. Finally, maspin-overexpressing BIU87-CisR cells were used to confirm the effect of maspin on the sensitivity of the cells to cisplatin. The expression levels of IGFBP-2 in chemoresistant patients and BIU87-CisR cells were significantly increased, compared with those in the chemosensitive patients and BIU87 cells, respectively. However, the expression levels of maspin were lower in the cisplatin-resistant tissue and cells, and was enhanced by IGFBP-2 inhibition. Cisplatin (3 μM) caused marked proliferation inhibition, cell cycle arrest and apoptosis of the BIU87-CisR cells, the effect of which was enhanced by IGFBP-2 silencing. Overexpression of maspin also improved the sensitivity of the BIU87-CisR cells to cisplatin. In conclusion, inhibition of IGFBP-2 improved the sensitivity of bladder cancer cells to cisplatin by elevating the expression of maspin.

Ma S, Pang C, Song L, et al.
The expression of ATF3, MMP-2 and maspin in tissue chip of glioma.
Pak J Pharm Sci. 2015; 28(3 Suppl):1059-63 [PubMed] Related Publications
This paper tested and analyzed the expression of ATF3 (activating transcription factor), MMP-2 (matrix metalloprotease) and maspin in tissue chip of glioma and its correlation with glioma advancement. Based on immunohistochemical staining, this paper selected 100 patients with glioma and 13 healthy persons to test the relative expression of ATF3, MMP-2 and maspin. The result witnessed 72.0% of ATF3 expression in glioma and 15.4% in healthy brain tissues with P<0.05; glioma had 76.0% of MMP-2 expression while healthy brain tissues only had 7.7% (P<0.05); but maspin expression with 53.0% in glioma was much lower than that with 100% in healthy tissues with P<0.05. If the pathological stage of glioma rose up, the expression of ATF3 and MMP-2 accordingly increased while maspin expression decreased. The correlation between ATF3 expression and MMP-2 expression was positive with r=0.553 and p<0.01; negative correlation between ATF3 expression and maspin expression was found with r=-0.457 and p<0.01; and the expression of MMP-2 and maspin were negatively related with r=-0.551 and p<0.01. According to the above results, it could be concluded that the expression of ATF3, MMP-2 and maspin did relate with each other. Besides, the high expression of ATF3 and MMP-2 as well as the low expression of maspin had great influence on glioma, playing a key role in glioma's occurrence, advancement, invasion and metastasis.

Kim JH, Cho NY, Bae JM, et al.
Nuclear maspin expression correlates with the CpG island methylator phenotype and tumor aggressiveness in colorectal cancer.
Int J Clin Exp Pathol. 2015; 8(2):1920-8 [PubMed] Free Access to Full Article Related Publications
It has been suggested that nuclear expression of maspin (mammary serine protease inhibitor; also known as SERPINB5) in colorectal cancer (CRC) is associated with proximal colonic tumor location, mucinous and poorly differentiated histology, microsatellite instability-high (MSI-H), and poor prognosis. Based on these findings, there may be a potential association between nuclear maspin expression and the CpG island methylator phenotype (CIMP) in CRC, but no study has elucidated this issue. Here, we evaluated maspin protein expression status by immunohistochemistry in 216 MSI-H CRCs. CIMP status was also determined by methylation-specific quantitative PCR method (MethyLight) using eight CIMP markers (MLH1, NEUROG1, CRABP1, CACNA1G, CDKN2A (p16), IGF2, SOCS1, and RUNX3) in 216 MSI-H CRCs. Associations between maspin expression status and various pathological, molecular, and survival data were statistically analyzed. Among the 216 MSI-H CRCs, 111 (51%) cases presented nuclear maspin-positive tumors. Nuclear maspin-positive MSI-H CRCs were significantly associated with proximal tumor location (P = 0.003), tumor budding (P < 0.001), lymphovascular invasion (P = 0.001), perineural invasion (P = 0.008), absence of peritumoral lymphoid reaction (P = 0.045), lymph node metastasis (P = 0.003), distant metastasis (P = 0.005), advanced AJCC/UICC stage (stage III/IV) (P = 0.001), and CIMP-high (CIMP-H) status (P < 0.001). Patients with nuclear maspin-positive tumors showed worse disease-free survival than patients with nuclear maspin-negative tumors (log-rank P = 0.025). In conclusion, nuclear maspin expression is molecularly associated with CIMP-H rather than MSI-H, and clinicopathologically correlates with tumor aggressiveness in CRC.

Jung I, Gurzu S, Turdean S, et al.
Relationship of endothelial area with VEGF-A, COX-2, maspin, c-KIT, and DOG-1 immunoreactivity in liposarcomas versus non-lipomatous soft tissue tumors.
Int J Clin Exp Pathol. 2015; 8(2):1776-82 [PubMed] Free Access to Full Article Related Publications
Soft tissue tumors are rare tumors that show a heterogeneous structure; thus far, their molecular behavior has not been elucidated. The aim of our study was to define the relationship between microvessel density (MVD), evaluated with CD31, and other immunohistochemical markers, such as vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), CD34, maspin, DOG-1, and c-KIT. Immunostains were done in 55 cases consisting of benign and malignant tumors, such as liposarcomas, dermatofibrosarcomas, and tumors with histiocytic differentiation. Renal tubes were used as external control for VEGF, maspin, and DOG-1. Although DOG-1 is considered a specific marker for gastrointestinal tumors (GISTs), its positivity, correlated with c-KIT and VEGF immunoexpression, was also shown by dermatofibrosarcomas and tumors with histiocytic and lipomatous differentiation, suggesting its possible pro-angiogenic role. Maspin expression was observed in adipose tissue tumors only. Regarding angiogenesis, 31 of the 55 cases were VEGF-positive, such positivity being directly correlated with COX-2 and CD34 positivity as evaluated in the tumor cells and also with MVD. Although no significant differences in angiogenic activity were found between benign and malignant non-lipomatous tumors, the MVD was directly correlated with the histological type/grade of liposarcomas. Based on these aspects, we conclude that VEGF/COX-2-induced angiogenesis is specific for non-lipomatous tumors, whereas liposarcomas are dependent on the VEGF/maspin angiogenic pathway. The DOG-1/c-KIT/VEGF target may be used for further personalized therapy of soft tissue sarcomas. No data about DOG-1 and maspin positivity in liposarcomas have been published to date.

Zhu H, Yun F, Shi X, Wang D
VEGF-C inhibition reverses resistance of bladder cancer cells to cisplatin via upregulating maspin.
Mol Med Rep. 2015; 12(2):3163-9 [PubMed] Related Publications
The aim of the current study was to elucidate the association between vascular endothelial growth factor C (VEGF-C) and resistance of bladder cancer cells to cisplatin and the underlying mechanism involving maspin. A total of 32 bladder cancer tissue samples from patients (18 males and 14 females with an average age of 65.9 years) were collected from the Fifth Affiliated Hospital of Zhengzhou University (Zhengzhou, China). All patients had undergone cisplatin-based combination chemotherapy. In addition, the BIU87 human bladder cancer cell line was cultured and a cisplatin-resistant subline (BIU87-CisR) was established by continuous exposure to cisplatin. The mRNA expression levels of VEGF-C and maspin in tissue samples, BIU87 cells and BIU87-CisR cells were analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Targeted inhibition of VEGF-C in BIU87-CisR cells was performed using small interfering (si)RNA technology and the alteration in levels of maspin was confirmed by RT-qPCR and western blot analysis. siRNA-treated and -untreated BIU87-CisR cells were divided into the following four groups: Control group (no drug treatment), 3 μM cisplatin treated group, 3 μM cisplatin + siRNA treated group and the siRNA treated group. Cell viability following treatment in each group was evaluated by the cell counting kit 8 assay. The cell cycle and apoptotic rate of BIU87-CisR cells was analyzed by propidium iodide (PI) staining and Annexin V-PI double staining with flow cytometry. Furthermore, pcDNA-maspin transfected BIU78-CisR cells were used to establish the effect of maspin on the sensitivity to cisplatin. VEGF-C expression in chemoresistant patients and BIU87-CisR cells was significantly increased compared with chemosensitive patients and normal BIU87 cells, respectively. By contrast, maspin levels were lower in chemoresistant patients and BIU87-CisR cells. Subsequent to VEGF-C inhibition, maspin expression was markedly increased. Cisplatin (3 μM) resulted in moderate proliferation inhibition of BIU87-CisR cells without siRNA pretreatment; however, significant inhibition was observed in the VEGF-C siRNA treated group. In addition, the cell cycle arrest and apoptosis induced by cisplatin was enhanced by VEGF-C inhibition. Overexpression of maspin was able to improve the sensitivity of BIU87-CisR cells to cisplatin. In conclusion, the resistance of bladder cancer cells to cisplatin may be induced by upregulation of VEGF-C, and inhibition of VEGF-C reverses resistance by elevating maspin expression levels.

Ma S, Pang C, Song L, et al.
Activating transcription factor 3 is overexpressed in human glioma and its knockdown in glioblastoma cells causes growth inhibition both in vitro and in vivo.
Int J Mol Med. 2015; 35(6):1561-73 [PubMed] Free Access to Full Article Related Publications
Glioblastomas are highly malignant gliomas that are extremely invasive with high rates of recurrence and mortality. It has been reported that activating transcription factor 3 (ATF3) is expressed in elevated levels in multiple malignant tumors. The purpose of this study was to investigate the function of ATF3 in the development of glioma and its clinical significance. Immunohistochemical staining, western blot analysis and RT-qPCR revealed that the mRNA and protein levels of ATF3 and matrix metalloproteinase 2 (MMP2) were higher in the glioma than in the normal human brain tissues, and that their levels were proportional to the pathological grades. By contrast, the mRNA and protein levels of mammary serine protease inhibitor (maspin; SERPINB5) were significantly lower in the glioma than in the normal brain tissue, and maspin expression was inversely proportional to the glioma pathological grade. The transfection of U373MG glioblastoma cells with ATF3-siRNA induced a number of changes in cell behavior; the cell proliferative activity was decreased and flow cytometry revealed an increased proportion of cells arrested in the G0/G1 phase of the cell cycle. In addition, TUNEL staining indicated an increased proportion of cells undergoing apoptosis and Transwell assays revealed impaired cell mobility. The sizes of the tumors grown as xenografts in nude mice were also significantly reduced by treatment of host mice with ATF3-siRNA. Taken together, these results suggest that ATF3 promotes the progression of human gliomas.

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