Fascin Overexpression Research Articles

Hypoxia-Inducible Factor-1 Promotes Pancreatic Ductal Adenocarcinoma Invasion and Metastasis by Activating Transcription of the Actin-Bundling Protein Fascin

Because of the early onset of local invasion and distant metastasis, pancreatic ductal adenocarcinoma (PDAC) is the most lethal human malignant tumor, with a 5-year survival rate of less than 5%. In this study, we investigated the role of fascin, a prometastasis actin-bundling protein, in PDAC progression, invasion, and the molecular mechanisms underlying fascin overexpression in PDAC. Our data showed that the expression levels of fascin were higher in cancer tissues than in normal tissues, and fascin overexpression correlated with the PDAC differentiation and prognosis. Fascin overexpression promoted PDAC cell migration and invasion by elevating matrix metalloproteinase-2 (MMP-2) expression. Fascin regulated MMP-2 expression through protein kinase C and extracellular signal-regulated kinase. Importantly, our data showed that hypoxia induced fascin overexpression in PDAC cells by promoting the binding of hypoxia-inducible factor-1 (HIF-1) to a hypoxia response element on the fascin promoter and transactivating fascin mRNA transcription. Intriguingly, HIF-1α expression levels in PDAC patient specimens significantly correlated with fascin expression. Moreover, immunohistochemistry staining of consecutive sections demonstrated colocalization between HIF-1α and fascin in PDAC specimens, suggesting that hypoxia and HIF-1α were responsible for fascin overexpression in PDAC. When ectopically expressed, fascin was able to rescue PDAC cell invasion after HIF-1α knockdown. Our results demonstrated that fascin is a direct target gene of HIF-1. Our data suggested that the hypoxic tumor microenvironment in PDAC might promote invasion and metastasis by inducing fascin overexpression, and fascin might be targeted to block PDAC progression.

Fascin regulates chronic inflammation‐related human colon carcinogenesis by inhibiting cell anoikis

By a proteomics-based approach, we identified an overexpression of fascin in colon adenocarcinoma cells (FPCKpP-3) that developed from nontumorigenic human colonic adenoma cells (FPCK-1-1) and were converted to tumorigenic by foreign-body-induced chronic inflammation in nude mice. Fascin overexpression was also observed in the tumors arising from rat intestinal epithelial cells (IEC 6) converted to tumorigenic in chronic inflammation which was induced in the same manner. Upregulation of fascin expression in FPCK-1-1 cells by transfection with sense fascin cDNA converted the cells tumorigenic, whereas antisense fascin-cDNA-transfected FPCKpP-3 cells reduced fascin expression and lost their tumor-forming ability in vivo. The tumorigenic potential by fascin expression was consistent with their ability to survive and grow in the three-dimensional multicellular spheroids. We found that resistance to anoikis (apoptotic cell death as a consequence of insufficient cell-to-substrate interactions), which is represented by the three-dimensional growth of solid tumors in vivo, was regulated by fascin expression through caspase-dependent apoptotic signals. From these, we demonstrate that fascin is a potent suppressor to caspase-associated anoikis and accelerator of the conversion of colonic adenoma cells into adenocarcinoma cells by chronic inflammation.

GATA3 Transcription Factor Abrogates Smad4 Transcription Factor-mediated Fascin Overexpression, Invadopodium Formation, and Breast Cancer Cell Invasion

Transforming growth factor β (TGFβ) is a potent and context-dependent regulator of tumor progression. TGFβ promotes the lung metastasis of basal-like (but not the luminal-like) breast cancer. Here, we demonstrated that fascin, a pro-metastasis actin bundling protein, was a direct target of the canonical TGFβ-Smad4 signaling pathway in basal-like breast cancer cells. TGFβ and Smad4 induced fascin overexpression by directly binding to a Smad binding element on the fascin promoter. We identified GATA3, a transcription factor crucial for mammary gland morphogenesis and luminal differentiation, as a negative regulator of TGFβ- and Smad4-induced fascin overexpression. When ectopically expressed in basal-like breast cancer cells, GATA-3 abrogated TGFβ- and Smad4-mediated overexpression of fascin and other TGFβ response genes, invadopodium formation, cell migration, and invasion, suggesting suppression of the canonical TGFβ-Smad signaling axis. Mechanistically, GATA3 abrogated the canonical TGFβ-Smad signaling by abolishing interactions between Smad4 and its DNA binding elements, potentially through physical interactions between the N-terminal of GATA3 and Smad3/4 proteins. Our findings provide mechanistic insight into how TGFβ-mediated cell motility and invasiveness are differentially regulated in breast cancer.

Differential Expression of Fascin, E-cadherin and Vimentin: Proteins Associated With Survival of Cholangiocarcinoma Patients

IntroductionThis study investigated the differential expression of fascin, E-cadherin and vimentin in human carcinogenesis. MethodsThis study detected their expressions in 142 cholangiocarcinoma and 20 benign bile duct tissue specimens using immunohistochemistry. Clinicopathologic characteristics and survival data were also collected and analyzed for their association with expression of these 3 proteins. ResultsThe data showed that both fascin and vimentin proteins were significantly overexpressed in cholangiocarcinoma, whereas E-cadherin expression was reduced in cholangiocarcinoma compared with normal tissues. Fascin protein expression was associated with tumor dedifferentiation, venous invasion and lymph node or distant metastasis. Similarly, vimentin expression was associated with tumor dedifferentiation and venous invasion, as well as hepatitis virus infection. In contrast, loss of E-cadherin expression was associated with tumor dedifferentiation (P<0.05). Because the functions of these 3 proteins were closely related, the data showed that fascin and E-cadherin protein expression was reversely associated. However, fascin and vimentin protein expression was positively associated with cholangiocarcinoma. Cox multiple regression analysis showed that distant tumor metastasis, tumor differentiation and overexpression of fascin and vimentin proteins were all independent risk factors for prognosis (P<0.05). ConclusionThe data from the current study demonstrated that overexpression of fascin and vimentin proteins could be further evaluated as biomarkers for the prediction of cholangiocarcinoma patient survival.

Strong association of fascin expression with triple negative breast cancer and basal-like phenotype in African-American women

BackgroundFascin, an actin bundling protein, plays a critical role in cell motility due to formation of actin rich protrusions called filopodia, important in cell migration, invasion and metastatic spread. Fascin...

OP050: Expression of fascin in squamous cell carcinoma of the oral cavity: Clinicopathological, prognostic significance and cell line study

Head and neck squamous cell carcinoma (HNSCC) is one of the most common head and neck cancers. The prognosis of HNSCC is usually poor because of extensive local invasion at initial diagnosis. Fascin, an actin-bundling protein, has been reported responsible for cell motility and overexpression of Fascin contributes to an unfavorable clinical course in several malignancies. Nevertheless, the roles of Fascin protein playing in aggressiveness of HNSCC and their potential mechanisms need to be elucidated. Tca8113(cell lines of OSCC) via the vector-based small interfering RNA (siRNA) to suppress the expression of the Fascin gene were used. Subsequent analyses and observation regarding the expression of Fascin protein and cyto-morphological alterations were detected by Western blot and Boyden chamber invasion assay, cell migration assay and adhesion assay were also applied to investigate the functional changes of Tca8113. Paraffin sections using tissue microarrays of 84 patients with OSCC were investigated immunohistochemically, to determine the level of expression of Fascin labelling index in tumor specimens. The role of Fascin in OSCC was evaluated by correlation with clinical-pathological parameters. There were statistically significant differences ( P < 0.05) of Fascin expression before and after silencing. Down-regulation of Fascin protein directly resulted in suppression of migration, invasion and increase of adhesion in cell line ( P < 0.05). Overexpression of Fascin was significantly associated with regional lymph node metastases ( P = 0.044),advanced T stage (T1 vs T2-4, P = 0.046) advanced tumor stage (I/II vs III/IV, P = 0.049), histologic grade (well vs moderately/poorly, P = 0.018). In 54 patients with tongue carcinoma, overexpression of Fascin was significantly associated with muscle invasion ( P = 0.002). Our results suggest that expression of Fascin protein may play an essential role in regulation of progression of OSCC. Overexpression of Fascin contributes to a more aggressive clinical course and suggests that Fascin has the potential of being a new molecular target for therapeutic intervention.

The Role of Fascin in Migration and Invasion of Urothelial Carcinoma of the Bladder

Introduction: To investigate the roles of fascin in migration and invasiveness in bladder urothelial carcinoma. Materials and Methods: Immunohistochemical detection of fascin in urothelial carcinoma samples and inhibition the expression of fascin in the urothelial carcinoma cell line were performed, then the differences in cell behaviors before and after silencing of the fascin gene were tested. Results: In our study, we found that overexpression of fascin was more frequent in urothelial carcinoma tissues (p < 0.001). Fascin expression was positively correlated with histological grade (p = 0.024) and pT stage (p < 0.001). After transfection of fascin shRNA, the expressions of fascin in 5637 cells and BIU87 cells were efficiently decreased according to real-time RT-PCR and Western blot analysis. When fascin was inhibited, a significant decrease in migration and invasion, and increase in adhesion were observed in 5637 cells and BIU87 cells. However, there was no significant change in the proliferation of 5637 cells or BIU87 cells with or without inhibition of the fascin gene. Conclusions: Fascin expression can be used as a predictor for transformation and progression of urothelial carcinoma, and reduction of fascin levels may represent a novel therapeutic strategy for urothelial carcinoma of the bladder.

Expression of extracellular matrix metalloproteinase inducer and fascin in urinary bladder cancer: Correlation with clinicopathological characteristics

Expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and fascin have recently received considerable attention as emerging key markers of cell invasion and metastasis in various types of cancers. The present study aimed to characterize the expression of EMMPRIN and fascin in a cohort of bladder cancer patients and to verify the association with clinicopathological characteristics. Immunohistochemical analysis of EMMPRIN and fascin was performed in 125 bladder cancer specimens, including 86 transitional cell carcinoma (TCC) and 39 squamous cell carcinoma (SCC) cases. Overexpression of EMMPRIN and fascin was detected in 71.2 and 83.2% of bladder carcinomas, respectively, while neither was detectable in the normal adjacent epithelium. In SCC, EMMPRIN and fascin expression scores were found to be higher compared to TCC cases (P=0.031 and 0.053, respectively). Higher EMMPRIN and fascin immunoscores markedly correlated with tumor pathological (pT) stage in TCC (P<0.001) and SCC (P=0.004 and 0.001, respectively). High EMMPRIN expression was strongly associated with advanced grades in TCC and SCC (P=0.003 and 0.002, respectively). Cases were then stratified, according to the joint expression status of EMMPRIN and fascin, into four immunoprofiles. A highly significant association was found between various tumor immunoprofiles and pathological stage. Of those, the EMMPRIN-/fascin-positive immunophenotype was closely associated with pT3 and pT4 tumors. The findings suggested an association between increased EMMPRIN and fascin expression and increased progression of bladder cancer. Additionally, these two markers may act in concert to mediate a more aggressive behavior through enhanced tumor cell invasion.

DrosophilaFascin is a novel downstream target of prostaglandin signaling during actin remodeling

Although prostaglandins (PGs)-lipid signals produced downstream of cyclooxygenase (COX) enzymes-regulate actin cytoskeletal dynamics, their mechanisms of action are unknown. We previously established Drosophila oogenesis, in particular nurse cell dumping, as a new model to determine how PGs regulate actin remodeling. PGs, and thus the Drosophila COX-like enzyme Pxt, are required for both the parallel actin filament bundle formation and the cortical actin strengthening required for dumping. Here we provide the first link between Fascin (Drosophila Singed, Sn), an actin-bundling protein, and PGs. Loss of either pxt or fascin results in similar actin defects. Fascin interacts, both pharmacologically and genetically, with PGs, as reduced Fascin levels enhance the effects of COX inhibition and synergize with reduced Pxt levels to cause both parallel bundle and cortical actin defects. Conversely, overexpression of Fascin in the germline suppresses the effects of COX inhibition and genetic loss of Pxt. These data lead to the conclusion that PGs regulate Fascin to control actin remodeling. This novel interaction has implications beyond Drosophila, as both PGs and Fascin-1, in mammalian systems, contribute to cancer cell migration and invasion.

Fascin controls neuronal class-specific dendrite arbor morphology

The branched morphology of dendrites represents a functional hallmark of distinct neuronal types. Nonetheless, how diverse neuronal class-specific dendrite branches are generated is not understood. We investigated specific classes of sensory neurons of Drosophila larvae to address the fundamental mechanisms underlying the formation of distinct branch types. We addressed the function of fascin, a conserved actin-bundling protein involved in filopodium formation, in class III and class IV sensory neurons. We found that the terminal branchlets of different classes of neurons have distinctive dynamics and are formed on the basis of molecularly separable mechanisms; in particular, class III neurons require fascin for terminal branching whereas class IV neurons do not. In class III neurons, fascin controls the formation and dynamics of terminal branchlets. Previous studies have shown that transcription factor combinations define dendrite patterns; we find that fascin represents a downstream component of such programs, as it is a major effector of the transcription factor Cut in defining class III-specific dendrite morphology. Furthermore, fascin defines the morphological distinction between class III and class IV neurons. In fact, loss of fascin function leads to a partial conversion of class III neurons to class IV characteristics, while the reverse effect is obtained by fascin overexpression in class IV neurons. We propose that dedicated molecular mechanisms underlie the formation and dynamics of distinct dendrite branch types to elicit the accurate establishment of neuronal circuits.

Abstract 692: Prognostic indicators associated with breast cancer molecular subtypes in African-American women

Abstract Background: Overexpression of Fascin, Endoglin (CD105), and Beta-Catenin has been found to be associated with unfavorable prognosis and progression in hormone-receptor negative breast carcinomas. Specifically, fascin promotes cell motility, while Beta-catenin is involved in cancer invasion, cellular transformation, and metastasis. CD105 is selectively upregulated in small, immature tumor vessels in malignant tumors. The objective of this study was to correlate fascin, CD105, and Beta-Catenin protein expression with clinicopathological factors including age, grade, tumor size, stage, regional node status, survival, and with the four major molecular breast cancer subtypes (luminal A, luminal B, HER2 positive, and Triple Negative [TN]). Methods: Tissue microarrays (TMAs) were constructed from optimally-fixed formalin-fixed, paraffin-embedded tumor blocks from primary breast carcinomas in 203 African-American females. Sections were stained with antitibodies against fascin, CD105, and beta-catenin. The sections were evaluated for the intensity of reactivity (0-3) and the percentage of reactive cells. Cases were categorized as having negative/weak (score &amp;lt;10) or moderate/strong (score &amp;gt;10) fascin expression, negative (score=0) or positive (score&amp;gt;0) CD105 (in tumor cells only) and beta-catenin (cytoplasmic and nuclear) expression. Bivariate analysis was done via χ2 analysis and survivability data was calculated via the generation of Kaplan-Meier curves (SPSS v19). Statistical significance was assumed if P &amp;lt; 0.05. Results: On the TMA, there were 67 triple negatives, 88 Luminal As, 29 Luminal Bs, and 18 Her2 overexpressing cancers. The mean age for the patients in the study was 57.65. Fascin expression was significantly linked to the triple negative subtype (p&amp;lt;0.0001), ER negativity (p&amp;lt;0.0001), PR negativity (0.0001), and Grade III differentiation (p=0.03). CD105 cytoplasmic expression significantly correlated with HER2 positive subtype (p&amp;lt;0.0001), Luminal B subtype (0.01), HER2 positivity (p&amp;lt;0.0001), tumor size (p&amp;lt;0.01) and was associated with decreased disease-free survival (p=0.038). Cytoplasmic beta-catenin expression was significantly associated with triple negative subtype (p&amp;lt;0.03), HER2+ subtype (p&amp;lt;0.001), ER negativity (p&amp;lt;0.001), PR negativity (p&amp;lt;0.001), and HER2 negativity (p=0.03). Conclusions: Our results indicate that fascin, CD105, and Beta-catenin may be potential markers of aggressive breast cancer subtypes and predictors of recurrence and survival. These data also support pharmacological targets for these aggressive subtypes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 692. doi:1538-7445.AM2012-692

Fascin expression in skull base chordoma: correlation with tumor recurrence and dura erosion

Skull base chordomas are invasive tumors, with high rate of local recurrence even when totally extracted. The aggressive biological behavior in chordoma remains unclear. The purpose of this study was to investigate the relationship between fascin expression and tumor biological behavior in skull base chordoma. Using immunohistochemical techniques, we investigated the expression of fascin in 34 patients with skull base chordomas (19 primary tumors and 20 recurrent tumors). Correlation between fascin expression and clinicopathological factors such as patient's age, sex, tumor locations, and fascin expression in recurrent tumor and in tumor with dura mater erosion was analyzed. Various extent of fascin expression was observed in all tumors. There was a higher fascin expression in recurrent chordoma than in primary chordoma, and the difference was statistically significant (p=0.031). No difference of fascin expression was found between histology types. Interestingly, in 8 tumors where the cranial base dura was eroded, there was a high level of fascin expression (p=0.047). These immunohistochemical findings suggest that fascin expression was correlated with tumor recurrence and high invasiveness, and that fascin overexpression may play an important role in the biologic behavior of skull base chordomas.

Fascin overexpression promotes neoplastic progression in oral squamous cell carcinoma

BackgroundFascin is a globular actin cross-linking protein, which plays a major role in forming parallel actin bundles in cell protrusions and is found to be associated with tumor cell invasion and metastasis in various type of cancers including oral squamous cell carcinoma (OSCC). Previously, we have demonstrated that fascin regulates actin polymerization and thereby promotes cell motility in K8-depleted OSCC cells. In the present study we have investigated the role of fascin in tumor progression of OSCC.MethodsTo understand the role of fascin in OSCC development and/or progression, fascin was overexpressed along with vector control in OSCC derived cells AW13516. The phenotype was studied using wound healing, Boyden chamber, cell adhesion, Hanging drop, soft agar and tumorigenicity assays. Further, fascin expression was examined in human OSCC samples (N = 131) using immunohistochemistry and level of its expression was correlated with clinico-pathological parameters of the patients.ResultsFascin overexpression in OSCC derived cells led to significant increase in cell migration, cell invasion and MMP-2 activity. In addition these cells demonstrated increased levels of phosphorylated AKT, ERK1/2 and JNK1/2. Our in vitro results were consistent with correlative studies of fascin expression with the clinico-pathological parameters of the OSCC patients. Fascin expression in OSCC showed statistically significant correlation with increased tumor stage (P = 0.041), increased lymph node metastasis (P = 0.001), less differentiation (P = 0.005), increased recurrence (P = 0.038) and shorter survival (P = 0.004) of the patients.ConclusionIn conclusion, our results indicate that fascin promotes tumor progression and activates AKT and MAPK pathways in OSCC-derived cells. Further, our correlative studies of fascin expression in OSCC with clinico-pathological parameters of the patients indicate that fascin may prove to be useful in prognostication and treatment of OSCC.

Fascin Protein Is Critical for Transforming Growth Factor β Protein-induced Invasion and Filopodia Formation in Spindle-shaped Tumor Cells

Fascin, an actin-bundling protein overexpressed in all carcinomas, has been associated with poor prognosis, shorter survival, and more metastatic diseases. It is believed that fascin facilitates tumor metastasis by promoting the formation of invasive membrane protrusions. However, the mechanisms by which fascin is overexpressed in tumors are not clear. TGFβ is a cytokine secreted by tumor and mesenchymal cells and promotes metastasis in many late stage tumors. The pro-metastasis mechanisms of TGFβ remain to be fully elucidated. Here we demonstrated that TGFβ induced fascin expression in spindle-shaped tumor cells through the canonical Smad-dependent pathway. Fascin was critical for TGFβ-promoted filopodia formation, migration, and invasion in spindle tumor cells. More importantly, fascin expression significantly correlates with TGFβ1 and TGFβ receptor I levels in a cohort of primary breast tumor samples. Our results indicate that elevated TGFβ level in the tumor microenvironment may be responsible for fascin overexpression in some of the metastatic tumors. Our data also suggest that fascin could play a central role in TGFβ-promoted tumor metastasis.

Fascin promotes the motility and invasiveness of pancreatic cancer cells

To explore the role of actin-bundling protein, fascin during the progression of pancreatic cancer. The plasmid expressing human fascin-1 was stably transfected into the pancreatic cancer cell line MIA PaCa-2. The proliferation, cell cycle, motility, scattering, invasiveness and organization of the actin filament system in fascin-transfected MIA PaCa-2 cells and control non-transfected cells were determined. Heterogeneous overexpression of fascin markedly enhanced the motility, scattering, and invasiveness of MIA PaCa-2 cells. However, overexpression of fascin had minimal effect on MIA PaCa-2 cell proliferation and cell cycle. In addition, cell morphology and organization of the actin filament system were distinctly altered in fascin overexpressed cells. When transplanted into BALB/c-nu mice, fascin-transfected pancreatic cancer cells developed solid tumors at a slightly slower rate, but these tumors displayed more aggressive behavior in comparison with control tumors. Fascin promotes pancreatic cancer cell migration, invasion and scattering, thus contributes to the aggressive behavior of pancreatic cancer cells.

Fascin stain as a potential marker of invasiveness in carcinomas of the urinary bladder: A retrospective study with biopsy and cytology correlation

The evaluation of invasion in urothelial carcinomas of the urinary bladder cannot be determined on cytology and can be particularly challenging in biopsy cases with limited sampling. Recent studies of bladder resection specimens suggest that fascin overexpression may be a marker of aggressive urothelial carcinomas and can help facilitate the assessment of invasion. In this study, we evaluated urine cytology and corresponding biopsy specimens with proven invasive urothelial carcinoma for fascin expression by immunohistochemistry. Thirty-five patients diagnosed with positive urine cytology and biopsy-proven invasive urothelial carcinoma between January 2003 and February 2009 were identified. We found increased fascin expression in 100% (35/35) of SurePath™ urine cytology preparations as well as 100% (35/35) of corresponding biopsy cases with invasive urothelial carcinoma. On urine cytology, cytoplasmic fascin staining was moderate to intense in malignant tumor cell clusters and single cells and not observed in benign urothelial cells. Staining in biopsy cases was generally intense and cytoplasmic and present in both the invasive (100%) and noninvasive (31%) components of the lesion. These findings uphold the association of increased fascin expression in invasive urothelial carcinomas of the urinary bladder. We furthermore demonstrate that fascin staining can be performed successfully on SurePath™ urine cytology preparations in which increased fascin expression correlates with invasion on biopsy. While not a definitive marker of invasion, as it is observed in in situ carcinoma, we conclude that the utilization of fascin immunohistochemistry on urine cytology might serve as a useful adjunct in predicting invasiveness in subsequent biopsies.

Fascin is a predictor for invasiveness and recurrence of urothelial carcinoma of bladder

ObjectivesTo evaluate the expression of fascin in bladder urothelial carcinoma, and to analyze its association with clinicopathologic features and prognosis of urinary bladder urothelial carcinoma. Materials and methodsImmunohistochemistry was used to detect the expression of fascin, Ki-67, p53, CK20, and multidrug resistance gene (MDR) in 111 bladder urothelial carcinoma and 42 normal epithelial tissues. The association between fascin expression and clinicopathologic parameters and prognostic factors on tumor recurrence was analyzed by Kaplan-Meier method, log-rank test, and Cox proportional hazards model. ResultsNinety-four of 111 cases of bladder urothelial carcinoma showed positive fascin expression, while no fascin expression was detected in normal transitional epithelium. There was a significant difference in the expression of fascin in normal epithelium and bladder urothelial carcinoma (P = 0.000). Fascin expression was positively correlated with pT stage (P = 0.001) and tumor size (P = 0.011), while it had no association with age, gender, and tumor grade (P > 0.05). pT stage and the expression of fascin, Ki-67, p53, and CK20 were significantly correlated with urothelial carcinoma recurrence, and fascin expression was an independent factor predicting tumor recurrence. ConclusionsFascin expression was up-regulated in bladder urothelial carcinoma. Over-expression of fascin might play an important role in invasiveness and recurrence of bladder urothelial carcinoma. Fascin may be used as a prognostic marker and a new target for the treatment of bladder urothelial carcinoma.

Cortactin, Fascin and Survivin Expression Associated with Clinicopathological Parameters in Brain Gliosarcoma

Gliosarcoma is a very rare primary neoplasm of the central nervous system classified as a variant of glioblastoma. Cortactin, fascin and survivin have been found in several human cancers to play important roles in tumor progression, but the expression pattern of these biomarkers in gliosarcoma is unclear. Immunostaining for cortactin, fascin and survivin was assessed in 6 surgical specimens of brain gliosarcoma, and the relationship between the expression of these biomarkers and tumor size or clinical parameters were examined. Five of our six patients with gliosarcoma survived 3-17 months. One patient is still alive for more than 24 months. The mean immunostaining scores for cortactin were significantly higher in the gliomatous (score 236.6 +/- 45.4) and sarcomatous (score 233.3 +/- 51.4) components than in normal brain tissues (score 21.6 +/- 6.6). The mean cytoplasmic immunostaining scores for fascin and survivin were also significantly higher in the gliomatous and sarcomatous components than in normal brain tissues. In addition, survivin was also stained in the nucleus of tumor cells. Linear regression analysis showed that fascin score in the gliomatous component was significantly associated with tumor size (R = 0.69) and the fascin score in the sarcomatous component was significantly associated with patient's age (R = 0.87). In addition, the survivin cytoplasmic scores in the gliomatous and sarcomatous components were inversely associated with tumor size. Our results demonstrated that over-expression of cortactin, fascin and survivin is associated with malignant transformation of brain gliosarcoma. Development of drugs that target cortactin, fascin and survivin expression may be therapeutic to patients with gliosarcoma.

Effects of small interfering RNAs targeting fascin on human esophageal squamous cell carcinoma cell lines

BackgroundFascin induces membrane protrusions and cell motility. Fascin overexpression was associated with poor prognosis, and its downregulation reduces cell motility and invasiveness in esophageal squamous cell carcinoma (ESCC). Using a stable knockdown cell line, we revealed the effect of fascin on cell growth, cell adhesion and tumor formation.MethodsWe examined whether fascin is a potential target in ESCC using in vitro and in vivo studies utilizing a specific siRNA. We established a stable transfectant with downregulated fascin from KYSE170 cell line.ResultsThe fascin downregulated cell lines showed a slower growth pattern by 40.3% (p < 0.01) and detachment from collagen-coated plates by 53.6% (p < 0.01), compared to mock cells, suggesting that fascin plays a role in cell growth by maintaining cell adhesion to the extracellular matrix. In vivo, the tumor size was significantly smaller in the tumor with fascin knockdown cells than in mock cells by 95% at 30 days after inoculation.ConclusionsThese findings suggest that fascin overexpression plays a role in tumor growth and progression in ESCC and that cell death caused by its downregulation might be induced by cell adhesion loss. This indicates that targeting fascin pathway could be a novel therapeutic strategy for the human ESCC.

Specificity protein 1 regulates fascin expression in esophageal squamous cell carcinoma as the result of the epidermal growth factor/extracellular signal-regulated kinase signaling pathway activation.

The overexpression of fascin in human carcinomas is associated with aggressive clinical phenotypes and poor prognosis. However, the molecular mechanism underlying the increased expression of fascin in cancer cells is largely unknown. Here, we identified a Sp1 binding element located at -70 to -60 nts of the FSCN1 promoter and validated that Sp1 specifically bound to this element in esophageal carcinoma cells. Fascin expression was enhanced by Sp1 overexpression and blocked by Sp1 RNAi knockdown. Specific inhibition of ERK1/2 decreased phosphorylation levels of Sp1, and thus suppressed the transcription of the FSCN1, resulting in the down-regulation of fascin. Stimulation with EGF could enhance fascin expression via activating the ERK1/2 pathway and increasing phosphorylation levels of Sp1. These data suggest that FSCN1 transcription may be subjected to the regulation of the EGF/EGFR signaling pathway and can be used as a viable biomarker to predict the efficacy of EGFR inhibitors in cancer therapies.