Upregulation Of Fascin Research Articles

Fascin promotes lung cancer growth and metastasis by enhancing glycolysis and PFKFB3 expression

Fascin is a pro-metastatic actin-bundling protein that is upregulated in all metastatic carcinomas. Fascin promotes cancer cell migration and invasion by facilitating membrane protrusions, such as filopodia and invadopodia. Aerobic glycolysis is a key feature of cancer metabolism and provides critical intermediate metabolites for tumor growth. Here, we report that fascin increases glycolysis in lung cancer to promote tumor growth and metastasis. Fascin promotes glycolytic flux by increasing the expression and activities of phosphofructose-kinases 1 and 2 (PFK1 and 2). Fascin mediates glycolytic functions via activation of yes-associated protein 1 (YAP1) through its canonical actin-bundling activity by promoting the binding of YAP1 to a TEAD1/4 binding motif located 30 bp upstream of the PFKFB3 transcription start site to activate its transcription. Examination of the TCGA database suggests that the fascin-YAP1-PFKFB3 axis is likely conserved across different types of cancers. Importantly, pharmacological inhibitors of fascin suppressed YAP1-PFKFB3 signaling and glycolysis in cancer cell lines, organoid cultures, and xenograft metastasis models. Taken together, our data reveal that the glycolytic function of fascin is essential for the promotion of lung cancer growth and metabolism, and suggest that pharmacological inhibitors of fascin may be used to reprogram cancer metabolism in lung and potentially other cancers with fascin upregulation.

Interdependence of Filament Nucleation, Elongation and Crosslinking in Actin Bundle Assembly

A network of actin-binding proteins tightly regulates each stage of actin assembly, including filament nucleation, elongation and crosslinking. These processes are integrated together to assemble higher-order actin structures specialized for specific cellular roles. Actin bundles are composed of unbranched filaments that are crosslinked in parallel or anti-parallel orientations by bundling proteins. These structures form the basis of a number of cytoskeletal assemblies, including the contractile ring, stress fibers, and filopodia. Aberrant regulation of actin bundles and their associated proteins is linked to diseases such as focal segmental glomerulosclerosis and metastatic cancers. Yet despite their importance, the dynamic properties of actin bundles are not well understood. To gain insight into the mechanism of bundle assembly, we investigated how the processes of nucleation, elongation, and crosslinking influence each other. We utilized formins, which function as both nucleators and actin polymerases, to elucidate the interdependence between nucleation and elongation. We found that, whereas filament nucleation necessarily precedes and promotes filament elongation, the dependence of both processes on actin monomer availability gives rise to competition that ultimately favors nucleation over elongation. To investigate the relationship between elongation and crosslinking, we generated pools of actin filaments of uniform lengths and analyzed their kinetics of crosslinking by the bundling protein fascin. We found that fascin crosslinks short filaments more slowly than long filaments, suggesting that filament elongation plays a role in regulating filament bundling. We propose that elongating filaments undergo changes in curvature and rotational diffusion that modulate the probability of filament alignment and ultimately dictate the efficiency of fascin-mediated crosslinking. This work suggests that upregulation of fascin might alter the mechanical properties of bundled actin structures by promoting the incorporation of short filaments.

Leucine aminopeptidase 3 promotes migration and invasion of breast cancer cells through upregulation of fascin and matrix metalloproteinases-2/9 expression.

Overexpression of leucine aminopeptidase 3 (LAP3) is involved in proliferation, migration, and invasion of several tumor cells and plays a crucial role in tumor metastasis. However, the related mechanism remains unknown. In this study, we used MDA-MB-231 and MCF7 breast cancer cell lines to explore the role of LAP3 in the regulation of cancer cell migration and invasion by employing the natural LAP3 inhibitor bestatin and a lentivirus vector that overexpresses or knocks down LAP3. Bestatin inhibited tumor cell migration and invasion in a dose-dependent manner. Western blot assay showed that bestatin and knockdown of LAP3 upregulated phosphorylation of Hsp27 and downregulated expression of fascin. Phosphorylation of Akt and expression of matrix metalloproteinase-2/9 can also be downregulated. LAP3 overexpression showed the opposite results. Immunohistochemistry analysis was conducted to detect expression levels of LAP3 in breast cancer tissues. High LAP3 expression was correlated with the grade of malignancy. Findings of this study uncovered the molecular mechanism of LAP3 on breast cancer metastasis and indicated that LAP3 may act as a potential antimetastasis therapeutic target.

Fascin expression in undifferentiated and dedifferentiated endometrial carcinoma.

The actin-binding protein fascin promotes cellular invasion, and increased fascin expression correlates with adverse prognostic factors in a variety of tumors. Fascin up-regulation may also be associated with epithelial-mesenchymal transition in neoplastic epithelial cells. This study investigated fascin expression in undifferentiated and dedifferentiated endometrial carcinoma (UEC), a clinically aggressive variant of endometrial neoplasia. Twenty-two UECs, 5 of which were entirely undifferentiated and 17 dedifferentiated, were examined. In the dedifferentiated group, staining was compared between the differentiated and undifferentiated tumor components. Where applicable, fascin expression was noted in foci of lymphovascular space invasion. The mean age was 67.6 years, and 11 patients (50%) presented with stage III or IV disease. The undifferentiated tumor component showed diffuse fascin expression in 20 cases (91%) including 4 of 5 pure undifferentiated carcinomas and 16 of 17 dedifferentiated carcinomas. In contrast, the low-grade endometrioid carcinoma component of 13 (77%) of 17 dedifferentiated carcinomas was fascin negative or showed only focal staining. Intravascular undifferentiated tumor cells were identified in 16 cases, and these were consistently fascin positive, whereas low-grade intravascular tumor cells, present in 2 cases, were not stained. Fascin up-regulation may be a contributory factor toward the highly invasive character of UEC and could represent an epithelial-mesenchymal transition-like process in these tumors. Fascin expression in intravascular tumor cells may be permissive toward intravascular survival and metastatic risk.

Fas Signaling Promotes Gastric Cancer Metastasis through STAT3-Dependent Upregulation of Fascin

BackgroundFas signaling-activated signal transducers and activators of transcription 3 (STAT3) is required for Fascin upregulation. As an actin-bundling protein, Fascin can mediate gastric cancer (GC) cell migration.MethodsGastric cancer AGS cells were treated with anti-Fas (5 μg/ml) for 2 h, in order to stimulate the activation of the Fas signaling. The in vitro migration of Fas signaling-activated AGS cells was assessed using Transwell chambers. The levels of Fascin and phosphorylated STAT3 were detected by Western blotting analyses. Nude mice were injected intravenously with AGS cells treated with anti-Fas or treated with STAT3 inhibitor without anti-Fas; tumor pulmonary metastases were measured. Fascin protein expression in tumor tissues was detected by immunohistochemistry. The Fas and Fascin mRNA levels in tumor tissues from patients with GC were measured by real-time PCR and their correlation was analyzed.ResultsThe activation of Fas signaling promoted cell migration and resulted in STAT3-dependent Fascin upregulation in AGS cells. STAT3 enhanced Fascin levels in vivo. Fascin was the mediator of Fas signaling-induced AGS cell migration in vitro and in vivo. Furthermore, there was a positive correlation between Fas and Fascin mRNA levels in tumor tissues from GC patients.ConclusionsFas signaling promotes GC metastasis through the STAT3/Fascin pathway, which may provide a new target for GC therapy.

Fascin Overexpression Promotes Cholangiocarcinoma RBE Cell Proliferation, Migration, and Invasion.

Fascin is overexpressed in various tumor tissues and is closely related to tumor metastasis and invasion. However, the role of fascin in cholangiocarcinoma RBE cells has not been clearly reported. This study aimed to establish a cholangiocarcinoma cell line with stable and high expression of fascin to observe the effect of fascin on cell proliferation, migration, and invasion. A fascin overexpression vector, pcDNA3.1-Fascin, was constructed and transfected into the human cholangiocarcinoma RBE cell line. The results of real-time polymerase chain reaction, Western blot, and immunofluorescence indicated that fascin was steadily and highly expressed in RBE cells. The results of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide and colony formation assay indicated that upregulated fascin expression could enhance cholangiocarcinoma cell proliferation. The results of wound healing assay and transwell assay indicated that fascin could promote cholangiocarcinoma cell migration and invasion, and a further study found that the nuclear factor-κB signaling pathway was activated after upregulation of fascin, whereas E-cadherin expression in these cells was significantly decreased. Additionally, E-cadherin expression was significantly increased after inhibiting nuclear factor-κB activity using inhibitor or small interfering RNA, and E-cadherin expression was decreased by fascin overexpression after nuclear factor-κB inhibition, suggesting that nuclear factor-κB signaling pathway was not involved in the regulation of E-cadherin by fascin. In summary, the results of this study demonstrated that fascin effectively promoted cholangiocarcinoma RBE cell proliferation, migration, and invasion. This study provides evidence for fascin as a potential target in the treatment of cholangiocarcinoma.

The tumor marker Fascin is induced by the Epstein-Barr virus-encoded oncoprotein LMP1 via NF-κB in lymphocytes and contributes to their invasive migration.

BackgroundThe actin-bundling protein Fascin (FSCN1) is a tumor marker that is highly expressed in numerous types of cancer including lymphomas and is important for migration and metastasis of tumor cells. Fascin has also been detected in B lymphocytes that are freshly-infected with Epstein-Barr virus (EBV), however, both the inducers and the mechanisms of Fascin upregulation are still unclear.ResultsHere we show that the EBV-encoded oncoprotein latent membrane protein 1 (LMP1), a potent regulator of cellular signaling and transformation, is sufficient to induce both Fascin mRNA and protein in lymphocytes. Fascin expression is mainly regulated by LMP1 via the C-terminal activation region 2 (CTAR2). Block of canonical NF-κB signaling using a chemical inhibitor of IκB kinase β (IKKβ) or cotransfection of a dominant-negative inhibitor of IκBα (NFKBIA) reduced not only expression of p100, a classical target of the canonical NF-κB-pathway, but also LMP1-induced Fascin expression. Furthermore, chemical inhibition of IKKβ reduced both Fascin mRNA and protein levels in EBV-transformed lymphoblastoid cell lines, indicating that canonical NF-κB signaling is required for LMP1-mediated regulation of Fascin both in transfected and transformed lymphocytes. Beyond that, chemical inhibition of IKKβ significantly reduced invasive migration of EBV-transformed lymphoblastoid cells through extracellular matrix. Transient transfection experiments revealed that Fascin contributed to LMP1-mediated enhancement of invasive migration through extracellular matrix. While LMP1 enhanced the number of invaded cells, functional knockdown of Fascin by two different small hairpin RNAs resulted in significant reduction of invaded, non-attached cells.ConclusionsThus, our data show that LMP1-mediated upregulation of Fascin depends on NF-κB and both NF-κB and Fascin contribute to invasive migration of LMP1-expressing lymphocytes.

Fascin upregulation in primary head and neck squamous cell carcinoma is associated with lymphatic metastasis.

Fascin is an actin-bundling protein that is associated with cellular motility and cancer-cell invasion. The present study aimed to examine the expression of fascin in head and neck squamous cell carcinoma (HNSCC) and its potential use as a biomarker. In a prospective study with a median follow-up time of 48.8 months, tumor tissues, adjacent healthy tissues and cervical lymph node metastases were collected from 25 patients and analyzed by immunohistochemistry. The specimens were scored according to the intensity of fascin staining and the percentage of tumor cells stained using a semi-quantitative scoring approach; the data were analyzed and correlated with clinical follow-up observations. All of the investigators were blinded to the origin of the specimens. The expression levels of fascin were significantly increased in the tumor tissues (P=0.03) and lymph node metastases (P=0.03) compared with that of the normal tissues. The high expression level of fascin in the tumor tissues was correlated with the N-status, however, not with overall survival. Therefore, fascin may be a suitable marker for the prediction of regional lymphatic metastasis in HNSCC.

Signal transducer and activator of transcription 3 signaling upregulates fascin via nuclear factor-κB in gastric cancer: Implications in cell invasion and migration

Fascin protein plays important roles in tumor metastasis and is prognostically relevant to human gastric cancer (GC). However, its role in the development and progression of GC has not been comprehensively investigated. In the present study, results revealed that upregulation of fascin by interleukin-6 promotes GC cell migration and invasion in a signal transducer and activator of transcription 3 (STAT3)-dependent manner in MKN45 cells. Furthermore, STAT3 directly regulated fascin expression and nuclear factor-κB (NF-κB) bound to the fascin promoter in a STAT3-dependent and Notch-independent manner. Therefore, results demonstrate that STAT3 and NF-κB are required for upregulation of fascin and for cell migration and invasion in MKN45 cells. Effects of the treatments on cell signaling were detected by qPCR, western blot analysis and chromatin immunoprecipitation (ChIP) assay. Cell migration and invasion were analyzed using in vitro scratch wound healing assay, transwell and Matrigel assays, and xenograft model. In addition, the STAT3-NF-κB-fascin signaling axis is identified as a therapeutic target for blocking GC cell invasion and migration.

The tumour marker Fascin is strongly induced by Tax of HTLV-1 through NF-κB signals in T lymphocytes

In search of novel biomarkers of HTLV-1- transformed cells with relevance to oncogenesis, we identified the tumour marker and actin-bundling protein Fascin (FSCN1) to be specifically and strongly upregulated in both HTLV-1-transformed and ATLL-patient-derived CD4+ T cells. Fascin is important for migration and metastasis in various types of cancer. Here we report that a direct link can exist between a single viral oncoprotein and Fascin expression, as the viral oncoprotein Tax of HTLV-1 was sufficient to induce high levels of Fascin. In contrast, Tax-2 of HTLV-2 could not induce Fascin. Expression of Fascin was also detectable in primary CD4+ T cells of ATLL-patients after they expressed Tax spontaneously. Immunofluorescence analysis revealed that Fascin could colocalize with Actin in the cytoplasm and at the membrane of HTLV-1-transformed cells. We found a novel mode of transcriptional regulation of Fascin by showing the importance of NF-κB signals for Tax-mediated induction of Fascin in T cells. Chemical and dominant-negative inhibition of the NF-κB pathway as well as a NF-κB-deficient Tax-mutant led to a strong decrease of Fascin mRNA and protein in Tax-transfected Jurkat cells. Additionally, in HTLV-1-/Tax-transformed cells Fascin transcripts were strongly reduced after chemical inhibition of IκB-kinase. Knockdown of Fascin by lentiviral transduction of shRNA decreased the invasive capacity of ATLL-derived cells into extracellular matrix. Thus, we have clearly shown that the tumour marker Fascin can be induced by the viral Tax oncoprotein through NF-κB signals. Our data suggest that Fascin up-regulation by Tax contributes to the development of HTLV-1-associated pathogenesis.

The tumor marker Fascin is strongly induced by the Tax oncoprotein of HTLV-1 through NF-κB signals

AbstractOncogenic transformation of CD4+ T cells by human T-cell lymphotropic virus type 1 (HTLV-1) is understood as the initial step to adult T-cell leukemia/lymphoma, a process that is mainly initiated by perturbation of cellular signaling by the viral Tax oncoprotein, a potent transcriptional regulator. In search of novel biomarkers with relevance to oncogenesis, we identified the tumor marker and actin-bundling protein Fascin (FSCN1) to be specifically and strongly up-regulated in both HTLV-1–transformed and adult T-cell leukemia/lymphoma patient-derived CD4+ T cells. Fascin is important for migration and metastasis in various types of cancer. Here we report that a direct link can exist between a single viral oncoprotein and Fascin expression, as the viral oncoprotein Tax was sufficient to induce high levels of Fascin. Nuclear factor-κB signals were important for Tax-mediated transcriptional regulation of Fascin in T cells. This suggests that Fascin up-regulation by Tax contributes to the development of HTLV-1–associated pathogenesis.

Immunohistochemical Analysis of Oral Dysplasia: Diagnostic Assessment by Fascin and Podoplanin Expression

The aim of this study was to investigate fascin and podoplanin expression in oral dysplasia and carcinoma in situ (CIS) immunohistochemically, and to evaluate their relationship to histopathological diagnosis based on architectural and cytological features. Fascin and podoplanin expression patterns were analyzed immunohistologically in 26 specimens of oral lesions, including benign disease (hyperplasia, papilloma, and others), intraepithelial neoplasia/borderline disease (dysplasia), and malignant disease (CIS, invasive squamous cell carcinoma). Fascin expression was scored into four original categories, and podoplanin expression was scored into five previously established categories. The relationship between the immunohistochemically determined scores of fascin and podoplanin expression and the architectural and cytological features in the hematoxylin-eosin-stained slides was analyzed statistically. The immunostaining scores for fascin and podoplanin were significantly higher in dysplasia and CIS than in benign disease (p=0.0011, p=0.00036), and they were significantly higher in dysplasia than in benign disease (p=0.0087, p=0.0032). In all cases of invasive SCC, fascin was expressed mainly in the cytoplasm of the tumor cells and fascin expression extended from the destruction of the basal layer of the epithelium to the upper layer of the epithelium and podoplanin was expressed in the cytoplasm and membrane of the tumor cells. This was the first report of up-regulation of fascin in oral dysplasia. Our results suggest that it would be helpful for improving the diagnostic accuracy of oral dysplasia and CIS to assess the expression of fascin and podoplanin immunohistochemically.

Fascin Over Expression is Associated with Dysplastic Changes in Sinonasal Inverted Papillomas: A Study of 47 Cases

Sinonasal inverted papilloma (IP) is a primary benign lesion with a tendency for local recurrence. Malignant transformation may develop in up to 15% of cases. Fascin (Fascin 1) is an actin cross-link binding protein required for the formation of actin-based cell-surface protrusions and cell motility. Fascin up-regulation in lung, gastric, breast and hepatobiliary carcinomas correlates with aggressiveness and decreased survival. Here we evaluate immunohistochemical expression of fascin in 47 sinonasal IPs from 34 patients. Fascin over-expression is significantly more common in sinonasal IP with high-grade dysplasia than in those with no dysplastic or low-grade dysplastic epithelium (P = 0.0001). No significant change in fascin expression is seen with recurrence. Over expression of fascin in high-grade dysplastic epithelium in IP may be associated with tumor progression and malignant transformation.

Fascin Expression in Serous Tumors of Ovary Correlates With Aggressiveness of Malignancy

Ovarian serous tumors make up about one-fourth of all ovarian tumors. There is a spectrum of proliferation and cellular atypia in these tumors with benign serous cystadenoma, borderline tumors, and low grade or type I serous carcinoma at the lower end and type II or high-grade serous papillary cystadenocarcinoma at the higher end. Fascin is a globular actin cross-linking protein involved in cell motility that has been shown to be upregulated in many human neoplasms and associated with the aggressiveness of malignancy. The aim of this study was to investigate fascin expression in serous tumors of ovary and to evaluate its relationship with the aggressiveness of tumor. Sections from a total of 66 serous tumors of ovary were collected including 26 serous carcinomas, 20 borderline serous tumors, and 20 benign serous cystadenomas. Ten benign ovaries with inclusion cysts were used as controls. Sections were immunostained with fascin. Fascin expression was significantly increased in borderline (13/20, 65%) and malignant serous tumors (22/26, 84%) compared with benign serous cystadenoma (0/20) (P<0.001). There was increased quantitative expression of fascin in carcinoma compared with borderline tumors (diffuse versus patchy). Fascin expression also correlated well with the tumor grade in serous carcinoma cases with 8/12 (66%) of grade I/II tumors staining positive compared with all 14 (100%) of grade III tumors showing fascin expression (P<0.05). Our findings suggest that upregulation of fascin plays a role in increasing aggressiveness of serous ovarian tumors and could potentially be a molecular therapeutic target and a prognostic marker.

Recurrence of pleomorphic adenoma of the parotid gland—predictive value of cadherin‐11 and fascin

The predictive value of cadherin-11, tenascin, fascin, and mucin-1 as markers for the likelihood of recurrence in pleomorphic adenoma of the parotid gland was examined. In this retrospective study we analysed 20 tumours from16 patients by immunohistochemistry. Staining intensities were measured using a semiquantitative scoring approach; localisation (tumour centre vs border) as well as clinical data were analysed and correlated with follow-up. Cadherin-11 was increased in recurrent tumours. However, no changes of fascin, tenascin or mucin-1 were observed. Cadherin-11 and fascin were increased in primary tumours of patients with later recurrence, with fascin upregulation restricted to the tumour border. In conclusion, cadherin-11 and fascin should be further analysed for their value as markers for later recurrence in pleomorphic adenoma. Our observations might reflect dysregulation of cellular pathways contributing to cellular dissemination, which might potentially result in later recurrence.

Expression of fascin in thyroid neoplasms: a novel diagnostic marker

Fascin, an actin-bundling protein, is markedly upregulated in several epithelial tumors and its expression often correlates with high-grade, extensive invasion, and distant metastasis. However, reports about fascin expression in endocrine tumors remain rare. The aim of the present study was to assess the diagnostic significance of fascin in thyroid neoplasms. Thyroid samples from 177 cases were examined for fascin and Ki-67 expression by immunohistochemistry. Fascin immunoreactivity was negative in normal follicles and nodular goiter. Fascin immunostaining was positive in 62.1% (41/66) of thyroid carcinomas and 26.4% (19/72) of thyroid adenomas; the difference being significant (P < 0.0001). In thyroid papillary carcinoma, upregulation of fascin was associated with both the Ki-67 labeling index and the occurrence of lymph node metastasis. Fascin may be a novel marker to distinguish thyroid carcinoma from benign lesions and may be involved in the proliferation and metastasis of papillary carcinoma.

Fascin is a potential biomarker for early-stage oesophageal squamous cell carcinoma

Background: Fascin, an actin-binding protein, is usually expressed at a low level in normal epithelium, but is markedly up regulated in several types of carcinomas. Reports on fascin expression in...

Fascin, an Actin-Bundling Protein, Modulates Colonic Epithelial Cell Invasiveness and Differentiation in Vitro

In epithelial tissue, cell-matrix and cell-cell adhesive interactions have important roles in the normal organization and stabilization of the cell layer. The malignant conversion of epithelial cells involves alterations in the expression and function of these adhesion systems that enable a switch to a migratory phenotype in tumor invasion and metastasis. Fascin is an actin-crosslinking protein that is found in the core actin bundles of cell-surface spikes and projections that are implicated in cell motility. We demonstrate that fascin is not detectable in normal colonic epithelium, but is dramatically up-regulated in colorectal adenocarcinoma. To test the hypothesis that fascin could participate in tumor invasive behavior, we developed a cell culture model to examine the effect of fascin expression on the adhesive interactions, invasiveness, and differentiation of colonic epithelial cells. We report marked effects on the organization of cell-surface protrusions, actin cytoskeleton, and focal adhesions in the absence of alterations in the protein levels of the major components of these structures. These effects correlate with alterations in cell movements on two-dimensional matrix, and increased invasiveness in three-dimensional matrix. The cells also show increased proliferation and decreased capacity for normal glandular differentiation in collagen gels. We propose that up-regulation of fascin, by promoting the formation of protrusive, actin-based, cell-motility structures, could be a significant component in the acquisition of invasive phenotype in colonic carcinoma.

Fascin, an actin-bundling protein associated with cell motility, is upregulated in hormone receptor negative breast cancer

Loss of hormone receptor (HR) status in breast carcinomas is associated with increased tumour cell motility and invasiveness. In an immunohistological study of 58 primary breast cancers, oestrogen (ER) and progesterone (PR) receptor levels were inversely correlated with the expression of fascin, an actin-bundling protein associated with cell motility (P< 0.0001 and P = 0.0019, respectively). In addition, fascin was preferentially expressed in non-diploid tumours (P = 0.03). In summary, the upregulation of fascin in HR-negative breast cancers may contribute to their more aggressive behaviour. © 2000 Cancer Research Campaign