Fascin Expression Research Articles

The molecular mechanisms of apoptosis accompanied with the epigenetic regulation of the NY-ESO-1 antigen in non-small lung cancer cells treated with decitabine (5-aza-CdR)

Dysregulated epigenetic modifications are common in lung cancer but have been reversed using demethylating agent like 5-Aza-CdR. 5-Aza-CdR induces/upregulates the NY-ESO-1 antigen in lung cancer. Therefore, we investigated the molecular mechanisms accompanied with the epigenetic regulation of NY-ESO-1 in 5-Aza-CdR-treated NCI–H1975 cell line. We showed significant induction of the NY-ESO-1 protein (**p < 0.0097) using Cellular ELISA. Bisulfite-sequencing demonstrated 45.6% demethylation efficiency at the NY-ESO-1 gene promoter region and RT-qPCR analysis confirmed the significant induction of NY-ESO-1 at mRNA level (128-fold increase, *p < 0.050). We then investigated the mechanism by which 5-Aza-CdR inhibits cell proliferation in the NCI–H1975 cell line. Upregulation of the death receptors TRAIL (2.04-fold *p < 0.011) and FAS (2.1-fold *p < 0.011) indicate activation of the extrinsic apoptotic pathway. The upregulation of Voltage-dependent anion-selective channel protein 1 (1.9-fold), Major vault protein (1.8-fold), Bax (1.16-fold), and Cytochrome C (1.39-fold) indicate the activation of the intrinsic pathway. We also observed the differential expression of protein Complement C3 (3.3-fold), Destrin (−5.1-fold), Vimentin (−1.7-fold), Peroxiredoxin 4 (−1.6-fold), Fascin (−1.8-fold), Heme oxygenase-2 (−0.67-fold**p < 0.0055), Hsp27 (−0.57-fold**p < 0.004), and Hsp70 (−0.39-fold **p < 0.001), indicating reduced cell growth, cell migration, and metastasis. The upregulation of 40S ribosomal protein S9 (3-fold), 40S ribosomal protein S15 (4.2-fold), 40S ribosomal protein S18 (2.5-fold), and 60S ribosomal protein L22 (4.4-fold) implied the induction of translation machinery. These results reiterate the decisive role of 5-Aza-CdR in lung cancer treatment since it induces the epigenetic regulation of NY-ESO-1 antigen, inhibits cell proliferation, increases apoptosis, and decreases invasiveness.

Antagonism between wild-type and mutant β-catenin controls hepatoblastoma differentiation via fascin-1

β-catenin is a well-known effector of the Wnt pathway, and a key player in cadherin-mediated cell adhesion. Oncogenic mutations of β-catenin are very frequent in paediatric liver primary tumours. Those mutations are mostly heterozygous, which allows the co-expression of wild-type (WT) and mutated β-catenins in tumour cells. We investigated the interplay between WT and mutated β-catenins in liver tumour cells, and searched for new actors of the β-catenin pathway. Using an RNAi strategy in β-catenin-mutated hepatoblastoma (HB) cells, we dissociated the structural and transcriptional activities of β-catenin, which are carried mainly by WT and mutated proteins, respectively. Their impact was characterised using transcriptomic and functional analyses. We studied mice that develop liver tumours upon activation of β-catenin in hepatocytes (APCKO and β-cateninΔexon3 mice). We used transcriptomic data from mouse and human HB specimens, and used immunohistochemistry to analyse samples. We highlighted an antagonistic role of WT and mutated β-catenins with regard to hepatocyte differentiation, as attested by alterations in the expression of hepatocyte markers and the formation of bile canaliculi. We characterised fascin-1 as a transcriptional target of mutated β-catenin involved in tumour cell differentiation. Using mouse models, we found that fascin-1 is highly expressed in undifferentiated tumours. Finally, we found that fascin-1 is a specific marker of primitive cells including embryonal and blastemal cells in human HBs. Fascin-1 expression is linked to a loss of differentiation and polarity of hepatocytes. We present fascin-1 as a previously unrecognised factor in the modulation of hepatocyte differentiation associated with β-catenin pathway alteration in the liver, and as a new potential target in HB. The FSCN1 gene, encoding fascin-1, was reported to be a metastasis-related gene in various cancers. Herein, we uncover its expression in poor-prognosis hepatoblastomas, a paediatric liver cancer. We show that fascin-1 expression is driven by the mutated beta-catenin in liver tumour cells. We provide new insights on the impact of fascin-1 expression on tumour cell differentiation. We highlight fascin-1 as a marker of immature cells in mouse and human hepatoblastomas.

The Role of Fascin-1 in Human Urologic Cancers: A Promising Biomarker or Therapeutic Target?

Human cancer statistics show that an increased incidence of urologic cancers such as bladder cancer, prostate cancer, and renal cell carcinoma. Due to the lack of early markers and effective therapeutic targets, their prognosis is poor. Fascin-1 is an actin-binding protein, which functions in the formation of cell protrusions by cross-linking with actin filaments. Studies have found that fascin-1 expression is elevated in most human cancers and is related to outcomes such as neoplasm metastasis, reduced survival, and increased aggressiveness. Fascin-1 has been considered as a potential therapeutic target for urologic cancers, but there is no comprehensive review to evaluate these studies. This review aimed to provide an enhanced literature review, outline, and summarize the mechanism of fascin-1 in urologic cancers and discuss the therapeutic potential of fascin-1 and the possibility of its use as a potential marker. We also focused on the correlation between the overexpression of fascin-1 and clinicopathological parameters. Mechanistically, fascin-1 is regulated by several regulators and signaling pathways (such as long noncoding RNA, microRNA, c-Jun N-terminal kinase, and extracellular regulated protein kinases). The overexpression of fascin-1 is related to clinicopathologic parameters such as pathological stage, bone or lymph node metastasis, and reduced disease-free survival. Several fascin-1 inhibitors (G2, NP-G2-044) have been evaluated in vitro and in preclinical models. The study proved the promising potential of fascin-1 as a newly developing biomarker and a potential therapeutic target that needs further investigation. The data also highlight the inadequacy of fascin-1 to serve as a novel biomarker for prostate cancer.

Expression of Fascin and SALL4 in odontogenic cysts and tumors: an immunohistochemical appraisal.

Background: Various stemness markers (SOX2, OCT4, and NANOG) have been studied in odontogenic cysts and tumors. However, studies on SALL4 having similar properties of stemness has not been documented. Additionally, insight into fascin as a migratory molecule is less explored. In this study, the expression of SALL4 and fascin were evaluated in ameloblastoma, adenomatoid odontogenic tumor (AOT), odontogenic keratocyst (OKC), dentigerous cyst (DC), radicular cyst (RC), and calcifying odontogenic cyst (COC). Methods: Semi-quantitative analysis of fascin and SALL4 immuno-positive cells was done in a total of 40 cases of ameloblastoma (11 plexiform, 12 follicular, 12 unicystic, and 5 desmoplastic) variants, 6 cases of AOT, 15 each of OKC, DC, RC and 5 of COC. Chi-square test was applied to evaluate the association between SALL4 and fascin expression in odontogenic cysts and tumors. Results: Fascin immunopositivity was observed in peripheral ameloblast-like cells, and weak or absent in stellate reticulum-like cells. A moderate to weak immune-reactivity to SALL4 was observed in the cytoplasm of ameloblastoma, epithelial cells of dentigerous and radicular cysts, having a marked inflammatory infiltrate, which is an interesting observation. COC and AOT had negative to weak expressions. No recurrence has been reported. Conclusions: Expression of fascin in ameloblastomas elucidate their role in motility and localized invasion. Its expression in less aggressive lesions like DC, COC, AOT will incite to explore the other functional properties of fascin. SALL4 expression in the cytoplasm of odontogenic cysts and tumors may represent inactive or mutant forms which requires further validation.

Two Sides of the Same Transdifferentiated Coin: A Case Vignette and Review of the Literature Exploring the Relationship between B Cell Non-Hodgkin Lymphoma, Histiocytic Sarcoma and Interdigitating Dendritic Cell Sarcoma

WHO classifies Histiocytic Sarcoma (HS) and Interdigitating Dendritic Cell Sarcoma (IDCS) as separate, unrelated, entities under histiocytic/dendritic cell neoplasms. We do not fully understand the pathogenesis of HS and IDCS, yet both have been shown to transdifferentiate from B cell non-Hodgkin lymphomas. Diagnosis is challenging and requires application of a wide variety of immunohistochemical studies, flow cytometry and molecular analysis. We present a case of HS which evolved from CLL/SLL and presented as a diagnostic challenge due to unusual features overlapping with what is typically seen in IDCS. An 82-year-old male with a history of CLL/SLL presented with right infiltrative tonsillar mass and cervical lymphadenopathy. Biopsy of the lymph node revealed two abnormal populations of cells : Twenty percent of cells were consistent with CD20+ kappa surface light chain restricted CLL/SLL cells. Eighty percent of cells were histiocytic cells with an abnormal immunophenotype showing expression of CD4, CD43, fascin, HLA-DR, PU.1, (weak) S100 and CD1a without CD163, lysozyme, CD34, CD117, CD21, CD23 or CD14. Expert consultation favored the diagnosis of HS with transdifferentiation from CLL/SLL. PCR for IgH gene rearrangement, performed on separate HS-rich and CLL-rich areas of the biopsy detected identical clonal peaks. Next generation sequencing detected pathogenic KRAS mutations (p.G12D, p.A146P) and likely pathogenic BCOR (p.K839fs*17) and FBXW7 (p.R465S) mutations. While HS was the favored diagnosis, some immunophenotypic features were unusual, including diffuse fascin immunoreactivity, weak S100, and CD1a immunoreactivity which raised the possibility of so-called IDCS. While clonal evolution of HS and IDCS from B cell Non-Hodgkin lymphomas has been reported, there is a paucity of literature on these entities. We suggest that there may be a pathogenic relationship between these two neoplasms that has yet to be elucidated due to their rarity and diagnostic challenge. Few clinical laboratories can perform the breadth of markers required for diagnosis. Both neoplasms have varied clinical presentations with nodal or extranodal involvement and portend poor prognosis. Review of the literature shows significant overlap in immunophenotypic and genomic characteristics of IDCS and HS, suggesting they may be related manifestations of the same neoplasm. A case report has described the initial presentation of IDCS that subsequently developed into HS, although sampling may have been an issue. We identified 11 cases, including our case in the literature presenting with positive histiocytic and dendritic cell markers referred as hybrid dendritic-histiocytic sarcomas or histiocytic sarcoma with interdigitating dendritic cell differentiation. Immunohistochemical analysis of these cases showed positivity rates of S100 (100%), lysozyme (82%) and CD1a (18%). One case in the literature described fascin immunoreactivity, as was observed in our case. Four of six cases had CD163 immunoreactivity. A hybrid neoplasm with overlapping features of follicular and interdigitating dendritic cells has also been reported, further confounding our understanding of these neoplasms. Large studies analyzing genomic features of these neoplasms have shown recurrent mutations in RAS-MAPK pathway, as was seen in our case. Further studies of the relationship between HS, IDCS should include gene expression profiling of these entities which may also yield therapy targets. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Expression of fascin in Invasive mammary cancer - A study at a Tertiary care centre in Southern India

Introduction and Aim: Breast cancer is the commonest malignancy in women. Most women do not die of the primary tumor but from metastasis and local invasion. Augmented motility of cancer cells corroborates with greater metastatic potential, that is brought about by actin cytoskeleton. Fascin, a cytoplasmic F-actin-bundling protein that cross-links actin filaments and its overexpression is strongly associated with metastatic progression and poor prognosis. The present study aims to determine the fascin protein expression by immunohistochemistry in invasive breast carcinoma and to correlate the same with the existing prognostic factors. Methods: Immunohistochemical expression of fascin in 100 cases of invasive mammary carcinoma was studied. Data collected was scored based on intensity and statistically analyzed using GNU-PSPP version 0.10 software. To determine significant clinico-pathological differences between fascin expression in positive and negative tumors, Pearson Chi-square test was used. Results: It was noted that 22 of the 100 cases were positive with a score of 3 or more. A significant association of nodal status with fascin (p value &lt;0.05) was noted. Higher proportion of fascin positive tumors were node negative. There was an inverse correlation between ER/PR/HER2 status and fascin positivity. The corresponding p values for ER, PR and HER2 with fascin were &lt;0.05. On the contrary 12(57.15%) of the 21 triple negative cases were fascin positive. The p value was &lt;0.001 indicating a significant correlation between molecular subtypes and fascin expression. A more of the fascin positive tumors fell in the triple negative category. Conclusion: Higher proportion of fascin positive cases in the node negative category, an inverse correlation between fascin expression and individual ER/PR, HER2 expression and larger number of fascin positive cases in the triple negative category. These findings point an association of fascin with aggressive breast carcinomas.

Fascin expression in breast cancer

Background: The present study was conducted for assessing Fascin expression in breast cancer patients. Materials &amp; methods: A total of 50 patients diagnosed histopathologically with breast cancer were enrolled. Complete demographic details of all the subjects were recorded. Clinical and radiographic examination of all the subjects was done. Blood samples were obtained from all the subjects and biochemical along with haematological profile was assessed. Lymph node status in all the patients was evaluated. Fascin expression was assessed in all the patients. Results: Fascin expression was positive in 36 percent of the patients. Mean age of the patients with positive and negative Fascin expression was 52.3 percent and 55.4 percent respectively. Lympho-vascular expression was present in 66.67 percent and 50 percent of the patients with Fascin positive and negative expression respectively. Lymph node involvement was present in 72.22 percent and 62.5 percent of the patients with Fascin positive and negative expression respectively. Conclusion: Fascin expression in breast cancer cells offers a potential therapeutic intervention in breast cancer treatment.

Significance of Immunohistochemical Expression of Fascin-1 in Colorectal Carcinoma

Significance of Immunohistochemical Expression of Fascin-1 in Colorectal Carcinoma

Fascin is essential for mammary gland lactogenesis

Fascin expression has commonly been observed in certain subtypes of breast cancer, where its expression is associated with poor clinical outcome. However, its role in normal mammary gland development has not been elucidated. Here, we used a fascin knockout mouse model to assess its role in normal mammary gland morphogenesis and lactation. Fascin knockout was not embryonically lethal, and its effect on the litter size or condition at birth was minimal. However, litter survival until the weaning stage significantly depended on fascin expression solely in the nursing dams. Accordingly, pups that nursed from fascin−/− dams had smaller milk spots in their abdomen, suggesting a lactation defect in the nursing dams. Mammary gland whole-mounts of pregnant and lactating fascin−/− mice showed significantly reduced side branching and alveologenesis. Despite a typical composition of basal, luminal, and stromal subsets of mammary cells and normal ductal architecture of myoepithelial and luminal layers, the percentage of alveolar progenitors (ALDH+) in fascin−/− epithelial fraction was significantly reduced. Further in-depth analyses of fascin−/− mammary glands showed a significant reduction in the expression of Elf5, the master regulator of alveologenesis, and a decrease in the activity of its downstream target p-STAT5. In agreement, there was a significant reduction in the expression of the milk proteins, whey acidic protein (WAP), and β-casein in fascin−/− mammary glands. Collectively, our data demonstrate, for the first time, the physiological role of fascin in normal mammary gland lactogenesis, an addition that could reveal its contribution to breast cancer initiation and progression.

FSCN1 Promotes Glycolysis and Epithelial-Mesenchymal Transition in Prostate Cancer through a YAP/TAZ Signaling Pathway.

Objective The aim of the study is to investigate the role and possible mechanism of fascin-1 (FSCN1) in the invasion, migration, glycolysis, and epithelial-mesenchymal transition (EMT) of prostate cancer. Methods Real-time quantitative polymerase chain reaction (qRT-PCR) was utilized to determine the mRNA expression level of FSCN1 in prostate cancer tissues and prostate cancer cells PC-3 and DU145. The transwell and the scratch test were applied to detect the invasion and migration abilities of cells, respectively. A metabolic assay was used for measuring the glucose consumption, lactate production, and the extracellular acidification rate (ECAR) in cells; western blot was used for checking FSCN1, EMT, and yes-associated protein/transcriptional co-activators with the PDZ-binding motif (YAP/TAZ) signaling pathway-related protein expression level in cells or tissues. Results FSCN1 was significantly highly expressed in prostate cancer tissues and cells. On the one hand, interference with the expression of FSCN1 could inhibit the invasion, migration, EMT, and glycolysis of prostate cancer cells. On the other hand, overexpression of FSCN1 promoted the invasion, migration, EMT, and glycolysis of prostate cancer cells. Besides, further mechanistic studies revealed that FSCN1 could activate the YAP/TAZ signaling pathway in prostate cancer cells. Conclusion FSCN1 promotes invasion, migration, EMT, and glycolysis in prostate cancer cells by activating the YAP/TAZ signaling pathway. FSCN1 may be used as a biomarker for the diagnosis or treatment in prostate cancer.

Combined expression of fascin-1 and MAP17 in colorectal cancer: A group of patients in high risk

Abstract Objective Fascin and MAP17 are two well-known stem cell markers that have been previously shown to be associated with aggresive clinical features in cancer. This study aimed to assess their expression patterns and clinical significance in colorectal cancer. Methods Immunohistochemistry was used to assess the expression of fascin-1 and MAP17 in 111 specimens from patients with primary resectable colorectal cancer. Results were correlated with clinicopathological characteristics and survival data. Results Fascin-1 and MAP17 expression levels were associated with progressive anatomic disease extent (p=0.005), higher T classification (p=0.033), lymph node metastasis (p=0.002), high grade tumors (p=0.002), and vascular invasion (p=0.021). All patients with combined high fascin-1 and MAP17 expression died within 46 months after surgery, whereas patients with low fascin-1 and MAP17 expression had an excellent 5-year overall survival rate of 92.8% (95% CI: 83–98). Concerning 3-year PFS, only 14.3% (95%CI: 11–30) of patients with combined high expression of both biomarkers did not experience recurrence or death within 30 months of surgery. Conclusion Conclusions; Combined high expression of fascin-1 and MAP17 identifies a group of patiens with poor early overall survival, indicating therefore targeted therapy's necessity.

Alternative NF-κB Signaling Discriminates Induction of the Tumor Marker Fascin by the Viral Oncoproteins Tax-1 and Tax-2 of Human T-Cell Leukemia Viruses.

Simple SummaryThe actin-bundling protein Fascin is upregulated in many types of cancers, including adult T-cell leukemia/lymphoma, a tumor induced by the oncogenic retrovirus human T-cell leukemia virus type 1 (HTLV-1). Transcriptional regulation of Fascin is heterogeneous between different cell types and tissues, and Fascin is usually expressed at low levels in T-cells. We have previously shown that a single viral oncoprotein, Tax-1 of HTLV-1, is a potent inducer of Fascin in T-cells depending on classical NF-κB signaling. In this study, we discovered that transcriptional activation of Fascin by viral oncoproteins depends on activity of both the classical and the alternative NF-κB signaling cascade. Comparisons between Tax-1 and Tax-2 from the closely related but non-oncogenic HTLV-2 revealed that alternative NF-κB signaling discriminates transcriptional induction of Fascin by the Tax proteins encoded by HTLVs. Together, Tax-1 and Tax-2 proteins are useful tools to study oncogenic signaling in T-cells.Transcriptional regulation of the actin-bundling protein and tumor marker Fascin is highly diverse depending on cell and tumor type. Previously, we discovered that the viral oncoprotein Tax-1 of human T-cell leukemia virus type 1 (HTLV-1) considerably enhances Fascin expression in T-cells, depending on classical NF-κB signaling. In this study, we asked if the non-oncogenic Tax-2 of the related HTLV-2 is still able to induce Fascin by using luciferase assays, immunoblot, and qPCR. We found that Tax-2 only slightly induces Fascin expression compared to Tax-1; however, both Tax-1 and Tax-2 comparably activated a 1.6 kb fragment in the human Fascin promoter including Tax-responsive elements. Furthermore, we identified a link between Tax-induced activity of the alternative NF-κB pathway and Fascin induction. While treatment with the second mitochondria-derived activator of caspases (SMAC)-mimetic AZD5582, a compound known to robustly activate alternative NF-κB signaling, did not induce Fascin, combination of AZD5582 with activation of classical NF-κB signaling by Tax-2 significantly induced Fascin expression. In conclusion, our data demonstrate that both classical and alternative NF-κB activity are necessary for strong Fascin induction by the viral Tax oncoproteins, thus, shedding new light on the regulation of Fascin in T-cells and during viral transformation.

Fascin expression persists with fibronectin in embryonic rat hepatoblasts.

Both fascin and fibronectin are known to play important roles in cell adhesion and migration. They are noted as tumor markers or inhibiting target for tumor treatment. In this study, embryonic rat livers were obtained to examine the expression of fascin and fibronectin during liver development. Then, the effect of fibronectin on fascin expression was investigated. At embryonic day (ED) 10.5, when the foregut endoderm began to form the liver bud and spread into the septum transversum, fibrous extracellular matrix was observed between the space where the liver bud and the septum transversum merged. At ED11.5, fibronectin was observed surrounding the cluster of fascin-positive hepatoblasts. At ED13.5, hematopoietic cells emerged and both fibronectin and fascin expression started to decline. Fascin and fibronectin appeared temporarily and disappeared by ED 14.5. Their expression was chronologically synchronized. Subsequently, the effect of fibronectin on fascin was examined by cultivation of hepatoblasts that were isolated from the ED13.5 rat liver. As a result, with fibronectin, fascin was positive in most hepatoblasts, although, without fibronectin, fascin expression was remarkably declined. Presently, there are few studies about the relationship between fascin and fibronectin. Our findings suggest that fibronectin could regulate fascin expression in rat hepatoblasts.

Evaluation of Clinical and Immunohistochemical Factors Relating to Melanoma Metastasis: Potential Roles of Nestin and Fascin in Melanoma.

For melanoma treatment, an early diagnosis and a complete resection of the primary tumor is essential. In addition, detection of factors that may be related to metastasis is indispensable. A total of 30 Japanese patients with Stage I or II melanoma, diagnosed according to the classification of the American Joint Committee on Cancer, are included in this study. Clinical background (sex, onset age, primary tumor area, existence of remaining cancer cells at the resected tissue margin, and treatment after the primary surgery) and immunohistochemical staining (Nestin and Fascin) on the resected tissue were examined to detect factors statistically related to metastasis. The analysis result has shown that older onset age and positive immunohistochemical expressions of Nestin and Fascin are statistically related to metastasis. To facilitate meticulous observation of Nestin and Fascin expression at different timing (e.g., onset and metastasis), double immunofluorescence staining was performed. Nestin is a class VI intermediate filament protein, initially detected in neural stem cells. Fascin is an actin-bundling protein which regulates cell adhesion, migration and invasion. Nestin and Fascin are suggested to relate to melanoma metastasis, however, the potential role of Fascin is controversial. Analysis of variations in Fascin expression detected in this study may contribute to further investigations concerning potential roles of Fascin for progression of melanoma. This is the first study to report double immunofluorescent staining of Nestin and Fascin in melanoma. Nestin and Fascin double-positive melanoma cells were detected.

Effect of HER2 and Fascin expression on muscle-invasive bladder cancers: Classification by basaloid and luminal phenotypes

The present study aims to identify basaloid and luminal molecular groups and the p53-like sub-group, which is a sub-group of the luminal group, using a specific immunohistochemical panel and investigate human epithelial growth factor receptor 2 (HER2)/Neu and Fascin expression in these groups to analyze their relationship with clinicopathological features and prognosis in a cohort of cases with muscle-invasive urothelial bladder carcinoma (MIBC). An immunohistochemical panel that included GATA-3, CK20, CD44, and CK5/6 was used to identify molecular sub-groups based on expression in 44 cases of MIBC. HER2/Neu and Fascin expression in basal, luminal, and p53-like groups and the relationship with clinicopathological features and prognosis were investigated. The distribution of the molecular sub-groups determined by immunohistochemistry was as follows: 23 luminal cases (52.3%), 16 basal cases (36.4%), and 5 (11.4%) p53-like cases. There was a statistically significant difference in tumor size across the groups, with the greatest size in the p53-like group (p = 0.001). A statistically significant difference was observed in HER2/Neu expression between the molecular sub-groups (p = 0.017). Comparison of survival and HER2/Neu scores revealed shorter survival in patients with an HER2/Neu score of 3 + compared to those with scores of 0, 1+, and 2+ (p = 0.109). Fascin immunoreactivity was more common in the p53-like and basal groups compared to the luminal group (p = 0.036). Despite the limited number of cases in the MIBC group, our results support that HER2/Neu expression in the luminal sub-group and Fascin expression in basal and p53-like groups may be used as a negative prognostic marker. Multi-center studies that include large case series are warranted in this field.

Expression of fascin in association with p16 and Ki-67 in cervical lesions: immunohistochemical study Expression of fascin in association with p16 and Ki-67 in cervical lesions: immunohistochemical study

Annual gynecological examination with cervical cancer screening and HPV vaccination ensures the appropriate prevention of the onset and progression of cervical cancer. Currently, efforts are being made to find new diagnostic and prognostic biomarkers. Fascin, an actin-bundling protein, promotes cellular migration. Its overexpression has been observed in many types of squamous carcinomas and was usually correlated with aworse prognosis and metastasis. However, the data on fascin expression in cervical lesions are limited. This study focuses on the quantitative evaluation of fascin expression, the immunoreaction intensity and subcellular localization of fascin expression in low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL) and squamous cell carcinomas (SCC). Fascin expression was also correlated with the routinely used diagnostic markers p16 and Ki-67. Biopsy specimens (n = 67) of LSIL, HSIL and SCC were taken from adult women in the age range 20-86 years. Fascin expression was detected by immunohistochemical analysis and quantified using morphometric software. Analysis of variance confirmed statistically significant differences in the percentage of fascin-positive cells between the LSIL, HSIL and SCC groups. Finally, the results showed asignificant positive correlation between fascin expression and p16 and Ki-67 expression.

Do immunohistochemical studies have a role in predicting prognosis of laryngeal squamous cell carcinomas? CD44 and Fascin experience.

Background and objectives:The diagnosis of laryngeal squamous cell carcinoma (LSCC) can be made easily based on histopathological findings, but the relationship between morphological findings and prognosis is not clear. In addition to morphological findings, the use of novel markers may contribute to the development of new treatment strategies and improved patient prognosis. CD44, which is a cancer stem cell marker, and Fascin-1, an actin-binding protein has been associated with poor prognosis in many tumors. The aim of this study was to investigate the relationship between CD44 and Fascin-1 expression and clinicopathologic parameters in LSCC and their roles in the determination of clinical behavior and prognosis. The aim of this study is to investigate whether CD44 and Fascin have a relationship with clinicopathological parameters and have a role in determining clinical behavior and prognosis in LSCC.Methods:130 patients who were operated in our hospital for LSCC between 2012 and 2018 were included in this study. Fascin-1 and CD44 stains were applied immunohistochemically to the paraffin blocks of the tumors. Immunostained specimens were scored according to the intensity of staining and the percentage of staining for each marker. Overall scores were summed and was designated as immunoreactivity score (IRS). Finally, IRS was categorized into two groups; Low and High CD44/Fascin IRS.Results:There were no statistically significant differences between low and high CD44 and Fascin IRS groups in terms of clinicopathologic parameters, overall and disease-free survival (p> 0.05).Conclusion:Immunhistochemical studies are not yet sufficient to predict patient prognosis. Morphological findings still remain of priority and importance for pathologists. (www.actabiomedica.it)

Evaluation of Resistin and Fascin-1 Expression and their Correlation with Recurrence in the Patients of Oral Squamous Cell Carcinoma

Introduction: Squamous cell carcinoma is the most common epithelial malignancy of the oral cavity. The five years survival rate is approximately 50% and is even lower i.e, 30% in the patients with recurrence of this disease. Since recurrence has a major influence on five years survival, it becomes imperative to identify the molecular elements responsible for recurrence of oral squamous cell carcinoma. Aim: To evaluate the expression of resistin and fascin-1 and their correlation with recurrence in the patients of oral squamous cell carcinoma. Materials and Methods: A cohort study will be conducted in the Department of Oral Pathology, Sharad Pawar Dental College and Hospital, Wardha, Maharashtra, India. The duration of the study will be 24 months. A 4 μm thick section from paraffin embedded blocks of formalin fixed biopsy tissues of 60 cases having primary oral squamous cell carcinoma will be processed and stained for mouse monoclonal resistin (clone C-10) and mouse monoclonal fascin-1 (clone 55k-2) antibodies. Results: The results will be analysed by the correlation tests, Pearson and Spearman correlation coefficient. Conclusion: Local recurrence is influenced by site of tumour, depth of invasion, resection margins and lymphovascular spread. As recurrence is directly related to the poor prognosis and survival rate in the patients of oral squamous cell carcinoma, so it is essential to identify molecular markers indicative of recurrence. Fascin and resistin markers could be used to identify a subset of oral squamous cell carcinoma patients which are prone to recurrence.

STAT3/HIF-1α/fascin-1 axis promotes RA FLSs migration and invasion ability under hypoxia

Rheumatoid arthritis (RA) synovium was identified as “tumor-like” tissues because of the hypoxic microenvironment, significant cell proliferation, and invasion phenotypes. It was reported that hypoxia promoted tumor aggressiveness via up-regulated expression of fascin-1 in cancer. However, the role of fascin-1 in RA synovial hyperplasia and joint injury progression remains unknown. In the current study, we first identified that both fascin-1 and HIF-1α were highly expressed in the RA synovium, in which they were widely colocalized, compared to osteoarthritis(OA). As well, levels of fascin-1 in RA fibroblast-like synoviocytes(FLSs) were found significantly higher than those in OA FLSs. Further, it was demonstrated that the mRNA and protein levels of fascin-1 in RA FLSs were up-regulated in hypoxia (3 % O2) and experimental hypoxia induced by cobalt chloride. Mechanistically, the HIF-1α-mediated hypoxia environment activated the gene expression of the fascin-1 protein, which in turn promoted the migration and invasion of RA FLSs. Accordingly, the restoration of FLSs migration and invasion was observed following siRNA-mediated silencing of fascin-1 and HIF-1α expression. Notably, under the experimental hypoxia, we found that the expression levels of fascin-1, HIF-1α, and p-STAT3 were increased in a time-dependent manner, and fascin-1and HIF-1α expressions were dependent on p-STAT3. Our results indicated that hypoxia-induced fascin-1 up-regulation promoted RA FLSs migration and invasion through the STAT3/HIF-1α/fascin-1 axis, which might represent a novel therapeutic target for the treatment of RA.

LRRK2 regulates actin assembly for spindle migration and mitochondrial function in mouse oocyte meiosis.

Leucine-rich-repeat kinase 2 (LRRK2) belongs to the Roco GTPase family and is a large multidomain protein harboring both GTPase and kinase activities. LRRK2 plays indispensable roles in many processes, such as autophagy and vesicle trafficking in mitosis. In this study, we showed the critical roles of LRRK2 in mammalian oocyte meiosis. LRRK2 is mainly accumulated at the meiotic spindle periphery during oocyte maturation. Depleting LRRK2 led to the polar body extrusion defects and also induced large polar bodies in mouse oocytes. Mass spectrometry analysis and co-immunoprecipitation results showed that LRRK2 was associated with several actin-regulating factors, such as Fascin and Rho-kinase (ROCK), and depletion of LRRK2 affected the expression of ROCK, phosphorylated cofilin, and Fascin. Further analysis showed that LRRK2 depletion did not affect spindle organization but caused the failure of spindle migration, which was largely due to the decrease of cytoplasmic actin filaments. Moreover, LRRK2 showed a similar localization pattern to mitochondria, and LRRK2 was associated with several mitochondria-related proteins. Indeed, mitochondrial distribution and function were both disrupted in LRRK2-depleted oocytes. In summary, our results indicated the critical roles of LRRK2 in actin assembly for spindle migration and mitochondrial function in mouse oocyte meiosis.