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Background. Fascin is a protein that is increased in many epithelial cancers, and this increased expression is related to the more aggressive behavior and metastasis of many of these cancers. Considering the relatively high prevalence of oral lichen planus (OLP) and the inconsistencies regarding its malignant transformation potential, this study aimed to investigate the expression level of fascin in OLP and oral squamous cell carcinoma (OSCC). Methods. In this experimental study, 27 samples of erosive OLP and 30 samples of OSCC were immunohistochemically stained with fascin. The extent of fascin expression (epithelial cells with cytoplasmic immunoreactivity) in OLP was categorized into 4 scores based on the extent of epithelial staining. SCC specimens were scored according to the intensity and percentage of staining, and the sum of these two numbers was finally considered the total score, which ranged from 0 to 7. Fascin expression in two groups was compared using the Kruskal-Wallis test. Results. About half of the lichen planus samples (48.15%) received a score of 3. Most of the SCC samples received a score of 5 or 6. The comparison of the expression of fascin between the two groups demonstrated a statistically significant difference (P<0.001). Conclusion. The increased expression of fascin in lichen planus and SCC may indicate the role of fascin in carcinogenesis. Practical Implications. Overexpression of fascin in lichen planus and SCC may be a diagnostic marker for malignant transformation and a prognostic marker, respectively. [ABSTRACT FROM AUTHOR]

Background. Fascin is a protein that is increased in many epithelial cancers, and this increased expression is related to the more aggressive behavior and metastasis of many of these cancers. Considering the relatively high prevalence of oral lichen planus (OLP) and the inconsistencies regarding its malignant transformation potential, this study aimed to investigate the expression level of fascin in OLP and oral squamous cell carcinoma (OSCC). Methods. In this experimental study, 27 samples of erosive OLP and 30 samples of OSCC were immunohistochemically stained with fascin. The extent of fascin expression (epithelial cells with cytoplasmic immunoreactivity) in OLP was categorized into 4 scores based on the extent of epithelial staining. SCC specimens were scored according to the intensity and percentage of staining, and the sum of these two numbers was finally considered the total score, which ranged from 0 to 7. Fascin expression in two groups was compared using the Kruskal-Wallis test. Results. About half of the lichen planus samples (48.15%) received a score of 3. Most of the SCC samples received a score of 5 or 6. The comparison of the expression of fascin between the two groups demonstrated a statistically significant difference (P

Omics technologies provide useful tools for the identification of novel biomarkers in many diseases, including breast cancer, which is the most diagnosed cancer in women worldwide. We and others have reported a central role for the actin-bundling protein (fascin) in regulating breast cancer disease progression at different levels. However, whether fascin expression promotes metabolic molecules that could predict disease progression has not been fully elucidated. Here, fascin expression was manipulated via knockdown (fascinKD+NORF) and rescue (fascinKD+FORF) in the naturally fascin-positive (fascinpos+NORF) MDA-MB-231 breast cancer cells. Whether fascin dysregulates metabolic profiles that are associated with disease progression was assessed using untargeted metabolomics analyses via liquid chromatography–mass spectrometry. Overall, 12,226 metabolic features were detected in the tested cell pellets. Fascinpos+NORF cell pellets showed 2510 and 3804 significantly dysregulated metabolites compared to their fascinKD+NORF counterparts. Fascin rescue (fascinKD+FORF) revealed 2710 significantly dysregulated cellular metabolites compared to fascinKD+NORF counterparts. A total of 101 overlapped cellular metabolites between fascinKD+FORF and fascinpos+NORF were significantly dysregulated in the fascinKD+NORF cells. Analysis of the significantly dysregulated metabolites by fascin expression revealed their involvement in the metabolism of sphingolipid, phenylalanine, tyrosine, and tryptophan biosynthesis, and pantothenate and CoA biosynthesis, which are critical pathways for breast cancer progression. Our findings of fascin-mediated alteration of metabolic pathways could be used as putative poor prognostic biomarkers and highlight other underlying mechanisms of fascin contribution to breast cancer progression. [ABSTRACT FROM AUTHOR]

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 the expression was 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 was 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.

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 the expression was 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 was 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.

Fascin displays elevated expression in malignant tumors, such as esophageal squamous cell carcinoma, and exerts a pro-cancer effect that is closely associated with poor prognosis among cancer patients. In recent years, our research, along with that of others, has consistently demonstrated that phosphorylation or acetylation modifications can effectively reverse the oncogenic function of Fascin, just like the “face-changing” in Sichuan Opera. Recently, we have further revealed that post-translational modifications of Fascin affect the anticancer efficacy of small-molecule Fascin inhibitors. This finding suggests that therapeutics targeting Fascin should incorporate the status of post-translational modifications of Fascin into the drug efficacy evaluation framework. Here, we present a review on the oncogenic function of Fascin, focusing on discussing the effect of post-translational modifications on the function of Fascin and the efficacy of small-molecule Fascin inhibitors, and provide insights into future research directions in the field of Fascin. [ABSTRACT FROM AUTHOR]

Fascin actin‐bundling protein 1 (Fascin) is highly expressed in a variety of cancers, including esophageal squamous cell carcinoma (ESCC), working as an important oncogenic protein and promoting the migration and invasion of cancer cells by bundling F‐actin to facilitate the formation of filopodia and invadopodia. However, it is not clear how exactly the function of Fascin is regulated by acetylation in cancer cells. Here, in ESCC cells, the histone acetyltransferase KAT8 catalyzed Fascin lysine 41 (K41) acetylation, to inhibit Fascin‐mediated F‐actin bundling and the formation of filopodia and invadopodia. Furthermore, NAD‐dependent protein deacetylase sirtuin (SIRT) 7‐mediated deacetylation of Fascin‐K41 enhances the formation of filopodia and invadopodia, which promotes the migration and invasion of ESCC cells. Clinically, the analysis of cancer and adjacent tissue samples from patients with ESCC showed that Fascin‐K41 acetylation was lower in the cancer tissue of patients with lymph node metastasis than in that of patients without lymph node metastasis, and low levels of Fascin‐K41 acetylation were associated with a poorer prognosis in patients with ESCC. Importantly, K41 acetylation significantly blocked NP‐G2‐044, one of the Fascin inhibitors currently being clinically evaluated, suggesting that NP‐G2‐044 may be more suitable for patients with low levels of Fascin‐K41 acetylation, but not suitable for patients with high levels of Fascin‐K41 acetylation. © 2024 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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 the expression was 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 was 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.

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 the expression was 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 was 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.

Fascin is a major actin‐binding protein (ABP) in filopodia and is highly expressed in metastatic tumors. To inhibit its function, a potent inhibitor called NP‐G2‐044 is currently in phase II clinical trials. However, the binding mode of this inhibitor remains unclear. In this study, the binding mode of NP‐G2‐044 in fascin and predicted drug resistance mutations is investigated. The rough binding position and pose can be deduce based on information from its derivant NP‐G2‐029, whose crystal structure with fascin has been solved. Molecular docking, free energy perturbation (FEP) simulation and metadynamics simulation are performed to confirm the binding pose. Based on the molecular docking results, two binding modes of NP‐G2‐044, pose A and B, are obtained, with pose A being more favorable. For pose A, the planar indazole moiety has the same orientation as NP‐G2‐029 in the complex with fascin, while for pose B, it rotates ≈90°. FEP and metadynamics simulations indicate that both binding poses are possible. Relative binding free energies for mutation effects calculated by FEP predict E215A and R217A are drug resistance mutations. These findings are important for further drug development targeting fascin. [ABSTRACT FROM AUTHOR]

Liver cancer is one of the most prevalent cancers in Japan with hepatocellular carcinoma (HCC) as the major histological subtype. Successful novel treatments for HCC have been reported; however, recurrences or metastasis may occur, which results in poor prognoses and high mortality of HCC patients. Fascin, an actin-bundling protein, regulates cell adhesion, migration, and invasion. Its overexpression positively correlates with poor prognosis of malignant tumors, and Fascin is considered as one of the tumor biomarkers and therapeutic target proteins. In this study, we attempted to reveal the relationship between Fascin and HCC using HLE, one of the human HCC cell lines. We performed the study with classical immunocytochemistry and recently developed techniques, such as wound-healing assay, spheroid cultivation, and low-vacuum scanning electron microscopy (LV-SEM). Non-Fascin-knockdown (FKD) cell spheroid had a regular spherical appearance with tight cell–cell connections, while FKD cell spheroid had an irregular shape with loose cell–cell connections. Cells of non-FKD spheroid presented fibrous protrusions on the cell surface, contrarily, cells of FKD spheroids showed bulbous-shaped protrusions. Morphological observation of FKD and non-FKD HLE spheroids were performed using LV-SEM. Our study may help to reveal the roles of Fascin in the process of HCC formation and its malignancy. [ABSTRACT FROM AUTHOR]

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.

Gastric carcinoma (GC) is one of the most prevalent cancers worldwide and the fourth leading cause of cancer-related death. Studying the molecular profile of GC is essential for developing targeted therapies. β-catenin, Tenascin, and Fascin expression are among the molecular abnormalities that are claimed to cause GC progression and chemoresistance. Therefore, they could be used as potential therapeutic targets. This study aimed to evaluate β-catenin, Tenascin, and Fascin expression and their possible roles as prognostic and predictive biomarkers in GC using immunohistochemistry. This retrospective study included 84 GC cases. Tissue microarrays were constructed, followed by β-catenin, Tenascin, and Fascin immunostaining. Their expression was assessed and compared with clinicopathological parameters and survival data. The study results revealed that β-catenin nucleocytoplasmic expression, positive Tenascin, and Fascin expressions were detected in 86.9%, 70%, and 59.5% of cases, respectively. Their expression was significantly associated with poor prognostic parameters, such as deeper tumor invasion, lymph node metastasis, advanced pathological stage, vascular invasion, positive omental nodules, poor response to chemotherapy, and short overall survival. Hence, nucleocytoplasmic β-catenin expression together with Tenascin and Fascin positivity can be potential prognostic and predictive markers, and they can be used as therapeutic targets for GC. [ABSTRACT FROM AUTHOR]

Filopodia are dynamic cell surface protrusions used for cell motility, pathogen infection, and tissue development. The molecular mechanisms determining how and where filopodia grow and retract need to integrate mechanical forces and membrane curvature with extracellular signaling and the broader state of the cytoskeleton. The involved actin regulatory machinery nucleates, elongates, and bundles actin filaments separately from the underlying actin cortex. The refined membrane and actin geometry of filopodia, importance of tissue context, high spatiotemporal resolution required, and high degree of redundancy all limit current models. New technologies are improving opportunities for functional insight, with reconstitution of filopodia in vitro from purified components, endogenous genetic modification, inducible perturbation systems, and the study of filopodia in multicellular environments. In this review, we explore recent advances in conceptual models of how filopodia form, the molecules involved in this process, and our latest understanding of filopodia in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Cancer cell migration and metastasis are the biggest problems in the treatment of cancer patients. The most aggressive breast cancer (BC) is the triple-negative type. Therefore, effective therapeutic targets that limit cell migration are sought. One such target may be fascin, as its overexpression is characteristic to triple-negative breast cancer. The high level of fascin enables the formation of protrusion and thus promotes the invasion of cancer cells. Fascin also shows co-localization or functional relationships with other proteins. These are proteins involved in the epithelial-mesenchymal transition process, vimentin, cadherins, β-catenin, and matrix metalloproteinases 2/9 (MMP-2/9). Fascin is also involved in many signaling pathways protein kinase C-δ (PKCδ), Wnt/β-catenin, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and phosphatidylinositol 3-kinase (PI3K)-Akt. Therefore, in this article, we review currently available in vitro studies and compare them with The Cancer Genome Atlas (TCGA) data analysis of BC patients to demonstrate the role of fascin in the migration and invasion of cancer cells. [ABSTRACT FROM AUTHOR]

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. Following a thorough literature search we hypothesize that fascin might contribute for the local migratory behaviour of the odontogenic epithelial cells in tumors and cysts while SALL4 may contribute to stemness property. Thus, the aim of the present study was to evaluate the expression of fascin and SALL4 in histopathological variants of Ameloblastoma, Adenomatoid Odontogenic Tumor (AOT) and various odontogenic cysts namely 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 evaluated in a total of 40 cases of ameloblastoma (11 plexiform, 12 follicular, 12 unicystic, and 5 desmoplastic) variants, 6 cases of AOT, 15 cases 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 the expression was 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 DC and RC having a marked inflammatory infiltrate, which was an interesting observation. COC and AOT had negative to weak expressions. Conclusion: 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.

Simple Summary: Fascin is an actin-bundling protein that is highly expressed in mature dendritic cells and intratumoral dendritic cells. Dendritic cells are professional antigen-presenting cells of the immune system. Fascin is responsible for regulating dendritic cell migrations and tumor metastasis. The mechanism by which fascin regulates the functions of dendritic cells is currently being explored. In this review, we summarize fascin's involvement in the physiological processes of normal dendritic cells including dendritic cell maturation, migration, and antigen presentation. In cancer patients, there is a subset of dendritic cells with high levels of fascin; activation of this subset of dendritic cells has been shown to enhance antitumor immune response. Fascin inhibitors increase intratumoral dendritic cell accumulation and activation, and cooperate with immune checkpoint inhibitors. Dendritic cells (DCs) are professional antigen-presenting cells that play a crucial role in activating naive T cells through presenting antigen information, thereby influencing immunity and anti-cancer responses. Fascin, a 55-kDa actin-bundling protein, is highly expressed in mature DCs and serves as a marker protein for their identification. However, the precise role of fascin in intratumoral DCs remains poorly understood. In this review, we aim to summarize the role of fascin in both normal and intratumoral DCs. In normal DCs, fascin promotes immune effects through facilitating DC maturation and migration. Through targeting intratumoral DCs, fascin inhibitors enhance anti-tumor immune activity. These roles of fascin in different DC populations offer valuable insights for future research in immunotherapy and strategies aimed at improving cancer treatments. [ABSTRACT FROM AUTHOR]

The left–right (L‐R) asymmetry of the cells, or cell chirality, is a well‐known intrinsic property derived from the dynamic organization of the actin cytoskeleton. Cell chirality can be regulated by actin‐binding proteins such as α‐actinin‐1 and can also be mediated by certain signaling pathways, such as protein kinase C (PKC) signaling. Fascin, an actin crosslinker known to mediate parallel bundling of actin filaments, appears as a prominent candidate in cell chirality regulation, given its role in facilitating cell migration as an important PKC substrate. Here, it is shown that the chirality of NIH/3T3 cells can be altered by PKC activation and fascin manipulation. With either small‐molecule drug inhibition or genetic knockdown of fascin, the chirality of 3T3 cells is reversed from a clockwise (CW) bias to a counterclockwise (CCW) bias on ring‐shaped micropatterns, accompanied by the reversal in cell directional migration. The Ser‐39 fascin‐actin binding sites are further explored in cell chirality regulation. The findings of this study reveal the critical role of fascin as an important intermediator in cell chirality, shedding novel insights into the mechanisms of L‐R asymmetric cell migration and multicellular morphogenesis. [ABSTRACT FROM AUTHOR]

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 a worse 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 a significant positive correlation between fascin expression and p16 and Ki-67 expression.

Cells use the actin cytoskeleton for many of their functions, including their division, adhesion, mechanosensing, endo- and phagocytosis, migration, and invasion. Actin bundles are the main constituent of actin-rich structures involved in these processes. An ever-increasing number of proteins that crosslink actin into bundles or regulate their morphology is being identified in cells. With recent advances in high-resolution microscopy and imaging techniques, the complex process of bundles formation and the multiple forms of physiological bundles are beginning to be better understood. Here, we review the physiochemical and biological properties of four families of highly conserved and abundant actin-bundling proteins, namely, α-actinin, fimbrin/plastin, fascin, and espin. We describe the similarities and differences between these proteins, their role in the formation of physiological actin bundles, and their properties—both related and unrelated to their bundling abilities. We also review some aspects of the general mechanism of actin bundles formation, which are known from the available information on the activity of the key actin partners involved in this process. [ABSTRACT FROM AUTHOR]

Fascin is an actin-bundling protein overexpressed in various invasive metastatic carcinomas through promoting cell migration and invasion. Therefore, blocking Fascin binding sites is considered a vital target for antimetastatic drugs. This inspired us to find new Fascin binding site blockers. First, we built an active compound set by collecting reported small molecules binding to Fascin's binding site 2. Consequently, a high-quality decoys set was generated employing DEKOIS 2.0 protocol to be applied in conducting the benchmarking analysis against the selected Fascin structures. Four docking programs, MOE, AutoDock Vina, VinaXB, and PLANTS were evaluated in the benchmarking study. All tools indicated better-than-random performance reflected by their pROC-AUC values against the Fascin crystal structure (PDB: ID 6I18). Interestingly, PLANTS exhibited the best screening performance and recognized potent actives at early enrichment. Accordingly, PLANTS was utilized in the prospective virtual screening effort for repurposing FDA-approved drugs (DrugBank database) and natural products (NANPDB). Further assessment via molecular dynamics simulations for 100 ns endorsed Remdesivir (DrugBank) and NANPDB3 (NANPDB) as potential binders to Fascin binding site 2. In conclusion, this study delivers a model for implementing a customized DEKOIS 2.0 benchmark set to enhance the VS success rate against new potential targets for cancer therapies. [ABSTRACT FROM AUTHOR]

Fascin is a filamentous actin (F‐actin) bundling protein, which cross‐links F‐actin into bundles and becomes an important component of filopodia on the cell surface. Fascin is overexpressed in many types of cancers. The mutation of fascin affects its ability to bind to F‐actin and the progress of cancer. In this paper, we have studied the effects of residues of K22, K41, K43, K241, K358, K399, and K471 using molecular dynamics (MD) simulation. For the strong‐effect residues, that is, K22, K41, K43, K358, and K471, our results show that the mutation of K to A leads to large values of root mean square fluctuation (RMSF) around the mutated residues, indicating those residues are important for the flexibility and thermal stability. On the other hand, based on residue cross‐correlation analysis, alanine mutations of these residues reinforce the correlation between residues. Together with the RMSF data, the local flexibility is extended to the entire protein by the strong correlations to influence the dynamics and function of fascin. By contrast, for the mutants of K241A and K399A those do not affect the function of fascin, the RMSF data do not show significant differences compared with wild‐type fascin. These findings are in a good agreement with experimental studies. [ABSTRACT FROM AUTHOR]

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. [Display omitted] [ABSTRACT FROM AUTHOR]

The post-translational modifications (PTMs), which are crucial in the regulation of protein functions, have great potential as biomarkers of cancer status. Fascin (Fascin actin-bundling protein 1, FSCN1), a key protein in the formation of filopodia that is structurally based on actin filaments (F-actin), is significantly associated with tumor invasion and metastasis. Studies have revealed various regulatory mechanisms of human Fascin, including PTMs. Although a number of Fascin PTM sites have been identified, their exact functions and clinical significance are much less explored. This review explores studies on the functions of Fascin and briefly discusses the regulatory mechanisms of Fascin. Next, to review the role of Fascin PTMs in cell biology and their associations with metastatic disease, we discuss the advances in the characterization of Fascin PTMs, including phosphorylation, ubiquitination, sumoylation, and acetylation, and the main regulatory mechanisms are discussed. Fascin PTMs may be potential targets for therapy for metastatic disease. [ABSTRACT FROM AUTHOR]

Rationale: During neoplastic transformation, epithelial cells become mobile, which is one of the main mechanisms of metastatic disease and recurrence. Cell motility is regulated by actin-binding proteins, which ensure the association/dissociation of actin filaments and their interaction with the cell membrane. Previously, we have shown the presence of actin-binding proteins in the serum from patients with squamous cell carcinoma of the head and neck (HNSCC); however, their association with the development of metastases and relapses in cancer patients has not been sufficiently studied. Aim: To evaluate the serum levels of actin-binding proteins fascin-1 and ezrin in patients with HNSCC depending on the disease recurrence and lymphatic metastasis. Materials and methods: Serum fascin-1 and ezrin levels before combination therapy were measured with ELISA assay in 30 HNSCC (T1-4N0-2M0) patients (mean age 56 7 years). Results: The median fascin-1 level was significantly higher in the patients with lymphatic metastases, compared to those without metastases: 0.64 (0.40; 5.89) vs 6.35 (1.72; 8.35) ng/mL, respectively (p 0.001). At 12 to 36 months after combination therapy, the disease relapsed in 12 (40%) patients. Ezrin levels were significantly higher in the relapsed patients, compared to those without a relapse within 3 years after combination therapy: 2.55 (2.35; 2.75) vs 1.93 (1.87; 2.5) ng/mL (p = 0.02). The ROC analysis showed an association between fascin-1 serum levels with metastatic disease (AUC = 0.71, 95% confidence interval 0.570.85) and an association between ezrin levels and the disease relapse (AUC = 0.76, 95% confidence interval 0.570.94). Conclusion: These indicators can be used for the development of minimally invasive early detection of metastases in lymphatic nodes and for the prognosis of HNSCC recurrence.

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.

Abstract Background Fascin is crucial for cancer cell filopodium formation and tumor metastasis, and is functionally regulated by post‐translational modifications. However, whether and how Fascin is regulated by acetylation remains unclear. This study explored the regulation of Fascin acetylation and its corresponding roles in filopodium formation and tumor metastasis. Methods Immunoprecipitation and glutathione‐S‐transferase pull‐down assays were performed to examine the interaction between Fascin and acetyltransferase P300/CBP‐associated factor (PCAF), and immunofluorescence was used to investigate their colocalization. An in vitro acetylation assay was performed to identify Fascin acetylation sites by using mass spectrometry. A specific antibody against acetylated Fascin was generated and used to detect the PCAF‐mediated Fascin acetylation in esophageal squamous cell carcinoma (ESCC) cells using Western blotting by overexpressing and knocking down PCAF expression. An in vitro cell migration assay was performed, and a xenograft model was established to study in vivo tumor metastasis. Live‐cell imaging and fluorescence recovery after photobleaching were used to evaluate the function and dynamics of acetylated Fascin in filopodium formation. The clinical significance of acetylated Fascin and PCAF in ESCC was evaluated using immunohistochemistry. Results Fascin directly interacted and colocalized with PCAF in the cytoplasm and was acetylated at lysine 471 (K471) by PCAF. Using the specific anti‐AcK471‐Fascin antibody, Fascin was found to be acetylated in ESCC cells, and the acetylation level was consequently increased after PCAF overexpression and decreased after PCAF knockdown. Functionally, Fascin‐K471 acetylation markedly suppressed in vitro ESCC cell migration and in vivo tumor metastasis, whereas Fascin‐K471 deacetylation exhibited a potent oncogenic function. Moreover, Fascin‐K471 acetylation reduced filopodial length and density, and lifespan of ESCC cells, while its deacetylation produced the opposite effect. In the filipodium shaft, K471‐acetylated Fascin displayed rapid dynamic exchange, suggesting that it remained in its monomeric form owing to its weakened actin‐bundling activity. Clinically, high levels of AcK471‐Fascin in ESCC tissues were strongly associated with prolonged overall survival and disease‐free survival of ESCC patients. Conclusions Fascin interacts directly with PCAF and is acetylated at lysine 471 in ESCC cells. Fascin‐K471 acetylation suppressed ESCC cell migration and tumor metastasis by reducing filopodium formation through the impairment of its actin‐bundling activity.

Aim: Fascin is an actin-binding protein that promotes tumor metastasis. The inhibition of fascin on the progress of non-small cell lung cancer (NSCLC) is not very clear. Hence, this study explored the potential effect of NP-G2-044, a novel fascin inhibitor, in human NSCLC lines and the Lewis lung cancer (LCC) mice model., Methods: The growth of cells was analyzed via CCK-8 assays, and the flow cytometry was adopted for cell cycle and apoptosis analysis, as well as the migration and invasion of NSCLC cells with or without NP-G2-044. The therapy of NP-G2-044, which synergizes with cisplatin and PD-1, was evaluated in the established xenograft Lewis's lung cancer of mice., Results: Fascin was overexpressed in human NSCLC cells, and inhibition of fascin by NP-G2-044 attenuated NSCLC cell growth and remarkably undermined the ability of migration and invasion in vitro, which was related to the reduced epithelialmesenchymal transition (EMT) including downregulation of N-cadherin and vimentin, and upregulation of E-cadherin. Further results implied that the above changes may be partially mediated by the Wnt/β-catenin pathway. In vivo, NP-G2-044 slowed down tumor development and enhanced overall survival alone, leading to synergistic anticancer effects with cisplatin or PD-1 inhibitor., Conclusion: Fascin inhibition could inhibit the metastasis of NSCLC and has the potential to enhance the efficacy of cisplatin and PD-1 inhibitors by blocking the Wnt/β- catenin pathway., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The assembly of actin-based structures with precisely defined architectures supports essential cellular functions, including motility, intracellular transport, and division. The geometric arrangements of the filaments within actin structures are stabilized via the association of crosslinking proteins, which bind two filaments simultaneously. Because actin polymerization and crosslinking occur concurrently within the dynamic environment of the cell, these processes likely play interdependent roles in shaping the architectures of actin-based structures. To dissect the contribution of polymerization to the construction of higher-order actin structures, we investigated how filament elongation affects the formation of simple, polarized actin bundles by the crosslinking protein fascin. Using populations of actin filaments to represent distinct stages of elongation, we found that the rate of bundle assembly increases with filament length. Fascin assembles short filaments into discrete bundles, whereas bundles of long filaments merge with one another to form interconnected networks. Although filament elongation promotes bundle coalescence, many connections formed between elongating bundles are short-lived and are followed by filament breakage. Our data suggest that initiation of crosslinking early in elongation aligns growing filaments, creating a template for continued bundle assembly as elongation proceeds. This initial alignment promotes the assembly of bundles that are resistant to large changes in curvature that are required for coalescence into interconnected networks. As a result, bundles of short filaments remain straighter and more topologically discrete as elongation proceeds than bundles assembled from long filaments. Thus, uncoordinated filament elongation and crosslinking can alter the architecture of bundled actin networks, highlighting the importance of maintaining precise control over filament length during the assembly of specialized actin structures.

Background: Fascins belong to a family of actin-bundling proteins that are involved in a wide range of biological functions. FSCN3, a newly identified testis-specific actin-bundling protein, is specifically expressed in elongated spermatids. However, its in vivo function in mouse spermiogenesis remains unknown. Methods and results: We generated Fscn3 knockout mice through CRISPR/Cas9 gene-editing technology. Fscn3−/− mice displayed normal testis morphology and testis to bodyweight ratio, and sperm concentrations did not differ significantly between Fscn3+/+ and Fscn3−/− mice. Fertility assays consistently revealed that Fscn3−/− mice are completely fertile and their reproductive status does not differ from that of wild-type. Moreover, hematoxylin and eosin staining of the testis sections of Fscn3−/− mice detected various germ cells, ranging from spermatogonia to mature spermatozoa. Furthermore, the swimming velocity of the sperm of Fscn3−/− mice was comparable to that of their wild-type littermates. Both Fscn3+/+ and Fscn3−/−mice had normal sperm morphology, indicating that the disruption of Fscn3 does not affect sperm morphology. The analysis of meiotic prophase I progression demonstrated normal prophase-I phases (leptonema to diplonema) in both Fscn3+/+ and Fscn3−/− mice, suggesting that Fscn3 is not essential for meiosis I. Conclusion: Our study provides the first evidence that FSCN3 is a testis-specific actin-bundling protein that is not required for mouse spermatogenesis. Our results will help reproductive biologists focus their efforts on genes that are crucial for fertility and avoid research duplication. [ABSTRACT FROM AUTHOR]

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 a worse 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 a significant positive correlation between fascin expression and p16 and Ki-67 expression. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Fascin, a major actin cross-linking protein, is expressed in most vertebrate epithelial tissues. It organizes actin filaments into well-ordered bundles that are responsible for the extension of dynamic membrane protrusions, including microspikes, filopodia, and invadopodia from cell surfaces, which are involved in cell migration and invasion as critical components of cancer metastasis. However, it is not well-understood how fascin-1 induces actin binding/bundling and where fascin-1 localizes along the actin filaments, thus facilitating actin bundle formation. In the present study, we attempted to clarify these problems by using biochemical and electron microscopic analyses using various fascin-1 constructs. Three dimensional structures of actin/fascin-1 complex were obtained by electron microscopy (EM) with iterative helical real-space reconstruction (IHRSR) and tomography. We revealed that the N-terminal region containing the Actin-Binding Site 2 (ABS2) of fascin-1 is responsible for actin bundling and the C-terminal region is important for the dimerization of fascin-1. We also found that the dimerization of fascin-1 through intermolecular interactions of the C-terminal region is essential for actin bundling. Since fascin is an important factor in cancer development, it is expected that the findings of present study will provide useful information for development of therapeutic strategies for cancer. [ABSTRACT FROM AUTHOR]

Fascin is an important regulator of F-actin bundling leading to enhanced filopodia assembly. Fascin is also overexpressed in most solid tumours where it supports invasion through control of F-actin structures at the periphery and nuclear envelope. Recently, fascin has been identified in the nucleus of a broad range of cell types but the contributions of nuclear fascin to cancer cell behaviour remain unknown. Here, we demonstrate that fascin bundles F-actin within the nucleus to support chromatin organisation and efficient DDR. Fascin associates directly with phosphorylated Histone H3 leading to regulated levels of nuclear fascin to support these phenotypes. Forcing nuclear fascin accumulation through the expression of nuclear-targeted fascin-specific nanobodies or inhibition of Histone H3 kinases results in enhanced and sustained nuclear F-actin bundling leading to reduced invasion, viability, and nuclear fascin-specific/driven apoptosis. These findings represent an additional important route through which fascin can support tumourigenesis and provide insight into potential pathways for targeted fascin-dependent cancer cell killing.

Rearrangement of the actin cytoskeleton is a prerequisite for carcinoma cells to develop cellular protrusions, which are required for migration, invasion, and metastasis. Fascin is a key protein involved in actin bundling and is expressed in aggressive and invasive carcinomas. Additionally, fascin appears to be involved in tubulin-binding and microtubule rearrangement. Pharmacophoric-based in silico screening was performed to identify compounds with better fascin inhibitory properties than migrastatin, a gold-standard fascin inhibitor. We hypothesized that monastrol displays anti-migratory and anti-invasive properties via fascin blocking in colorectal cancer cell lines. Biophysical (thermofluor and ligand titration followed by fluorescence spectroscopy), biochemical (NMR), and cellular assays (MTT, invasion of human tissue), as well as animal model studies (zebrafish invasion) were performed to characterize the inhibitory effect of monastrol on fascin activity. In silico analysis revealed that monastrol is a potential fascin-binding compound. Biophysical and biochemical assays demonstrated that monastrol binds to fascin and interferes with its actin-bundling activity. Cell culture studies, including a 3D human myoma disc model, showed that monastrol inhibited fascin-driven cytoplasmic protrusions as well as invasion. In silico , confocal microscopy, and immunoprecipitation assays demonstrated that monastrol disrupted fascin-tubulin interactions. These anti-invasive effects were confirmed in vivo. In silico confocal microscopy and immunoprecipitation assays were carried out to test whether monastrol disrupted the fascin-tubulin interaction. This study reports, for the first time, the in vitro and in vivo anti-invasive properties of monastrol in colorectal tumor cells. The number and types of interactions suggest potential binding of monastrol across actin and tubulin sites on fascin, which could be valuable for the development of antitumor therapies. [ABSTRACT FROM AUTHOR]

Incidence and progression of skin cancer has progressively elevated in the last decades because of the increase in risk factors such as ultraviolet radiation. In addition, adiponectin exerts therapeutic effects against many types of tumors. Therefore, we aimed to investigate therapeutic effects of adiponectin on skin cancer and to study its effects on inflammation and tumor invasion in a mice model of skin cancer. Skin cancer was induced using 7,12-Dimethylbenz (a) anthracene (DMBA) and croton oil on the dorsal skin of mice. Skin samples were obtained for estimation of gene and protein expression of sulfatase-2, matrix metalloproteinase (MMP)9, heparan sulfate proteoglycans (HSPGs), glypican-3 (GPC3), fascin, nuclear factor (NF)κB; protein kinase C (PKC) and syndecan-1. Part of the skin is immune stained with cytokeratin. Skin cancer-induced elevation in activity of sulfatase-2 and MMP9 enzymes leading to reduction in HSPGs. All these effects were ameliorated by adiponectin. Finally, treatment with adiponectin markedly attenuated skin cancer-induced elevation in the expression of PKC, NFκB, fascin and syndecan-1. In conclusion, besides its antioxidant activities, adiponectin produced therapeutic effects against skin cancer through increasing HSPGs and inhibition of both inflammatory and tumor invasion pathways. Highlights: • Adiponectin exerts therapeutic effects against many types of tumors. • Treatment of skin cancer mice with adiponectin increases HSPGs. • Adiponectin inhibits both inflammatory and tumor invasion pathways. [ABSTRACT FROM AUTHOR]

Desmoplastic melanoma is a rare variant of melanoma and it does not show the classical clinicopathological features of melanoma. Immunohistochemically HMB-45 and Melan-A negativity in desmoplastic melanoma creates difficulty in diagnosis and causes misdiagnosis. For this reason, additional immunohistochemical markers besides S-100 are needed. In our case series, we aimed to investigate the diagnostic utility of fascin as an ancillary marker for the diagnosis of desmoplastic malignant melanoma. Sections obtained from five desmoplastic malignant melanoma cases diagnosed histopathologically and immunohistochemically were stained by automated slide stainer for immunohistochemistry. The cases showing cytoplasmic immunoreactivity were evaluated as 'positive' and the ones with no immunoreactivity as 'negative'. All desmoplastic melanoma cases with immunohistochemically negative for melanocyte markers except S-100 were positive for fascin. Fascin positivity was diffuse and strong in three cases. There is a difficulty in diagnosis of desmoplastic melanoma due to its peculiar clinical and histopathological features. Accurate differential diagnosis is extremely important for the correct treatment of the demoplastic melanoma. Therefore, we think that showing fascin positivity besides S-100 will be also useful in the diagnostic process. [ABSTRACT FROM AUTHOR]

The intracellular pathogen Chlamydia trachomatis secretes multiple early effectors into the host cell to promote invasion. A key early effector during host cell entry, Tarp (translocated actin-recruiting phosphoprotein) is comprised of multiple protein domains known to have roles in cell signaling, G-actin nucleation and F-actin bundle formation. In vitro , the actin bundles generated by Tarp are uncharacteristically flexible, however, in vivo , the biological significance of Tarp-mediated actin bundles remains unknown. We hypothesize that Tarp's ability to generate unique actin bundles, in part, facilitates chlamydial entry into epithelial cells. To study the in vivo interaction between Tarp and F-actin, we transgenically expressed Tarp in Drosophila melanogaster tissues. Tarp expressed in Drosophila is phosphorylated and forms F-actin-enriched aggregates in tissues. To gain insight into the significance of Tarp actin bundles in vivo , we utilized the well-characterized model system of mechanosensory bristle development in Drosophila melanogaster. Tarp expression in wild type flies produced curved bristles, indicating a perturbation in F-actin dynamics during bristle development. Two F-actin bundlers, Singed/Fascin and Forked/Espin, are important for normal bristle shape. Surprisingly, Tarp expression in the bristles displaced Singed/Fascin away from F-actin bundles. Tarp's competitive behavior against Fascin during F-actin bundling was confirmed in vitro. Loss of either singed or forked in flies leads to highly deformed bristles. Strikingly, Tarp partially rescued the loss of singed , reducing the severity of the bristle morphology defect. This work provides in vivo confirmation of Tarp's F-actin bundling activity and further uncovers a competitive behavior against the host bundler Singed/Fascin during bundle assembly. Also, we demonstrate the utility of Drosophila melanogaster as an in vivo cell biological platform to study bacterial effector function. [ABSTRACT FROM AUTHOR]

Abstract Background Fascin is an actin-binding protein and highly expressed in ovarian cancer cells. It is associated with metastasis of cancer and may be a useful prognostic factor. Anticancer activity of curcumin is related to its effect on several signaling mechanisms. Although there have been many reports regarding the anticancer properties of curcumin, its inhibitory effects on migration and invasion of ovarian cancer cells, particularly in the context of fascin expression, have not been reported. The purpose of this study was to investigate the effect of curcumin on fascin expression in ovarian cancer cells and to propose a possible mechanism for the anticancer activity of curcumin through reduced fascin expression. Methods SKOV3, human epithelial ovary cancer cell line, was cultured with curcumin at various dose and duration. The fascin was quantified using cell viability test and Western blot. To determine the effect of curcumin on the upstream pathway of fascin expression, the signal transducer and activator of transcription 3 (STAT3) was analyzed by sandwich-ELISA. Attachment assay, migration assay and invasion assay were analyzed to approve the change of cellular invasiveness of ovary cancer after curcumin. To determine the morphological changes of ovarian cancer cells by curcumin, immunofluorescence was performed. Results MTS assays showed that cell viability was different at various concentration of curcumin, and as concentration increased, cell viability tended to decrease. Curcumin appears to suppress fascin expression, even with a minimal concentration and short exposure time. Also, curcumin may suppress fascin expression in ovarian cancer cells through STAT3 downregulation. The attachment assay, migration assay and invasion assay of the ovarian cancer cells exhibited a statistically significant decrease. Immunofluorescence revealed a change of cell shape from a typical form of uninfluenced cells to a more polygonal appearance, with a significant reduction in filopodia formation. Conclusions Curcumin reduces fascin expression through JAK/STAT3 pathway inhibition, which interferes with the cellular interactions essential for the metastasis and recurrence of ovarian cancer cells. Higher curcumin concentrations and longer exposure times concomitantly decreased fascin expression.

Background and purpose: Squamous cell carcinoma (SCC) is the eighth most common cancer in men and the fifteenth in women. Localized recurrence and metastasis to regional lymph nodes are major problems in these patients. Fascin is a 55- kDa protein from the family of actin-binding proteins that is expressed in cells with membranous bronchial tubes. The aim of this study was to evaluate the expression of fascin in oral SCC. Materials and methods: A descriptive cross-sectional study was performed in 60 patients with OSCC attending Yazd Shahid Sadoughi Hospital, 2017. After preparing four-micrometer sections from paraffin blocks, the immunohistochemistry was performed using Fascin (as a tumor marker). Data were analyzed in SPSS V23 applying Chi-square test, Mann-Whitney test, and Kruskal-Wallis test. Results: Most of the samples showed poor to moderate expression of fascin, and there were significant relationships between expression level of fascin and age, sex, and degree of microscopic grading (P=0.002, P=0.009, P=0.011). High expression of fascin was seen in samples with recurrence and metastasis, but no significant relationship was detected (P=0.525, P=0.769). Conclusion: The expression level of fascin in SCC probably indicates its role in increasing the movement and migration of cancer cells and the likelihood of recurrence and metastasis.

In the present study, we tried to evaluate the relationship between Fascin molecule expression and other histopathologic parameters, especially tumor grade and hormone profile. Sixty-one malignant breast tumors were enrolled in this study. Fascin marker staining was performed on paraffin blocks of breast samples using immunohistochemistry (IHC) method. The age range of patients was 26-87 years, with an average of 48.41 ±1.68. Our results showed that fascin expression was significantly higher in tumors with high grade histology, lymph node involvement and larger tumor size (p = 0.04, 0.04, 0.04, respectively). Also fascin expression in triple negative tumors was significantly higher than other molecular subtypes (p = 0.001). fascin can be used as an important marker in evaluating breast cancer especially in triple negative tumors.

Filopodia are cellular protrusions that respond to a variety of stimuli. Filopodia are formed when actin is bound to the protein Fascin, which may play a crucial role in cellular interactions and motility during cancer metastasis. Significantly, the noncanonical features of Fascin-1 are gradually being clarified, including the related molecular network contributing to metabolic reprogramming, chemotherapy resistance, stemness ac-tivity, and tumor microenvironment events. However, the relationship between biological characteristics and pathological features to identify effective therapeutic strategies needs to be studied further. The pur-pose of this review article is to provide a broad overview of the latest molecular networks and multiomics research regarding fascins and cancer. It also highlights their direct and indirect effects on available cancer treatments. With this multidisciplinary approach, researchers and clinicians can gain the most relevant in-formation on the function of fascins in cancer progression, which may facilitate clinical applications in the future.

Cells use the actin cytoskeleton for many of their functions, including their division, adhesion, mechanosensing, endo- and phagocytosis, migration, and invasion. Actin bundles are the main constituent of actin-rich structures involved in these processes. An ever-increasing number of proteins that crosslink actin into bundles or regulate their morphology is being identified in cells. With recent advances in high-resolution microscopy and imaging techniques, the complex process of bundles formation and the multiple forms of physiological bundles are beginning to be better understood. Here, we review the physiochemical and biological properties of four families of highly conserved and abundant actin-bundling proteins, namely, α-actinin, fimbrin/plastin, fascin, and espin. We describe the similarities and differences between these proteins, their role in the formation of physiological actin bundles, and their properties—both related and unrelated to their bundling abilities. We also review some aspects of the general mechanism of actin bundles formation, which are known from the available information on the activity of the key actin partners involved in this process.

Fascin is an actin-bundling protein overexpressed in various invasive metastatic carcinomas through promoting cell migration and invasion. Therefore, blocking Fascin binding sites is considered a vital target for antimetastatic drugs. This inspired us to find new Fascin binding site blockers. First, we built an active compound set by collecting reported small molecules binding to Fascin’s binding site 2. Consequently, a high-quality decoys set was generated employing DEKOIS 2.0 protocol to be applied in conducting the benchmarking analysis against the selected Fascin structures. Four docking programs, MOE, AutoDock Vina, VinaXB, and PLANTS were evaluated in the benchmarking study. All tools indicated better-than-random performance reflected by their pROC-AUC values against the Fascin crystal structure (PDB: ID 6I18). Interestingly, PLANTS exhibited the best screening performance and recognized potent actives at early enrichment. Accordingly, PLANTS was utilized in the prospective virtual screening effort for repurposing FDA-approved drugs (DrugBank database) and natural products (NANPDB). Further assessment via molecular dynamics simulations for 100 ns endorsed Remdesivir (DrugBank) and NANPDB3 (NANPDB) as potential binders to Fascin binding site 2. In conclusion, this study delivers a model for implementing a customized DEKOIS 2.0 benchmark set to enhance the VS success rate against new potential targets for cancer therapies.

This study focuses on the assessment of fascin expression in the small intestinal tissue of rats orally administered a food additive E407a (processed Eucheuma seaweed), which is widely used to improve the texture of food products. The issue of its safety is under debate nowadays. Small intestinal expression of fascin, an actin-bundling cytoskeletal protein involved in the formation of filopodia and microspikes, was evaluated immunohistochemically in 9 rats exposed to 140 mg of E407a per kg of weight daily during two weeks and 8 control animals. Fascin was found to be upregulated both in the lamina propria and epithelia of the small intestine in rats administered processed Eucheuma seaweed compared with the control group. Thus, oral consumption of E407a is associated with overexpression of fascin in the small intestine of rats.

The actin cytoskeleton governs the dynamic functions of cells, ranging from motility to phagocytosis and cell division. To elucidate the molecular mechanism, in vitro reconstructions of the actin cytoskeleton and its force generation process have played essential roles, highlighting the importance of efficient purification methods for actin-binding proteins. In this study, we introduce a unified purification method for actin-binding proteins, including capping protein (CP), cofilin, ADF, profilin, fascin, and VASP, key regulators in force generation of the actin cytoskeleton. Exploiting a His-Strep-tag combined with a TEV protease cleavage site, we purified these diverse actin-binding proteins through a simple two-column purification process: initial purification through a Strep-Tactin column and subsequent tag removal through the reverse purification by a Ni-NTA column. Biochemical and microscopic assays validated the functionality of the purified proteins, demonstrating the versatility of the approach. Our methods not only delineate critical steps for the efficient preparation of actin-binding proteins but also hold the potential to advance investigations of mutants, isoforms, various source species, and engineered proteins involved in actin cytoskeletal dynamics.•Unified purification method for various actin-binding proteins.•His-Strep-tag and TEV protease cleavage for efficient purification.•Functional validation through biochemical and microscopic assays., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

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 the expression was 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 was 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., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Kulkarni S et al.)

During mouse oocyte meiotic maturation, actin filaments play multiple roles in meiosis such as spindle migration and cytokinesis. FASCIN is shown to be an actin‐binding and bundling protein, making actin filaments tightly packed and parallel‐aligned, and FASCIN is involved in several cellular processes like adhesion and migration. FASCIN is also a potential prognostic biomarker and therapeutic target for the treatment of metastatic disease. However, little is known about the functions of FASCIN in oocyte meiosis. In the present study, we knocked down the expression of FASCIN, and our results showed that FASCIN was essential for oocyte maturation. FASCIN was all expressed in the different stages of oocyte meiosis, and it mainly localized at the cortex of oocytes from the GV stage to the MII stage and showed a similar localization pattern with actin and DAAM1. Depletion of FASCIN affected the extrusion of the first polar body, and we also observed that some oocytes extruded from the large polar bodies. This might have resulted from the defects of actin assembly, which further affected the meiotic spindle positioning. In addition, we showed that inhibition of PKC activity decreased FASCIN expression, indicating that FASCIN might be regulated by PKC. Taken together, our results provided evidence for the important role of FASCIN on actin filaments for spindle migration and polar body extrusion in mouse oocyte meiosis. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies. Increasing evidence revealed that long noncoding RNAs (lncRNAs) were frequently involved in various malignancies. Here, we explored the clinical significances, roles, and mechanisms of lncRNA ADORA2A antisense RNA 1 (ADORA2A-AS1) in HCC. Methods: The clinical significances of ADORA2A-AS1 in HCC were analyzed using RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) project. The expressions of ADORA2A-AS1, Fascin Actin-Bundling Protein 1 (FSCN1), Matrix Metallopeptidase 2 (MMP2), and Baculoviral IAP Repeat Containing 7 (BIRC7) in HCC tissues and cells were measured by qRT-PCR. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), caspase-3 activity assay, transwell migration and invasion assays, and xenograft growth and metastasis experiments were performed to evaluate the roles of ADORA2A-AS1 in HCC. RNA pull-down, RNA immunoprecipitation, qRT-PCR, Western blot, and RNA stability assay were performed to elucidate the mechanisms of ADORA2A-AS1 in HCC. Results: ADORA2A-AS1 was identified as an HCC-related lncRNA, whose low expression was correlated with advanced stage and poor outcome in HCC. Gain- and loss-of functional experiments demonstrated that ADORA2A-AS1 inhibited HCC cell proliferation, induced cell apoptosis, repressed cell migration and invasion, and repressed xenograft growth and metastasis in vivo. Mechanistically, ADORA2A-AS1 competitively bound HuR (Hu Antigen R), repressed the binding of HuR to FSCN1 transcript, decreased FSCN1 transcript stability, and downregulated FSCN1 expression. The expression of FSCN1 was negatively correlated with ADORA2A-AS1 in HCC tissues. Through downregulating FSCN1, ADORA2A-AS1 repressed AKT pathway activation. Functional rescue assays showed that blocking of FSCN1/AKT axis abrogated the roles of ADORA2A-AS1 in HCC. Conclusion: Low-expression ADORA2A-AS1 is correlated with poor survival of HCC patients. ADORA2A-AS1 exerts tumor-suppressive roles in HCC via binding HuR and repressing FSCN1/AKT axis. [ABSTRACT FROM AUTHOR]