FSCN1 Expression Research Articles

Ginsenoside Rb2 inhibits p300-mediated SF3A2 acetylation at lysine 10 to promote Fscn1 alternative splicing against myocardial ischemic/reperfusion injury

IntroductionGinsenosides (GS) derived from Panax ginseng can regulate protein acetylation to promote mitochondrial function for protecting cardiomyocytes. However, the potential mechanisms of GS for regulating acetylation modification are not yet clear. ObjectivesThis study aimed to explore the potential mechanisms of GS in regulating protein acetylation and identify ginsenoside monomer for fighting myocardial ischemia-related diseases. MethodsThe 4D-lable free acetylomic analysis was employed to gain the acetylated proteins regulated by GS pretreatment. The co-immunoprecipitation assay, immunofluorescent staining, and mitochondrial respiration measurement were performed to detect the effect of GS or ginsenoside monomer on acetylated protein level and mitochondrial function. RNA sequencing, site-specific mutation, and shRNA interference were used to explore the downstream targets of acetylation modificationby GS. Cellular thermal shift assay and surface plasmon resonance were used for identifying the binding of ginsenoside with target protein. ResultsIn the cardiomyocytes of normal, oxygen glucose deprivation and/or reperfusion conditions, the acetylomic analysis identified that the acetylated levels of spliceosome proteins were inhibited by GS pretreatment and SF3A2 acetylation at lysine 10 (K10) was significantly decreased as a potential target of GS. Ginsenoside Rb2 was identified as one of the active ginsenoside monomers for reducing the acetylation of SF3A2 (K10), which enhanced mitochondrial respiration against myocardial ischemic injury in in vivo and in vitro experiments. RNA-seq analysis showed that ginsenoside Rb2 promoted alternative splicing of mitochondrial function-related genes and the level of fascin actin-bundling protein 1 (Fscn1) was obviously upregulated, which was dependent on SF3A2 acetylation. Critically, thermodynamic, kinetic and enzymatic experiments demonstrated that ginsenoside Rb2 directly interacted with p300 for inhibiting its activity. ConclusionThese findings provide a novel mechanism underlying cardiomyocyte protection of ginsenoside Rb2 by inhibiting p300-mediated SF3A2 acteylation for promoting Fscn1 expression, which might be a promising approach for the prevention and treatment of myocardial ischemic diseases.

FSCN1 has a potential indication for the prognosis and regulates the migration of HNSCC.

The study of molecular markers for diagnosis and prognosis is of great clinical significance for HNSCC patients. In this study, we proposed that FSCN1 has a potential indication for prognosis and is essential for the migration of HNSCC. We analyzed the expression and survival association of FSCN1 in HNSCC using TCGA data. We compared the expression of FSCN1 in tumors from primary and metastasis HNSCC patients using QPCR, western blotting, and immunochemistry staining. We determined the migration velocity of multiple HNSCC cell lines using a chemotaxis migration assay. We analyzed the correlation between FSCN1 expression and HNSCC cell migration. We also test the effect of FSCN1 knockdown and overexpression on HNSCC cell migration. FSCN1 was overexpressed in HNSCC than pair normal tissues and metastasis HNSCC than primary HNSCC. FSCN1 expression was associated with significantly poorer overall survival of HNSCC patients. FSCN1 was potentially associated with immune cell infiltration and migration-associated genes. FSCN1 level was correlated with the migration in HNSCC cell lines. Knockdown of FSCN1 reduced the migration and the overexpression of FSCN1 promoted the migration of HNSCC cell lines. FSCN1 is a potential prognostic marker and a critical biomolecule for the migration of HNSCC.

FSCN1 and epithelial mesenchymal transformation transcription factor expression in human pancreatic intraepithelial neoplasia and ductal adenocarcinoma

BackgroundThe actin regulatory protein fascin (FSCN1) and epithelial mesenchymal transition (EMT) transcription factor (TF) SLUG/SNAI2 have been shown to be expressed in PDAC and its precursor lesions (pancreatic intraepithelial neoplasia (PanIN), graded 1–3) in in vitro and murine in vivo studies. Our aim was to investigate the expression of FSCN1 and EMT-TFs and their association with survival in human PanIN and PDAC. MethodsExpression was investigated in silico using TCGA PanCancer Atlas data (177 PDAC samples with mRNA data) and immunohistochemical staining of a tissue microarray (TMA) (59 PDAC patients). ResultsHigh FSCN1 expression was associated with poorer overall survival (p = 0.02) in the TCGA data. EMT-TF expression was not associated with survival, however FSCN1 expression correlated with that of the EMT-TFs SLUG/SNAI2 (rho = 0.49, p < 0.001) and TWIST1 (rho = 0.52, p < 0.001). TMA IHC showed low expression of SNAI2 and TWIST1 in normal ductal epithelium, while FSCN1 was not expressed. SNAI2 increased slightly in PanIN1–2, then decreased in higher grade lesions. TWIST1 increased in PanIN2–3 and was retained in PDAC. FSCN1 was increasingly expressed from PanIN2 onwards. SNAI2 and TWIST1 expression positively correlated in all grades of PanIN and PDAC (rho = 0.52, p < 0.001). FSCN1 correlated positively with SNAI2 in PanIN1 (rho = 0.56, p < 0.01). ConclusionsIncreased expression of EMT-TFs in low-grade PanIN followed by FSCN1 in PanIN3 and PDAC suggests EMT-TFs may trigger FSCN1 expression and are potential early diagnostic markers. FSCN1 expression correlated with overall survival in PDAC and may have value as a prognostic marker.

Screening and validation of differentially expressed genes in adipose tissue of patients with obesity and type 2 diabetes mellitus.

White adipose tissue (WAT) plays a pivotal role in the onset of type 2 diabetes mellitus (T2DM) and obesity. Despite its significance the underlying pathogenesis and key genes associated with it remain elusive. In our study, we screened the differentially expressed genes (DEGs) in intra-abdominal WAT of T2DM patients with obesity, as well as those with simple obesity, aiming to lay a foundational theory for an in-depth investigation of T2DM pathogenesis and the identification of novel therapeutic targets. Gene expression datasets (GSE16415 and GSE71416) were retrieved from the Gene Expression Omnibus (GEO) database. We employed R for screening DEGs and conducted a functional enrichment analysis using the Metascape database. Combined Lasso regression and Boruta feature selection algorithms were used to identify key DEGs. Subsequently, these were cross-verified using the GSE29231 dataset. Samples and medical records were collected from clinical study participants. The mRNA and protein expressions of the key DEGs were verified using qRT-PCR and western blotting, respectively. We discerned a total of 130 DEGs, with 40 being upregulated and 90 downregulated. Functional and pathway enrichment analyses illuminated that these genes are instrumental in mediating metabolite and energy production, neutrophil-mediated immunity, and other associated biological processes. This includes their involvement in the tricarboxylic acid cycle, glycolysis/gluconeogenesis, peroxisome proliferator-activated receptors, and other signalling pathways. Two genes, CIDEA and FSCN1 emerged as key DEGs. The low expression of CIDEA and high expression of FSCN1 in the T2DM and obesity group were verified in clinical samples (P < 0.05). We established that CIDEA and FSCN1 manifest significant differential expression in T2DM patients who are obese. This suggests their potential as risk assessment markers and therapeutic targets for T2DM.

Comprehensive analysis of the expression, prognosis and biological significance of FSCN family in clear cell renal cell carcinoma.

Fascin (FSCN) is an actin-binding protein that serves a critical role in cell migration and invasion, contributing to tumor metastasis. However, there is little known about the function of FSCN family in kidney renal clear cell carcinoma (KIRC). The present study used the UALCAN, gene expression profiling interactive analysis, The Cancer Genome Atlas, cBioPortal, STRING and The Tumor Immune Estimation Resource databases to investigate the transcription level, genetic alteration and biological function of FSCNs in KIRC and their association with the prognosis value and immune cell infiltration in patients with KIRC. Results showed that the expression of FSCN1 and FSCN3 was markedly upregulated in patients with KIRC, while the expression of FSCN2 showed an opposite trend, which was the same as the experiments. Furthermore, the expression levels of FSCNs were associated with pathological stage, molecular subtypes and tumor grade. The expression levels of FSCNs were statistically correlated with the immune cell infiltration in KIRC. Higher expression levels of FSCN1 and FSCN3 were associated with worse overall survival (OS) and progression-free interval of patients bearing KIRC. Univariate and multivariate analysis demonstrated that FSCN2 was an independent risk factor for OS time in KIRC. Furthermore, mutations in FSCNs were significantly associated with poor OS and progression-free survival in patients with KIRC. The FSCNs were involved in pathways including focal adhesion, endocytosis, hypertrophic cardiomyopathy, regulation of actin cytoskeleton. The results indicated that FSCN2 might serve as an independent prognostic factor for OS of KIRC and that FSCN1 and FSCN3 can be used as favorable biomarkers for predicting clinical outcomes in KIRC.

LncRNA PTOV1-AS2 Promotes Colon Cancer Progression through the miR-145-5p/FSCN1 Axis.

The long noncoding RNA (lncRNA) gene PTOV1-AS2 is a potentially oncogenic lncRNA gene. However, its role and regulatory mechanism in the occurrence and development of colon cancer are still unclear. In this study, the lncRNA PTOV1-AS2 was used as a starting point to investigate the role of competing endogenous RNA (ceRNA) regulatory mechanisms in colon cancer. The expression of lncRNA PTOV1-AS2 mRNA in colon cancer tissues and cell lines was measured by quantitative real-time polymerase chain reaction (qRT-PCR) and screened for differential expression in cells. We examined the effects of lncRNA PTOV1-AS2 overexpression or downregulation of its expression on various cellular processes in HCT116 and SW620 cells after the transfection with an overexpression construct or PTOV1-AS2p-specific shRNA, respectively. In particular, we examined the effects on cell proliferation, migration, and invasion using the cell counting kit-8 CCK-8 assay and Transwell migration and invasion assays, respectively. In addition, the binding targets of lncRNA PTOV1-AS2/miR-145-5p and miR-145-5p/FSCN1 were predicted using various bioinformatics tools and validated by a dual luciferase assay. We also examined the effect of the lncRNA PTOV1-AS2/miR-145-5p axis on FSCN1 expression by qRT-PCR analysis. Furthermore, we investigated the effect of the PTOV1-AS2/miR-145-5p/FSCN1 axis on the biological function of colon cancer cells using an in vitro colon cancer cell model with reduced expression of PTOV1-AS2 and simultaneous transfection of a miR-145-5p inhibitor or FSCN1 vector. Additionally, we established a colon cancer xenograft tumor nude mouse model and used it to investigate the effect of locally injected lncRNA PTOV1-AS2 vector on the tumor growth and survival status of tumor-bearing mice. We found that PTOV1-AS2 was highly expressed in colon cancer, which was associated with worse survival. High expression of PTOV1-AS2 promoted cell proliferation, migration, and invasion, while low expression of PTOV1-AS2 inhibited these processes in HCT116 and SW620 cells. The microRNA miR-145-5p was found to bind to the 3'-UTR region of both PTOV1-AS2 and FSCN1. In addition, miR-145-5p decreased the protein expression of its target gene FSCN1 and reduced the PTOV1-AS2-induced expression of FSCN1 in colon cancer cell lines. Also, silencing miR-145-5p or enhancing FSCN1 expression could partially restore the inhibition of cell proliferation, migration, invasion, and the tumorigenic capacity caused by silencing the expression of PTOV1-AS2 in vitro and in vivo. PTOV1-AS2 promotes colon cancer progression by "sponging" miR-145-5p to upregulate FSCN1.

Inhibitors of the Actin-Bundling Protein Fascin-1 Developed for Tumor Therapy Attenuate the T-Cell Stimulatory Properties of Dendritic Cells.

Simple SummaryExpression of the actin-bundling protein Fascin-1 (Fscn1) is largely restricted to neuronal cells and to activated dendritic cells (DCs). DCs are important inducers of (antitumor) immune responses. In tumor cells, de novo expression of Fscn-1 correlates with their invasive and metastatic activities. Pharmacological Fscn1 inhibitors, which are currently under clinical trials for tumor therapy, were demonstrated to counteract tumor metastasis. Within this study, we were interested in better understanding the effects of Fscn1 inhibitors on DCs and discovered that two distinct Fascin-1 inhibitors affect the immune-phenotype and T-cell stimulatory activity of DCs. Our results suggest that systemic application of Fscn1 inhibitors for tumor therapy may also modulate antitumor immune responses.Background: Stimulated dendritic cells (DCs), which constitute the most potent population of antigen-presenting cells (APCs), express the actin-bundling protein Fascin-1 (Fscn1). In tumor cells, de novo expression of Fscn1 correlates with their invasive and metastatic properties. Therefore, Fscn1 inhibitors have been developed to serve as antitumor agents. In this study, we were interested in better understanding the impact of Fscn1 inhibitors on DCs. Methods: In parallel settings, murine spleen cells and bone-marrow-derived DCs (BMDCs) were stimulated with lipopolysaccharide in the presence of Fscn1 inhibitors (NP-G2-044 and BDP-13176). An analysis of surface expression of costimulatory and coinhibitory receptors, as well as cytokine production, was performed by flow cytometry. Cytoskeletal alterations were assessed by confocal microscopy. The effects on the interactions of BMDCs with antigen-specific T cells were monitored by time lapse microscopy. The T-cell stimulatory and polarizing capacity of BMDCs were measured in proliferation assays and cytokine studies. Results: Administration of Fscn1 inhibitors diminished Fscn1 expression and the formation of dendritic processes by stimulated BMDCs and elevated CD273 (PD-L2) expression. Fscn1 inhibition attenuated the interaction of DCs with antigen-specific T cells and concomitant T-cell proliferation. Conclusions: Systemic administration of Fscn1 inhibitors for tumor therapy may also modulate DC-induced antitumor immune responses.

MicroRNA-133 suppresses cell viability and migration of rheumatoid arthritis fibroblast-like synoviocytes by down-regulation of MET, EGFR, and FSCN1 expression.

Aberrant proliferation and migration of fibroblast-like synoviocytes (FLS) are major characteristics of rheumatoid arthritis (RA). MicroRNA-133 (miR-133) is a tumor-suppressive miRNA that targets various genes responsive for cell proliferation and migration. The aim of this study was to examine the effect of miR-133 on RA FLS. A high throughput miRNA microarray was performed in synovium from mice with collagen-induced arthritis (CIA). Expression levels of miR-133 and the putative targets were determined in synovium and FLS from patients with RA and mice with CIA. Overexpression of miR-133 in RA FLS was performed by lentiviral vector-mediated transfer of precursor miRNA (pre-miR). The expression of miR-133a/b was decreased in the joint tissue and FLS of CIA mice, as determined by miRNA array and qRT-PCR. Down-regulation of miR-133a/b expression could also be observed in synovium and FLS from patients with RA. Overexpression of miR-133 reduced cell viability and migration of RA FLS, with decreased levels of FSCN1, EGFR, and MET. Our findings demonstrated the inhibitory effects of miR-133 on FLS viability and migration, and might contribute to the pharmacologic development of miR-133 therapeutics in patients with RA.

Functional analysis of the miR-145/Fascin1 cascade in canine oral squamous cell carcinoma.

Canine oral squamous cell carcinoma (SCC) often develops in the gingiva and tonsils. The biological behavior of canine oral SCC is similar to that of human head and neck SCC (HNSCC). Inhibiting invasion and metastasis is major importance for the treatment of canine and human HNSCC. In this study, the significance of microRNA (miR)-145 and Fascin1 (FSCN1) in the invasion of canine oral SCC was explored. Canine oral SCC tissues and cell lines were used for miR-145 and FSCN1 expression analysis via real-time PCR and immunohistochemistry. Canine oral SCC cell lines were used for in vitro assays. miR-145 was downregulated while FSCN1mRNA was upregulated in canine oral SCC. Immunohistochemistry revealed that FSCN1 was upregulated in SCC when compared to normal mucosa. Transfection of canine SCC cells with miR-145 or FSCN1siRNA suppressed cell growth and attenuated cell migration as well as invasion by inhibiting the epithelial-to-mesenchymal transition. Furthermore, the promoter region of miR-145 was highly methylated in SCC cell lines and tissues. The expression profile and functions of miR-145 in canine oral SCC are similar to those in human HNSCC. Thus, canine oral SCC may represent a valuable preclinical model for human HNSCC.

TKI resistant-based prognostic immune related gene signature in LUAD, in which FSCN1 contributes to tumor progression

Drug resistance reflects the evolution of tumors, which is the main cause of recurrence and death. Currently, EGFR-TKI treatment is the first-line therapy for lung adenocarcinoma (LUAD) patients. Although EGFR-TKI achieved good effects at the beginning, most of the LUAD patients eventually acquired resistance. Therefore, it's urgently need to develop a strong criterion for identifying these patients who may benefit from additional therapy. In this study, we established a three TKI resistant-related gene signature (DDIT4, OAS3, FSCN1), and determined that's an accuracy, independent and specific prognostic model for LUAD patients. Patients categorized as high-risk by this signature showed more sensitive to chemotherapy, and exhibited higher expression of common immune checkpoints such as PD-L1/B7H3/PD-L2/IDO1. Moreover, these patients were characterized by increased infiltration of M0 macrophage and activated memory CD4+ T cells. The expression and prognostic values of DDIT4, FSCN1 and OAS3 were further confirmed in clinical data. In addition, experimental data showed that FSCN1 promoted LUAD development via PI3K/AKT signaling. In conclusion, this signature is highly predictive of prognostic in LUAD patients, and may serve as a powerful prediction tool for LUAD patients to further choose chemo- and immunotherapies.

MicroRNA-133 Suppresses Cell Viability and Migration of Fibroblast-Like Synoviocytes by Down-Regulation of MET, EGFR, and FSCN1 Expression

MicroRNA-133 Suppresses Cell Viability and Migration of Fibroblast-Like Synoviocytes by Down-Regulation of MET, EGFR, and FSCN1 Expression

ASXL1 promotes adrenocortical carcinoma and is associated with chemoresistance to EDP regimen.

Adrenocortical carcinoma (ACC) is a rare but aggressive disease that lacks definitive treatment. We aim to evaluate role of ASXL1 in ACC and exploit its therapeutic merits therein. We performed in silico reproduction of datasets of the Cancer Genome Atlas (TCGA), GDSC (Genomics of Drug Sensitivity in Cancer) and Human Protein Atlas using platforms of cBioPortal, UALCAN, NET-GE, GSEA and GEPIA. Validation in ACC was performed in tissue, in vitro and in vivo using the NCI-H295R and SW-13 cells. ASXL1 was gained in over 50% of ACC cases with its mRNA overexpressed in DNA gained cases. ASXL1 overexpression was associated with recurrence and worsened prognosis in ACC. ASXL1 gain was associated with resistance to etoposide, doxorubicin and cisplatin (EDP). ASXL1 expression was positively correlated with FSCN1 expression. Targeting ASXL1 significantly impaired fitness of ACC cells, which could be in part rescued by FSCN1 overexpression. Targeting FSCN1 however could not rescue resistance to EDP induced by ASXL1 overexpression. Targeting ASXL1 sensitized ACC cells to EDP regimen but constitutive ASXL3 overexpression in SW-13 cells could induce resistance upon prolonged treatment. Functional gain of ASXL1 was common in ACC and exerted pro-tumorigenic and chemoresistance role. Targeting ASXL1 hold promise to ACC treatment.

LncRNA LOC146880 promotes esophageal squamous cell carcinoma progression via miR-328-5p/FSCN1/MAPK axis.

We investigated the role of long non-coding RNA (lncRNA) LOC146880 in esophageal squamous cell carcinoma (ESCC). LOC146880 was significantly upregulated in ESCC tissues (n = 21) and cell lines compared to the corresponding controls. Higher LOC146880 expression correlated with poorer overall survival (OS) of ESCC patients. Moreover, CREB-binding protein (CBP) and H3K27 acetylation levels were significantly higher in the LOC146880 promoter in ESCC cell lines than in the controls. LOC146880 silencing inhibited in vitro proliferation, invasion, migration, and epithelial-mesenchymal transition of ESCC cells. LOC146880 silencing also induced G1-phase cell cycle arrest and apoptosis in ESCC cells. Bioinformatics analysis, dual luciferase reporter assays, and RNA immunoprecipitation assays showed that LOC146880 regulates FSCN1 expression in ESCC cells by sponging miR-328-5p. Moreover, FSCN1 expression correlated with activation of the MAPK signaling pathway in ESCC cells and tissues. In vivo xenograft tumor volume and liver metastasis were significantly reduced in nude mice injected with LOC146880-silenced ESCC cells as compared to those injected with control shRNA-transfected ESCC cells. These findings show that the LOC146880/miR-328-5p/FSCN1/MAPK axis regulates ESCC progression in vitro and in vivo. LOC146880 is thus a promising prognostic biomarker and potential therapeutic target in ESCC.

CircPTPRA blocks the recognition of RNA N6-methyladenosine through interacting with IGF2BP1 to suppress bladder cancer progression

BackgroundCircular RNAs (circRNAs) have been found to have significant impacts on bladder cancer (BC) progression through various mechanisms. In this study, we aimed to identify novel circRNAs that regulate the function of IGF2BP1, a key m6A reader, and explore the regulatory mechanisms and clinical significances in BC.MethodsFirstly, the clinical role of IGF2BP1 in BC was studied. Then, RNA immunoprecipitation sequencing (RIP-seq) analysis was performed to identify the circRNAs interacted with IGF2BP1 in BC cells. The overall biological roles of IGF2BP1 and the candidate circPTPRA were investigated in both BC cell lines and animal xenograft studies. Subsequently, we evaluated the regulation effects of circPTPRA on IGF2BP1 and screened out its target genes through RNA sequencing. Finally, we explored the underlying molecular mechanisms that circPTPRA might act as a blocker in recognition of m6A.ResultsWe demonstrated that IGF2BP1 was predominantly binded with circPTPRA in the cytoplasm in BC cells. Ectopic expression of circPTPRA abolished the promotion of cell proliferation, migration and invasion of BC cells induced by IGF2BP1. Importantly, circPTPRA downregulated IGF2BP1-regulation of MYC and FSCN1 expression via interacting with IGF2BP1. Moreover, the recognition of m6A-modified RNAs mediated by IGF2BP1 was partly disturbed by circPTPRA through its interaction with KH domains of IGF2BP1.ConclusionsThis study identifies exonic circular circPTPRA as a new tumor suppressor that inhibits cancer progression through endogenous blocking the recognition of IGF2BP1 to m6A-modified RNAs, indicating that circPTPRA may serve as an exploitable therapeutic target for patients with BC.

LncRNA PRNCR1 aggravates the malignancy of oral squamous cell carcinoma by regulating miR-326/FSCN1 axis.

The important regulatory mechanism of lncRNA PRNCR1 has been emphasized in malignant tumors. However, the role of lncRNA PRNCR1 remains unclear in oral squamous cell carcinoma (OSCC). The purpose of this study is to reveal the role of lncRNA PRNCR1 in OSCC. RT-qPCR was used to detect mRNA expression. The functional mechanism of lncRNA PRNCR1 in OSCC was investigated by CCK-8, transwell and Luciferase reporter assays. LncRNA PRNCR1 was upregulated in OSCC and promoted cell proliferation, migration and invasion. LncRNA PRNCR1 directly binds to miR-326. The mutual inhibition between the expressions of lncRNA PRNCR1 and miR-326 was identified in OSCC. In addition, miR-326 restrained cell proliferation, migration and invasion in OSCC. Further, miR-326 directly targets FSCN1. FSCN1 expression was positively regulated by lncRNA PRNCR1 in OSCC. And FSCN1 promoted the progression of OSCC and aggravated the carcinogenic effect of lncRNA PRNCR1 in OSCC. LncRNA PRNCR1 promotes the progression of OSCC by functioning as a miR-326 'sponge' to upregulate FSCN1 expression.

Effect of rs67085638 in long non‐coding RNA (CCAT1) on colon cancer chemoresistance to paclitaxel through modulating the microRNA‐24‐3p and FSCN1

It has been reported that rs67085638 in long non‐coding RNAs (lncRNA)‐CCAT1 was associated with the risk of tumorigenesis. Also, CCAT1 could affect chemoresistance of cancer cells to paclitaxel (PTX) via regulating miR‐24‐3p and FSCN1 expression. In this study, we aimed to investigate the effect of rs67085638 on the expression of CCAT1/miR‐24‐3p/FSCN1 and the response of colon cancer to the treatment of PTX. 48 colon cancer patients were recruited and grouped by their genotypes of rs67085638 polymorphism as a CC group (N = 28) and a CT group (N = 20). PCR analysis, IHC assay and Western blot, TUNEL assay and flow cytometry were conducted. LncRNA‐CCAT1 and FSCN1 mRNA/protein were overexpressed, whereas miR‐24‐3p was down‐regulated in the CT‐genotyped patients and cells compared with those in the CC‐genotyped patients and cells. The survival of colon cancer cells was decreased, whereas the apoptosis of colon cancer cells was increased by PTX treatment in a dose‐dependent manner. MiR‐24‐3p was validated to target lncRNA‐CCAT1 and FSCN1 mRNA, and the overexpression of CCAT1 could reduce the expression of miR‐24‐3p although elevating the expression of FSCN1. Knockdown of lncRNA‐CCAT1 partly reversed the suppressed growth of CT‐genotyped tumours. And the knockdown of lncRNA‐CCAT1 partly reversed the dysregulation of lncRNA‐CCAT1 and FSCN1 mRNA/protein in rs67085638‐CT + NC shRNA mice. The findings of this study demonstrated that the presence of the minor allele of rs67085638 increased the expression of CCAT1 and accordingly enhanced the resistance to PTX. Down‐regulation of CCAT1 significantly re‐stored the sensitivity to PTX of colon cancer cells.

WITHDRAWN: Exosomes from microRNA-145-5p-modified HUCB-MSCs attenuate CCl4-induced hepatic fibrosis via down-regulating FSCN1 expression

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Prognostic significance of FSCN family in multiple myeloma.

Multiple myeloma (MM) is a hematologic tumor with monoclonal proliferation of malignant plasma cells in the bone marrow. Fascin (FSCN) is an actin-binding protein that plays a crucial role in cell migration and invasion, contributing to tumor metastasis. There are three members (FSCN1-3) in FSCN family. However, the prognostic role of FSCN family in MM remains unclear. In this study, we used four independent Gene Expression Omnibus (GEO) datasets to explore the relationships between FSCN1-3 expression profiles and patient survival in MM. We found that FSCN1 was dramatically down-regulated in MM compared to normal donors (p < 0.001) and monoclonal gammopathy of undetermined significance (MGUS) (p = 0.032). Patients with high expression of FSCN1 and FSCN2 had significantly longer OS (p = 0.023 and 0.028, respectively). Univariate and multivariate analysis showed that FSCN1 (p = 0.003, 0.002) and FSCN2 (p = 0.018, 0.013) were independent favorable prognostic factors for OS in MM. Moreover, the combination of high expression of FSCN1 and FSCN2 could effectively predict both longer EFS (p = 0.046) and OS (p = 0.015). Our study suggested that FSCN1 and FSCN2 can be used as favorable biomarkers for predicting clinical outcomes in MM.

Long intergenic non-coding RNA 00337 confers progression of esophageal cancer by mediating microrna-145-dependent fscn1.

Long non-coding RNAs (lncRNAs) have been highlighted as prominent genetic modulators involved in multiple important biological processes of cancer cells, especially in esophageal cancer (EC). We tried to elucidate the potential role of LINC00337 in the progression of EC. Based on TCGA database analysis and Reverse transcription quantitative polymerase chain reaction determination, high expression of LINC00337 and FSCN1 was detected, while miR-145 exhibited a low expression in EC. LINC00337 was identified to bind to miR-145 to impair the miR-145-dependent FSCN1 inhibition. The underlying regulatory mechanisms were evaluated by transfection with LINC00337 overexpression plasmid, siRNA against LINC00337, miR-145 mimic, or anta-miR-145. Downregulation of LINC00337 results in increased Bax level, decreased FSCN1, Bcl-2, VEGF, and p53 levels, in addition to diminished cell proliferation, migration, invasion and tumor growth, with accelerated cell apoptosis by upregulating miR-145. Taken together, the findings obtained provided evidence suggesting that LINC00337 acts as a tumor promoter in EC, providing insight and advancements for EC treatment.

SOX2 Promotes Brain Metastasis of Breast Cancer by Upregulating the Expression of FSCN1 and HBEGF

The prognosis of breast cancer brain metastasis (BCBM) is extremely poor due to its resistance to conventional therapy. Elucidation of the molecular mechanisms of BCBM could contribute to the development of new therapeutic targets. In this study, we isolated RNA samples from primary breast cancer or BCBM, and then performed mRNA profiling. We determined that SOX2 is associated with the occurrence of BCBM and could be a predictor of BCBM. High levels of SOX2 were significantly associated with decreasing BCBM-free survival in patients. Overexpression of SOX2 in breast cancer cells enhanced cancer cell adhesion to brain microvascular endothelial cells, transendothelial migration, and in vitro blood-brain barrier (BBB) migration, whereas silencing SOX2 inhibited these events. SOX2 can increase cancer cell migration and BBB permeability by upregulating FSCN1 and HBEGF, thereby promoting BBB migration of breast cancer cells. Moreover, high levels of FSCN1 and HBEGF were significantly associated with reducing BCBM-free survival in breast cancer patients. Further study indicated that SOX2 mediates the expression of HBEGF and FSCN1 by activating AKT and β-catenin signaling pathways. Additionally, in vivo experiments showed that SOX2 promotes the development of BCBM. This study demonstrated that SOX2 promotes BCBM by upregulating the expression of FSCN1 and HBEGF.