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Embryo implantation is a tightly regulated process, critical for a successful pregnancy. After attachment of the blastocyst to the surface epithelium of the endometrium trophoblast migrate from the trophectoderm and invade into the stromal component of endometrium. Alterations on either process will lead to implantation failure or miscarriage. Volatile organic compounds (VOCs) such as benzene induce pregnancy complications, including preterm birth and miscarriages. The mechanism of this effect is unknown. The objective of this study was to elucidate the impact of benzene metabolite, Hydroquinone, on trophoblast function. We tested the hypothesis that Hydroquinone activates the Aryl hydrocarbon receptor (AhR) pathway modulating trophoblast migration and invasion. First-trimester trophoblast cells (Sw.71) were treated with hydroquinone (6 and 25 μM). Trophoblast migration and invasion was evaluated using a 3D invasion/migration model. Gene expression was quantified by q-PCR and Western blot analysis. Hydroquinone impairs trophoblast migration and invasion. This loss is associated with the activation of the AhR pathway which reduced the expression of Twist1and IFITM1. IFITM1 overexpression can rescue impaired trophoblast migration. Our study highlights that hydroquinone treatment induces the activation of the AhR pathway in trophoblast cells, which impairs trophoblast invasion and migration. We postulate that activation of the AhR pathway in trophoblast suppress Twist1 and a subsequent IFITM1. Thus, the AhR-Twist1-IFITM1 axis represent a critical pathway involved in the regulation of trophoblast migration and it is sensitive to benzene exposure. These findings provide crucial insights into the molecular mechanisms underlying pregnancy complications induced by air pollution. [Display omitted] • Benzene exposure affects pregnancy outcome. • Hydroquinone treatment inhibits trophoblast migration and invasion. • The AhR pathway is functional in trophoblast cells. • Hydroquinone activates the Ahr pathway in trophoblast. • Twist1 and IFITM1 are major regulators of trophoblast migration. [ABSTRACT FROM AUTHOR]

Platinum-based chemotherapies, historically the cornerstone of first-line treatment for small-cell lung cancer (SCLC), face a major hurdle: the frequent emergence of chemoresistance, notably to cisplatin (CDDP). Current understanding of the mechanisms driving CDDP resistance in SCLC is incomplete. Notably, Interferon inducible transmembrane protein1 (IFITM1) has been identified as a key player in the distant metastasis of SCLC. Analysis of The Cancer Genome Atlas (TCGA) database revealed that IFITM1 expression is markedly elevated in tumor tissues as compared to that from adjacent normal tissues, correlating with a worse prognosis for patients with SCLC. Our research focused on investigating the role of IFITM1 in the acquisition of cisplatin resistance in SCLC. Further clinical sample analysis highlighted a significant increase in IFITM1 levels in SCLC tissues from cisplatin-resistant patients versus those were responsive to CCDP treatment, with similar trends observed in cisplatin-resistant SCLC cells. Crucially, overexpression of IFITM1 reduced the sensitivity of SCLC cells to cisplatin, while silencing IFITM1 enhanced chemosensitivity in cisplatin-resistant strains. Our in vivo studies further confirmed that silencing IFITM1 significantly boosted the efficacy of cisplatin in inhibiting growth of subcutaneous tumors of NCI–H466/CDDP cells (cisplatin-resistant SCLC cells) in a mouse model. Mechanistically, IFITM1 appears to foster cisplatin resistance through activation of the Wnt/β-catenin pathway. In summary, our findings suggest that targeting IFITM1, alongside cisplatin treatment, could offer a promising therapeutic strategy to overcome resistance and improve outcomes for SCLC patients.

Our previous study revealed that prolonged human rhinovirus (HRV) infection rapidly induces antiviral interferons (IFNs) and chemokines during the acute stage of infection. It also showed that expression levels of RIG-I and interferon-stimulated genes (ISGs) were sustained in tandem with the persistent expression of HRV RNA and HRV proteins at the late stage of the 14-day infection period. Some studies have explored the protective effects of initial acute HRV infection on secondary influenza A virus (IAV) infection. However, the susceptibility of human nasal epithelial cells (hNECs) to re-infection by the same HRV serotype, and to secondary IAV infection following prolonged primary HRV infection, has not been studied in detail. Therefore, the aim of this study was to investigate the effects and underlying mechanisms of HRV persistence on the susceptibility of hNECs against HRV re-infection and secondary IAV infection. We analyzed the viral replication and innate immune responses of hNECs infected with the same HRV serotype A16 and IAV H3N2 at 14 days after initial HRV-A16 infection. Prolonged primary HRV infection significantly diminished the IAV load of secondary H3N2 infection, but not the HRV load of HRV-A16 re-infection. The reduced IAV load of secondary H3N2 infection may be explained by increased baseline expression levels of RIG-I and ISGs, specifically MX1 and IFITM1, which are induced by prolonged primary HRV infection. As is congruent with this finding, in those cells that received early and multi-dose pre-treatment with Rupintrivir (HRV 3C protease inhibitor) prior to secondary IAV infection, the reduction in IAV load was abolished compared to the group without pre-treatment with Rupintrivir. In conclusion, the antiviral state induced from prolonged primary HRV infection mediated by RIG-I and ISGs (including MX1 and IFITM1) can confer a protective innate immune defense mechanism against secondary influenza infection. [ABSTRACT FROM AUTHOR]

Background: During viral infections such as SARS-CoV-2, epigenetic changes within the promoter region of the immune system genes would possibly occur and have an effect on the immune system response as well as disease outcome. We aimed to evaluate and compare the methylation level of the IFITM1 gene promoter in different stages of COVID-19 disease with a healthy control group. Methods: In this cross-sectional study, 75 COVID-19 patients (25 mild, 25 severe, and 25 critical in addition to 25 age- and gender-matched healthy volunteers) have been included. DNA was extracted from the peripheral white blood cells using a commercial DNA extraction kit. PCR was performed using two types of primers designed for the methylated and un-methylated forms of the IFITM1 gene promoter. Results: The mean age of the patient and healthy volunteer groups was 52.733 ± 13.780 and 49.120 ± 12.490, respectively. Out of a hundred participants, 52 were male. The results demonstrated that severe (p = 0.03, OR 6.729) and critical (p = 0.001, OR 11.156) patients were much more likely to show methylation of the IFITM1 gene in contrast with mild patients. Moreover, IFITM1 methylation was significantly higher in COVID-19 patients in comparison with the healthy volunteer group (p = 0.004, OR 3.17). Furthermore, IFITM1 methylation in male patients with critical status, (p = 0.01) was significantly higher than in male patients with mild status. In addition, IFITM1 methylation of male (p = 0.03) and female (p = 0.01) critical patients was considerably higher compared to males and females of volunteer group. Conclusions: Increased methylation of the IFITM1 gene in the severe and critical stage of COVID-19 diseases may indicate the role of SARS-CoV-2 infection in increasing methylation of this antiviral gene. This might be involved in suppressing the immune system, promoting SARS-CoV-2 replication and disease outcome. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the roles of DDR2 and IFITM1 in breast cancer (BC). Methods: The expression of DDR2 and IFITM1 in BC tissues and cell lines was measured. DDR2 and/or IFITM1 were knocked down in BT20 and MDA-MB-231 cells, after which the viability, mobility and apoptosis of the cells were tested. Xenograft mouse models were established through subcutaneous tumor transplantation. Results: DDR2 and IFITM1 were highly expressed in invasive BC tissues and cell lines. Overexpression of DDR2 and/or IFITM1 was associated with poorer clinical outcomes and patient survival. Knockdown of DDR2 or IFITM1 suppressed the viability and invasiveness of BT20 and MDA-MB-231 cells and restrained the growth of xenograft tumors in nude mice. Simultaneous knockdown of IFITM1 and DDR2 surpassed knockdown of IFITM1 alone in suppressing BC development. Conclusions: DDR2 and IFITM1 are co-expressed to facilitate the malignant behaviors of BC cells and promote the development of tumors. [ABSTRACT FROM AUTHOR]

IntroductionProstate adenocarcinoma (PRAD) is a highly aggressive malignancy with high mortality and poor prognosis, and its potential mechanism remains unclear. Our study aimed to identify novel markers for the prognosis of PRAD using bioinformatics technology.MethodsThe GSE32571 dataset was downloaded from the GEO database, and analyzed via the limma R package to identify differentially expressed genes (DEGs) and differentially expressed immune score-related genes (DEISRGs). The immune-related genes (IRGs) were further obtained by overlapping DEISRGs and DEGs, and the core gene was identified via survival analysis. Furthermore, the expression level, prognostic value, and potential functions of the core gene were evaluated via multiple bioinformatics databases.ResultsA total of 301 IRGs were identified from the GSE32571 dataset, and IFITM1 was a down-regulated gene in several types of cancer, including PRAD. Besides, low expression of IFITM1 was associated with a poor prognosis in PRAD. GSEA indicated that the vital pathways of IFITM1-associated genes were mainly enriched in primary immunodeficiency, Th17 cell differentiation, Th1, and Th2 cell differentiation, natural killer cell-mediated cytotoxicity, myeloid dendritic cell activation, regulation of leukocyte activation, etc. Furthermore, IFITM1 was closely correlated with 22 types of tumor-infiltrating immune cells.DiscussionIFITM1 was a prognostic biomarker for PRAD patients, and it can be acted as a potential immune therapy target in PRAD.

Abstract Background The differential diagnosis of endometrial stromal tumor (EST) and uterine cellular leiomyoma (CL) remains a challenge in clinical practice, especially low grade endometrial stromal sarcoma (ESS) and CL, suggesting the need for novel immunomarkers panels for differential diagnosis. Interferon-induced transmembrane protein 1 (IFITM1) is a novel immunomarker for endometrial stromal cells, h-caldesmon is an immunomarker for smooth muscle cells and has a higher specificity than smooth muscle actin (SMA). So this study aimed to evaluate whether IFITM1, cluster of differentiation 10(CD10), SMA, and h-caldesmon are useful biomarker combinations for the differential diagnosis of EST and CL. Methods Tissue microarrays were used to detect IFITM1, CD10, SMA, and h-caldesmon immunohistochemical staining in 30 EST and 33 CL cases. Results The expressions of IFITM1 and CD10 were high in EST (86.7 and 63.3%, respectively) but low in CL (18.2 and 21.2%), whereas those of h-caldesmon and SMA were high in CL (87.9 and 100%) and low in EST (6.9 and 40%). In diagnosing EST, IFITM1 shows better sensitivity and specificity (86.7 and 81.8%, respectively) than CD10 (63.3 and 78.8%). The specificity of h-caldesmon in diagnosing CL was significantly higher (93.1%) than that of SMA (60%). When all four antibodies were combined for the differential diagnosis, the area-under-the-curve (AUC) predictive value was 0.995. The best combination for diagnosing EST was IFITM1 (+) or CD10 (+) and h-caldesmon (−) (sensitivity 86.7%, specificity 93.9%). Conclusion The best combination for diagnosing CL were h-caldesmon (+) and SMA (+) (sensitivity 87.9%, specificity 100%). IFITM1, CD10, SMA, and h-caldesmon are a good combination for the differential diagnosis of EST and CL.

The majority of colorectal cancer (CRC) patients carry mutations in the APC gene, which lead to the unregulated activation of the Wnt pathway. Extracellular vesicles (EV) are considered potential therapeutic tools. Although CRC is a genetically heterogeneous disease, the significance of the intra-tumor heterogeneity in EV uptake of CRC cells is not yet known. By using mouse and patient-derived organoids, the currently available best model of capturing cellular heterogeneity, we found that Apc mutation induced the expression of interferon-induced transmembrane protein 1 (Ifitm1), a membrane protein that plays a major role in cellular antiviral responses. Importantly, organoids derived from IFITM1high CRC cells contained more proliferating cells and they had a markedly reduced uptake of fibroblast EVs as compared to IFITM1low/− cells. In contrast, there was no difference in the intensity of EV release between CRC subpopulations with high and low IFITM1 levels. Importantly, the difference in cell proliferation between these two subpopulations disappeared in the presence of fibroblast-derived EVs, proving the functional relevance of the enhanced EV uptake by IFITM1low CRC cells. Furthermore, inactivating IFITM1 resulted in an enhanced EV uptake, highlighting the importance of this molecule in establishing the cellular difference for EV effects. Collectively, we identified CRC cells with functional difference in their EV uptake ability that must be taken into consideration when using EVs as therapeutic tools for targeting cancer cells. [ABSTRACT FROM AUTHOR]

Background: The differential diagnosis of endometrial stromal tumor (EST) and uterine cellular leiomyoma (CL) remains a challenge in clinical practice, especially low grade endometrial stromal sarcoma (ESS) and CL, suggesting the need for novel immunomarkers panels for differential diagnosis. Interferon-induced transmembrane protein 1 (IFITM1) is a novel immunomarker for endometrial stromal cells, h-caldesmon is an immunomarker for smooth muscle cells and has a higher specificity than smooth muscle actin (SMA). So this study aimed to evaluate whether IFITM1, cluster of differentiation 10(CD10), SMA, and h-caldesmon are useful biomarker combinations for the differential diagnosis of EST and CL.Methods: Tissue microarrays were used to detect IFITM1, CD10, SMA, and h-caldesmon immunohistochemical staining in 30 EST and 33 CL cases.Results: The expressions of IFITM1 and CD10 were high in EST (86.7 and 63.3%, respectively) but low in CL (18.2 and 21.2%), whereas those of h-caldesmon and SMA were high in CL (87.9 and 100%) and low in EST (6.9 and 40%). In diagnosing EST, IFITM1 shows better sensitivity and specificity (86.7 and 81.8%, respectively) than CD10 (63.3 and 78.8%). The specificity of h-caldesmon in diagnosing CL was significantly higher (93.1%) than that of SMA (60%). When all four antibodies were combined for the differential diagnosis, the area-under-the-curve (AUC) predictive value was 0.995. The best combination for diagnosing EST was IFITM1 (+) or CD10 (+) and h-caldesmon (-) (sensitivity 86.7%, specificity 93.9%).Conclusion: The best combination for diagnosing CL were h-caldesmon (+) and SMA (+) (sensitivity 87.9%, specificity 100%). IFITM1, CD10, SMA, and h-caldesmon are a good combination for the differential diagnosis of EST and CL. [ABSTRACT FROM AUTHOR]

Overexpression of interferon induced transmembrane protein-1 (IFITM1) enhances tumor progression in multiple cancers, but its role in triple-negative breast cancer (TNBC) is unknown. Here, we explore the functional significance and regulation of IFITM1 in TNBC and strategies to target its expression. Immunohistochemistry staining of a tissue microarray demonstrates that IFITM1 is overexpressed in TNBC samples which is confirmed by TCGA analysis. Targeting IFITM1 by siRNA or CRISPR/Cas9 in TNBC cell lines significantly inhibits proliferation, colony formation, and wound healing in vitro. Orthotopic mammary fat pad and mammary intraductal studies reveal that loss of IFITM1 reduces TNBC tumor growth and invasion in vivo. RNA-seq analysis of IFITM1/KO cells reveals significant downregulation of several genes involved in proliferation, migration, and invasion and functional studies identified NF-κB as an important downstream target of IFITM1. Notably, siRNA knockdown of p65 reduces IFITM1 expression and a drug-repurposing screen of FDA approved compounds identified parthenolide, an NFκB inhibitor, as a cytotoxic agent for TNBC and an inhibitor of IFITM1 in vitro and in vivo. Overall, our findings suggest that targeting IFITM1 by suppressing interferon-alpha/NFκB signaling represents a novel therapeutic strategy for TNBC treatment. [ABSTRACT FROM AUTHOR]

Abstract Inflammatory breast cancer (IBC) is the most rare and aggressive subtype of breast cancer characterized by clusters of tumor cells invading lymph vessels, high rates of metastasis, and resistance to systemic chemotherapy. While significant progress has been made in understanding IBC, survival among IBC patients is still only one half that among patients with non-IBC. A major limitation to the development of more specific and effective treatments for IBC is a lack of identifiable molecular alterations that are specific to IBC. Emerging evidence suggests that the aggressive nature of IBC is not specific to IBC cells but instead driven by the interplay between autonomous signaling and context-dependent cytokine networks from the surrounding tumor microenvironment. Recently, the type I interferon, specifically the interferon alpha signature, has been identified as a pathway upregulated in IBC but few studies have addressed its role. Activation of the interferon alpha signaling pathway has been shown to contribute to apoptosis and cellular senescence but is also attributed to increased migration and drug resistance depending on the interferon-stimulated genes transcribed. The mechanisms promoting the increase in interferon alpha expression and the role interferon alpha plays in IBC remain speculative. Current hypotheses suggest that immune and stromal cells in the local tumor microenvironment contribute to the interferon alpha signaling cascade within the tumor cell and that this activation may further alter the immune and stromal cells within the microenvironment. This review serves as an overview of the role of interferon alpha signaling in IBC. Ideally, future experiments should investigate the mechanistic interplay of interferons in IBC to develop more efficacious treatment strategies for IBC patients.

Background: Long non-coding RNAs (lncRNAs) can remarkably regulate human malignancies in terms of the development and the progression. Previously, lncRNA LINC00847 (LINC00847) has been reported to present dysregulation in several tumors. However, the expression and function of LINC00847 in non-small cell lung cancer (NSCLC) have not been investigated.Methods: RT-qPCR was performed to determine the expressions of LINC00847 in collected tissue samples and cell lines. The clinical significance of LINC00847 was statistically analyzed. CCK-8 test, cell scratch test and trans-well test were used to evaluate the proliferation, invasion and migration abilities of NSCLC cells, respectively. The xenograft tumor model was constructed to confirm the effects of LINC00847 knockdown on NSCLC in vivo. Further, luciferase reporter assays and Western blot were performed to explore molecular mechanisms underlying the functions of LINC00847.Results: Increased expressions of LINC00847 were observed in NSCLC samples as well as cell lines. Additionally, E2F1 could be capable of directly binding to the LINC00847 promoter region, followed by promoting its expression. Clinically, LINC00847 high-expression could lead to poor prognosis of NSCLC patients. Functionally, LINC00847 knockdown noticeably repressed NSCLC cell growth and metastasis. Mechanically, miR-147a/IFITM1 axis was a downstream target of LINC00847, and silencing of miR-147a could rescue the anti-cancer effects of LINC00847 knockdown on NSCLC cell behaviors.Conclusion: Overall, up regulation of LINC00847 induced by E2F1 promoted the progression of NSCLC by modulating miR-147a/IFITM1 axis, representing a novel regulatory mechanism for NSCLC progression.

Interferon-induced transmembrane proteins (IFITMs) are novel viral restriction factors which inhibit numerous virus infections by impeding viral entry into target cells. To investigate the roles of IFITMs during fish virus infection, we cloned and characterized an IFITM1 homolog from orange spotted grouper (Epinephelus coioides) (EcIFITM1) in this study. EcIFITM1 encodes a 131-amino-acid polypeptide, which shares 64 and 43% identity with Seriola dumerili and Homo sapiens, respectively. The multiple sequence alignment showed that EcIFITM1 contained five domains, including NTD (aa 1–45), IMD (aa 46–67), CIL (aa 68–93), TMD (aa 94–119), and CTD (aa 120–131). In vitro, the level of EcIFITM1 mRNA expression was significantly up-regulated in response to Singapore grouper iridovirus (SGIV), or red-spotted grouper nervous necrosis virus (RGNNV) infection. EcIFITM1 encoded a cytoplasmic protein, which was partly colocalized with early endosomes, late endosomes, and lysosomes. The ectopic expression of EcIFITM1 significantly inhibited the replication of SGIV or RGNNV, which was demonstrated by the reduced virus production, as well as the levels of viral gene transcription and protein expression. In contrast, knockdown of EcIFITM1 using small interfering RNAs (siRNAs) promoted the replication of both viruses. Notably, EcIFITM1 exerted its antiviral activity in the step of viral entry into the host cells. Furthermore, the results of non-targeted lipometabolomics showed that EcIFITM1 overexpression induced lipid metabolism remodeling in vitro. All of the detected ceramides were significantly increased following EcIFITM1 overexpression, suggesting that EcIFITM1 may suppress SGIV entry by regulating the level of ceramide in the lysosomal system. In addition, EcIFITM1 overexpression positively regulated both interferon-related molecules and ceramide synthesis-related genes. Taken together, our results demonstrated that EcIFITM1 exerted a bi-functional role, including immune regulation and lipid metabolism in response to fish virus infections.

Despite improvements reported in diagnosis and treatments in recent decades, pancreatic cancer is still characterized by poor prognosis and low survival rate among solid tumors. Intensive interests have grown in exploring novel predictive biomarkers, aiming to enhance the efficiency in early detection and treatment prognosis. In this study, we identified the differentially expressed genes (DEGs) in pancreatic cancer by analyzing five gene expression profiles and established the functional modules according to the functional interaction (FI) network between the DEGs. A significant upregulation of the selected DEG, interferon (IFN)-induced transmembrane protein 1 (IFITM1), was evaluated in several bioinformatics online tools and verified with immunohistochemistry staining from samples of 90 patients with pancreatic cancer. Prognostic data showed that high expression of IFITM1 associated with poor survival, and multivariate Cox regression analysis showed IFITM1 was one of the independent prognostic factors for overall survival. Meanwhile, significant correlations of the expression of IFITM1 and the infiltration of immune cells were found by TIMER. Furthermore, a higher level of IFITM1 was assessed in pancreatic cancer cell lines compared to normal human pancreatic duct epithelial cells, and silencing IFITM1 in tumor cells remarkedly inhibited cancer tumorigenicity. Collectively, our findings suggested that IFITM1 might have promising utility for pancreatic cancer.

Background: The interferon-induced transmembrane (IFITM) protein family consists of interferon-stimulated genes (ISGs) that show potent antiviral capacity against a broad range of viruses. Many studies have been performed to investigate an association between IFITM3 polymorphisms and pandemic influenza A 2009 H1N1 virus infection. However, an association study of IFITM1 polymorphisms with susceptibility to this infection has not been reported thus far. Objective: To identify an association between the susceptibility to pandemic influenza A 2009 H1N1 virus infection and IFITM1 polymorphisms, we compared genotype, allele and haplotype frequencies of the IFITM1 gene between healthy controls and pandemic influenza A 2009 H1N1-infected patients. In addition, we investigated linkage disequilibrium (LD) by Haploview 4.2 and the binding ability of transcription factors according to IFITM1 polymorphism alleles by PROMO. Furthermore, we measured the LD value between the IFITM1 gene and the IFITM3 gene. Results: We found 3 novel single-nucleotide polymorphisms (SNPs) and did not find an association between IFITM1 SNPs and susceptibility to pandemic influenza A 2009 H1N1 virus infection. We found strong LD among IFITM1 SNPs but did not find a difference in the transcription factor-binding ability according to regulatory IFITM1 SNP alleles. In addition, we found strong LD between IFITM1 SNPs and IFITM3 SNPs. Conclusion: To the best of our knowledge, this report is the first association study of the susceptibility to pandemic influenza A 2009 H1N1 virus infection and IFITM1 polymorphisms. [ABSTRACT FROM AUTHOR]

Despite improvements reported in diagnosis and treatments in recent decades, pancreatic cancer is still characterized by poor prognosis and low survival rate among solid tumors. Intensive interests have grown in exploring novel predictive biomarkers, aiming to enhance the efficiency in early detection and treatment prognosis. In this study, we identified the differentially expressed genes (DEGs) in pancreatic cancer by analyzing five gene expression profiles and established the functional modules according to the functional interaction (FI) network between the DEGs. A significant upregulation of the selected DEG, interferon (IFN)-induced transmembrane protein 1 (IFITM1), was evaluated in several bioinformatics online tools and verified with immunohistochemistry staining from samples of 90 patients with pancreatic cancer. Prognostic data showed that high expression of IFITM1 associated with poor survival, and multivariate Cox regression analysis showed IFITM1 was one of the independent prognostic factors for overall survival. Meanwhile, significant correlations of the expression of IFITM1 and the infiltration of immune cells were found by TIMER. Furthermore, a higher level of IFITM1 was assessed in pancreatic cancer cell lines compared to normal human pancreatic duct epithelial cells, and silencing IFITM1 in tumor cells remarkedly inhibited cancer tumorigenicity. Collectively, our findings suggested that IFITM1 might have promising utility for pancreatic cancer. [ABSTRACT FROM AUTHOR]

Interferon-induced transmembrane proteins (IFITMs) are novel viral restriction factors which inhibit numerous virus infections by impeding viral entry into target cells. To investigate the roles of IFITMs during fish virus infection, we cloned and characterized an IFITM1 homolog from orange spotted grouper (Epinephelus coioides) (EcIFITM1) in this study. EcIFITM1 encodes a 131-amino-acid polypeptide, which shares 64 and 43% identity with Seriola dumerili and Homo sapiens , respectively. The multiple sequence alignment showed that EcIFITM1 contained five domains, including NTD (aa 1–45), IMD (aa 46–67), CIL (aa 68–93), TMD (aa 94–119), and CTD (aa 120–131). In vitro , the level of EcIFITM1 mRNA expression was significantly up-regulated in response to Singapore grouper iridovirus (SGIV), or red-spotted grouper nervous necrosis virus (RGNNV) infection. EcIFITM1 encoded a cytoplasmic protein, which was partly colocalized with early endosomes, late endosomes, and lysosomes. The ectopic expression of EcIFITM1 significantly inhibited the replication of SGIV or RGNNV, which was demonstrated by the reduced virus production, as well as the levels of viral gene transcription and protein expression. In contrast, knockdown of EcIFITM1 using small interfering RNAs (siRNAs) promoted the replication of both viruses. Notably, EcIFITM1 exerted its antiviral activity in the step of viral entry into the host cells. Furthermore, the results of non-targeted lipometabolomics showed that EcIFITM1 overexpression induced lipid metabolism remodeling in vitro. All of the detected ceramides were significantly increased following EcIFITM1 overexpression, suggesting that EcIFITM1 may suppress SGIV entry by regulating the level of ceramide in the lysosomal system. In addition, EcIFITM1 overexpression positively regulated both interferon-related molecules and ceramide synthesis-related genes. Taken together, our results demonstrated that EcIFITM1 exerted a bi-functional role, including immune regulation and lipid metabolism in response to fish virus infections. [ABSTRACT FROM AUTHOR]

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Platinum-based chemotherapies, historically the cornerstone of first-line treatment for small-cell lung cancer (SCLC), face a major hurdle: the frequent emergence of chemoresistance, notably to cisplatin (CDDP). Current understanding of the mechanisms driving CDDP resistance in SCLC is incomplete. Notably, Interferon inducible transmembrane protein1 (IFITM1) has been identified as a key player in the distant metastasis of SCLC. Analysis of The Cancer Genome Atlas (TCGA) database revealed that IFITM1 expression is markedly elevated in tumor tissues as compared to that from adjacent normal tissues, correlating with a worse prognosis for patients with SCLC. Our research focused on investigating the role of IFITM1 in the acquisition of cisplatin resistance in SCLC. Further clinical sample analysis highlighted a significant increase in IFITM1 levels in SCLC tissues from cisplatin-resistant patients versus those were responsive to CCDP treatment, with similar trends observed in cisplatin-resistant SCLC cells. Crucially, overexpression of IFITM1 reduced the sensitivity of SCLC cells to cisplatin, while silencing IFITM1 enhanced chemosensitivity in cisplatin-resistant strains. Our in vivo studies further confirmed that silencing IFITM1 significantly boosted the efficacy of cisplatin in inhibiting growth of subcutaneous tumors of NCI-H466/CDDP cells (cisplatin-resistant SCLC cells) in a mouse model. Mechanistically, IFITM1 appears to foster cisplatin resistance through activation of the Wnt/β-catenin pathway. In summary, our findings suggest that targeting IFITM1, alongside cisplatin treatment, could offer a promising therapeutic strategy to overcome resistance and improve outcomes for SCLC patients., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Haihong Qian reports financial support was provided by Yunnan Province Science and Technology Department 10.13039/501100003996Kunming Medical University applied basic research joint project. If there are other authors, they 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.)

Human brain microvascular endothelial cells (hBMECs) are the main component cells of the blood–brain barrier (BBB) and play a crucial role in responding to viral infections to prevent the central nervous system (CNS) from viral invasion. Interferon-inducible transmembrane protein 1 (IFITM1) is a multifunctional membrane protein downstream of type-I interferon. In this study, we discovered that hIFITM1 expression was highly upregulated in hBMECs during Japanese encephalitis virus (JEV) infection. Depletion of hIFITM1 with CRISPR/Cas9 in hBMECs enhanced JEV replication, while overexpression of hIFITM1 restricted the viruses. Additionally, overexpression of hIFITM1 promoted the monolayer formation of hBMECs with a better integrity and a higher transendothelial electrical resistance (TEER), and reduced the penetration of JEV across the BBB. However, the function of hIFITM1 is governed by palmitoylation. Mutations of palmitoylation residues in conserved CD225 domain of hIFITM1 impaired its antiviral capacity. Moreover, mutants retained hIFITM1 in the cytoplasm and lessened its interaction with tight junction protein Occludin. Taken together, palmitoylation of hIFITM1 is essential for its antiviral activity in hBMECs, and more notably, for the maintenance of BBB homeostasis. [ABSTRACT FROM AUTHOR]

Abstract Background Endothelial cells are believed to play an important role in response to virus infection. Our previous microarray analysis showed that H9N2 virus infection and inactivated viral particle inoculation increased the expression of interferon-inducible transmembrane protein 1 (IFITM1) in human umbilical vein endothelial cells (HUVECs). In present study, we deeply investigated the expression patterns of IFITM1 and IFITM1-mediated antiviral response induced by H9N2 virus infection and inactivated viral particle inoculation in HUVECs. Epithelial cells that are considered target cells of the influenza virus were selected as a reference control. Methods First, we quantified the expression levels of IFITM1 in HUVECs induced by H9N2 virus infection or viral particle inoculation using quantitative real-time PCR and western blot. Second, we observed whether hemagglutinin or neuraminidase affected IFITM1 expression in HUVECs. Finally, we investigated the effect of induced-IFITM1 on the antiviral state in HUVECs by siRNA and activation plasmid transfection. Results Both H9N2 virus infection and viral particle inoculation increased the expression of IFITM1 without elevating the levels of interferon-ɑ/β in HUVECs. HA or NA protein binding alone is not sufficient to increase the levels of IFITM1 and interferon-ɑ/β in HUVECs. IFITM1 induced by viral particle inoculation significantly decreased the virus titers in culture supernatants of HUVECs. Conclusions Our results showed that inactivated viral particle inoculation increased the expression of IFITM1 at mRNA and protein levels. Moreover, the induction of IFITM1 expression mediated the antiviral state in HUVECs.

Interferon-induced transmembrane proteins IFITM1 and IFITM3 (IFITM1/3) play a role in both RNA viral restriction and in human cancer progression. Using immunohistochemical staining of FFPE tissue, we identified subgroups of cervical cancer patients where IFITM1/3 protein expression is inversely related to metastasis. Guide RNA-CAS9 methods were used to develop an isogenic IFITM1/IFITM3 double null cervical cancer model in order to define dominant pathways triggered by presence or absence of IFITM1/3 signalling. A pulse SILAC methodology identified IRF1, HLA-B, and ISG15 as the most dominating IFNγ inducible proteins whose synthesis was attenuated in the IFITM1/IFITM3 double-null cells. Conversely, SWATH-IP mass spectrometry of ectopically expressed SBP-tagged IFITM1 identified ISG15 and HLA-B as dominant co-associated proteins. ISG15ylation was attenuated in IFNγ treated IFITM1/IFITM3 double-null cells. Proximity ligation assays indicated that HLA-B can interact with IFITM1/3 proteins in parental SiHa cells. Cell surface expression of HLA-B was attenuated in IFNγ treated IFITM1/IFITM3 double-null cells. SWATH-MS proteomic screens in cells treated with IFITM1-targeted siRNA cells resulted in the attenuation of an interferon regulated protein subpopulation including MHC Class I molecules as well as IFITM3, STAT1, B2M, and ISG15. These data have implications for the function of IFITM1/3 in mediating IFNγ stimulated protein synthesis including ISG15ylation and MHC Class I production in cancer cells. The data together suggest that pro-metastatic growth associated with IFITM1/3 negative cervical cancers relates to attenuated expression of MHC Class I molecules that would support tumor immune escape. Unlabelled Image • IFITM1/3 expression in cervical cancers inversely correlates with metastases. • Isogenic IFITM1 and IFITM3 null cervical cancer cells were developed. • Pulse SILAC approaches were used to define IFITM1/3 dependent signalling pathways. • The major IFITM1/3-interferon-γ dependent effectors are HLA-B and ISG15. • IFITM1/3 loss would be predicted to reduce HLA expression and ISG15ylation in vivo. [ABSTRACT FROM AUTHOR]

• KSHV is etiologically associated with KS, MCD, and PEL. • MicroRNAs (miRNAs) are a class of highly conserved small non-coding RNAs. • miRNAs are gene regulators for about 60% of protein-coding genes. • miRNAs regulate KSHV entry, lytic cycle, and latent phase of replication. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman Disease (MCD). Recent mechanistic advances have discerned the importance of microRNAs in the virus–host relationship. KSHV has two modes of replication: lytic and latent phase. KSHV entry into permissive cells, establishment of infection, and maintenance of latency are contingent upon successful modulation of the host miRNA transcriptome. Apart from host cell miRNAs, KSHV also encodes viral miRNAs. Among various cellular and molecular targets, miRNAs are appearing to be key players in regulating viral pathogenesis. Therefore, the use of miRNAs as novel therapeutics has gained considerable attention as of late. This innovative approach relies on either mimicking miRNA species by identical oligonucleotides, or selective silencing of miRNA with specific oligonucleotide inhibitors. Here, we provide an overview of KSHV pathogenesis at the molecular level with special emphasis on the various roles miRNAs play during virus infection. [ABSTRACT FROM AUTHOR]

Emerging data indicate that interferon‐induced transmembrane protein 1 (IFITM1) plays an important role in many cancers. However, it remains unclear whether IFITM1 is functionally indispensable in nonsmall cell lung cancer (NSCLC). Here, using NSCLC cell lines and patient‐derived samples, we show that IFITM1 is essentially required for the progression of NSCLC in vitro and in vivo. Specifically, IFITM1 depletion resulted in a significant reduction in sphere formation, migration, and invasion of NSCLC cells in vitro; these events were inversely correlated with the ectopic expression of IFITM1. In addition, tumor development was significantly impaired in the absence of IFITM1 in vivo. Mechanistically, epidermal growth factor receptor/sex‐determining region Y‐box 2 (EGFR/SOX2) signaling axis was compromised in the absence of IFITM1, and the ectopic expression of SOX2 partially rescued the defects caused by IFITM1 depletion. More importantly, using 226 patient‐derived samples, we demonstrate that a high level of IFITM1 expression is associated with a poor overall survival (OS) rate in adenocarcinoma but not in squamous cell carcinoma. Collectively, these data suggest that IFITM1 is a poor prognostic marker of adenocarcinoma and an attractive target to develop novel therapeutics for NSCLC. What's new? Interferon response genes play key roles in pathogen defense but emerging evidence also link them with cancer. The authors report that interferon‐induced transmembrane protein 1 (IFITM1) critically regulates epidermal growth factor receptor‐mediated signaling in nonsmall lung cancer models and is associated with a poor prognosis of patients with adenocarcinoma. This expands the function of this innate defense factor and might lead to improved clinical management of individuals afflicted with lung cancer. [ABSTRACT FROM AUTHOR]

Purpose Although the interferon α (IFNα) signaling and the paired-like homeodomain transcription factor 2 (PITX2) have both been implicated in the progression of breast cancer (BCa), it remains obscure whether these two pathways act in a coordinated manner. We therefore aimed to elucidate the expression and function of PITX2 during the pathogenesis of endocrine resistance in BCa. Materials and Methods PITX2 expression was assessed in BCa tissues using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunohistochemistry and in experimentally induced letrozole-resistant BCa cells using RT-qPCR and immunoblotting. Effects of PITX2 deregulation on BCa progression was determined by assessing MTT, apoptosis and xenograft model. Finally, using multiple assays, the transcriptional regulation of interferon-inducible transmembrane protein 1 (IFITM1) by PITX2 was studied at both molecular and functional levels. Results PITX2 expression was induced in letrozole-resistant BCa tissues and cells, and PITX2 induction by IFNα signaling powerfully protected BCa cells against letrozole insult and potentiated letrozole-resistance. Mechanistically, PITX2 enhanced IFNα-induced AKT activation by transactivating the transcription of IFITM1, thus rendering BCa cells unresponsive to letrozoleelicited cell death. Additionally, ablation of IFITM1 expression using siRNA substantially abolished IFNα-elicited AKT phosphorylation, even in the presence of PITX2 overexpression, thus sensitizing BCa cells to letrozole treatment. Conclusion These results demonstrate that constitutive upregulation of PITX2/IFITM1 cascade is an intrinsic adaptive mechanism during the pathogenesis of letrozole-resistance, and modulation of PITX2/IFITM1 level using different genetic and pharmacological means would thus have a novel therapeutic potential against letrozole resistance in BCa. [ABSTRACT FROM AUTHOR]

Zika virus has emerged as a severe health threat with a rapidly expanding range. The IFITM family of restriction factors inhibits the replication of a broad range of viruses, including the closely related flaviruses West Nile virus and dengue virus. Here, we show that IFITM1 and IFITM3 inhibit Zika virus infection early in the viral life cycle. Moreover, IFITM3 can prevent Zika-virus-induced cell death. These results suggest that strategies to boost the actions and/or levels of the IFITMs might be useful for inhibiting a broad range of emerging viruses.

Interferon-inducible transmembrane proteins (IFITM1/2/3) have been reported to suppress the entry of a wide range of viruses. However, their antiviral functional residues and specific mechanisms are still unclear. Here, we firstly resolved the topology of IFITM1 on the plasma membrane where N-terminus points into the cytoplasm and C-terminus resides extracellularly. Further, KRRK basic residues of IFITM1 locating at 62−67 of the conserved intracellular loop (CIL) were found to play a key role in the restriction on the Zika virus (ZIKV) and dengue virus (DENV). Similarly, KRRK basic residues of IFITM2/3 also contributed to suppressing ZIKV replication. Finally, IFITM1 was revealed to be capable of restricting the release of ZIKV particles from endosome to cytosol so as to impede the entry of ZIKV into host cells, which was tightly related with the inhibition of IFITM1 on the acidification of organelles. Overall, our study provided topology, antiviral functional residues and the mechanism of interferon-inducible transmembrane proteins.

Human influenza virus (IAV) are among the most common pathogens to cause human respiratory infections. A better understanding on interplay between IAV and host factors may provide clues for disease prevention and control. While many viruses are known to downregulate p53 upon entering the cell to reduce the innate host antiviral response, IAV infection is unusual in that it activates p53. However, it has not been clear whether this process has proviral or antiviral effects. In this study, using human isogenic p53 wild-type and p53null A549 cells generated from the CRISPR/Cas9 technology, we observed that p53null cells exhibit significantly reduced viral propagation when infected with influenza A virus (strain A/Puerto Rico/8/1934 H1N1). Genome-wide microarray analysis revealed that p53 regulates the expression of a large set of interferon-inducible genes, among which the interferon-induced transmembrane family members IFITM1, IFITM2, and IFITM3 were most significantly downregulated by the expression of p53. Knockdown of interferon-induced transmembrane proteins (IFITMs) by short interfering RNAs enhanced influenza virus infectivity in p53null A549 cells, while overexpressed IFITMs in A549 cells blocked virus entry. Intriguingly, regulation of IFITMs by p53 is independent of its transcriptional activity, as the p53 short isoform Δ40p53 recapitulates IFITM regulation. Taken together, these data reveal that p53 activation by IAV is an essential step in maintaining its infectivity. This novel association between human p53 and the broad spectrum antiviral proteins, the IFITMs, demonstrates a previous mechanism employed by influenza virus to enhance its propagation via p53 inhibition of IFITMs.

This research aimed to analyze the effect of IFITM1 on the radioresistance of oral neoplasm. Using a multi‐group heat map from GSE9716 analysis of the GEO database, IFITM1 was determined to be a relevant radioresistance gene. The TCGA database was analyzed before the expression of IFITM1 was analyzed. IFITM1 expression was quantified by quantitative RT‐PCR and immunohistochemistry in 19 paired oral neoplasm cases. The effects of time and dose of radiation on IFITM1 expression level in CAL27 and TSCC1 cell lines were tested by quantitative RT‐PCR. Oral neoplasm cells were transfected with siRNA after radiotherapy to disturb IFITM1 expression. After this, the survival rates, cell apoptosis, caspase‐3 viability, expression and γ‐H2AX were detected using colony formation, flow cytometry, western blot and immunofluorescence, respectively. Western blot was used for STAT1/2/3/p21‐related protein and phosphorylation changes. Finally, an in vivo nude mice tumor model was established to verify the effect of IFITM1 on oral neoplasm cells radioresistance. Through microarray analysis, the head and neck neoplasm radioresistance‐related gene IFITM1 was found to be overexpressed. IFITM1 overexpression was verified not only using the TCGA database but also in 19 paired cases of oral neoplasm tissues and cells. With increases of dose and time of radiation, the expression of IFITM1 was increased in CAL27 and TSCC1 cell lines. Furthermore, si‐IFITM1 may restrain cell proliferation, DNA damage and cell apoptosis in oral neoplasm cell lines. Finally, pSTAT1/2/p21 was found to be upregulated while pSTAT3/p‐p21 was downregulated due to IFITM1 inhibition after radiotherapy. The evidence suggested that IFITM1 in combination with radiotherapy can inhibit oral neoplasm cells. [ABSTRACT FROM AUTHOR]

The self-renewal capacity of germline derived stem cells (GSCs) makes them an ideal source for research and use in clinics. Despite the presence of active gene network similarities between embryonic stem cells (ESCs) and GSCs, there are unanswered questions regarding the roles of evolutionary conserved genes in GSCs. To determine the reprogramming potential of germ cell- specific genes, we designed a polycistronic gene cassette expressing Stella, Oct4 and Nanos2 in a lentiviral-based vector. Deep transcriptome analysis showed the activation of a set of pluripotency and germ-cell-specific markers and the downregulation of innate immune system. The global shut down of antiviral genes included MHC class I, interferon response genes and dsRNA 2′-5′-oligoadenylate synthetase are critical pathways that has been affected . Individual expression of each factor highlighted suppressive effect of Nanos2 on genes such as Isg15 and Oasl2 . Collectively, to our knowledge this is the first report showing that Nanos2 could be considered as an immunosuppressive factor. Furthermore , our results demonstrate suppression of endogenous retrotransposons that harbor immune response but further analysis require to uncover the correlation between transposon suppression and immune response in germ cell development. [ABSTRACT FROM AUTHOR]

Interferon-induced transmembrane protein 1 (IFITM1) is a member of the IFITM family that is associated with some acute-phase cytokine-stimulated response. Recently, we demonstrated that IFITM1 was significantly upregulated in the injured spinal cords at the mRNA level. However, its expression and cellular localization at the protein level is still unclear. Here, a rat model of spinal cord injury (SCI) was performed to investigate the spatio-temporal expression of IFITM1 after SCI. IFITM1 mRNA and protein were assessed by quantitative reverse transcription-PCR and western blot, respectively. IHC was used to identify its cellular localization. We revealed that IFITM1 could be found in sham-opened spinal cords and gradually increased after SCI. It reached peak at 7 and 14 days postinjury (dpi) and still maintained at a relatively higher level at 28 dpi. IHC showed that IFITM1 expressed in GFAP+ and APC+ cells in sham-opened spinal cords. After SCI, in addition to the above-mentioned cells, it could also be found in CD45+ and CD68+ cells, and its expression in CD45+, CD68+, and GFAP+ cells was increased significantly. These results demonstrate that IFITM1 is mainly expressed in astrocytes and oligodendroglia in normal spinal cords, and could rapidly increase in infiltrated leukocytes, activated microglia, and astrocytes after SCI. [ABSTRACT FROM AUTHOR]

Interferon-induced transmembrane protein 1 ( IFITM1), a member of the IFITM protein family, is a component of a multimeric complex involved in the transduction of antiproliferation and cell adhesion signals. IFITM1 is thought to play a role in antiproliferation and immune surveillance, and has been shown to restrict infection by numerous viruses. It is highly expressed in human embryonic stem cells ( hESCs) but its role in hESCs remains to be elucidated. In this study, knockout of IFITM1 mediated by CRISPR/Cas9 in hESCs did not affect self-renewal, pluripotency, telomerase activity or telomeres. However expression of human endogenous retroviruses ( HERVs) was higher than in wild-type hESCs, and there was also a reduced level of trimethylation of histone H3 on lysine 9 at HERV loci. These data show that IFITM1 suppresses HERVs in hESCs by regulating epigenetic modifications. [ABSTRACT FROM AUTHOR]

Interferon-induced transmembrane proteins (IFITMs 1, 2, and 3) play a critical role in preventing pathogen infection in vertebrates. They are also involved in the occurrence and prognosis of cancer. Myogenesis is a complex process regulated by several factors. This study disclosed that Ifitm1-3 were upregulated in the process of myogenic differentiation of C2C12 myoblasts on days 3, 5, and 7. This positively correlated with the expression of differentiation factors MyoD, myogenin, Mrf5, and desmin. Furthermore, knockdown of Ifitm1-3 by their individual siRNAs inhibited myogenesis of C2C12 myoblasts, with relative downregulation of MyoD, myogenin, Mrf5, and desmin. Subsequently, myotube formation and fusion percentage decreased. Co-immunoprecipitation combined with LC-MS/MS analysis uncovered the interaction proteins of IFITM1 and IFITM3 in C2C12 myoblasts. A total of 84 overlapped interaction proteins of IFITM1 and IFITM3 were identified, and one of the clusters was engaged in cytoskeletal and sarcomere proteins, including desmin, myosin, actin, vimentin, nestin, ankycorbin, and nucleolin. Hence, we hypothesize that these interacting proteins may function as scaffolds for IFITM1-3, possibly through the interaction protein desmin to initiate further interaction with other proteins to participate in myogenesis; however, the molecular mechanisms remain unclear. Our study may contribute to the development of novel therapeutics for myopathic diseases., Competing Interests: The authors have no conflicts of interest to disclose., (2023, International Research and Cooperation Association for Bio & Socio - Sciences Advancement.)

Objective To investigate the inhibitory effect of synthetic interferon-induced transmembrane protein 1(IFITM1) siRNA on the proliferation and migration of human ovarian cancer cell line CP70. Methods The siRNA targeted IFITM1 was transfected into CP70 cells by LipofectamineTM 2000. Expressions of IFITM1 mRNA and protein were examined by qRT-PCR and Western blot. Plate clone assay and Transwell chamber were used to observe the proliferation and migration of CP70 cells. Results IFITM1 siRNA significantly inhibited the expression of IFITM1 in human ovarian cancer cell line CP70 at both mRNA and protein levels. The colony formation assay indicated that the clone number was 84 in IFITM1siRNA, which was much fewer than 181 in negative control group and 178 in mock transfection group. The colony-forming efficiency (CFE) was 42%, 90.5% and 89%, respectively. Transwell chamber results showed that the number of migrated cells was 59, 121 and 126, respectively; the siRNA transfection group differed significantly from the other two groups, indicating that downregulated IFITM1 expression greatly inhibited the proliferation and migration of CP70 cells. Conclusion Knockdown of IFITM1 inhibited the proliferation and migration of CP70 cells. IFITM1 is a potential therapeutic target for human ovarian cancer. [ABSTRACT FROM AUTHOR]

Summary Zika virus has emerged as a severe health threat with a rapidly expanding range. The IFITM family of restriction factors inhibits the replication of a broad range of viruses, including the closely related flaviruses West Nile virus and dengue virus. Here, we show that IFITM1 and IFITM3 inhibit Zika virus infection early in the viral life cycle. Moreover, IFITM3 can prevent Zika-virus-induced cell death. These results suggest that strategies to boost the actions and/or levels of the IFITMs might be useful for inhibiting a broad range of emerging viruses. [ABSTRACT FROM AUTHOR]

Background: Distinguishing myometrial invasion from adenomyosis involvement is important for staging of endometrial endometrioid adenocarcinoma. We aimed to compare CD10, which has limited value in this scenario, with interferon-induced transmembrane protein 1 (IFITM1), a recently described sensitive and specific marker of endometrial stroma.Methods: We reviewed 25 hysterectomies containing endometrial endometrioid adenocarcinoma and adenomyosis. Tumor areas were classified as unequivocally myoinvasive or unequivocally noninvasive. Foci equivocal for invasion were also recorded. Immunohistochemistry for IFITM1 and CD10 was performed and scored in terms of intensity and distribution and classified as negative or positive.Results: Unlike CD10, IFITM1 staining showed significant differences in mean intensity (P < .0001) and distribution (P < .0001) between invasive vs noninvasive areas. Sixteen (84.2%) invasive and 34 (97.1%) noninvasive areas were positive for CD10 (P = .22). In contrast, none of the invasive vs 25 (71.4%) noninvasive areas were positive for IFITM1 (P < .0001). IFITM1 had 71.4% sensitivity and 100% specificity in detecting stroma surrounding endometrioid adenocarcinoma, hence excluding myoinvasion. Eleven (45.8%) of 24 foci designated as equivocal stained with IFITM1.Conclusions: Compared with CD10, IFITM1 has superior performance distinguishing endometrial stroma of adenomyosis from mesenchyma surrounding invasive endometrial adenocarcinoma. IFITM1 expression is highly predictive of the absence of invasion and may be valuable in cases in which determining myoinvasion has staging implications. [ABSTRACT FROM AUTHOR]

Background: Inflammatory breast cancer (IBC) is a very aggressive and lethal subtype of breast cancer that accounts for about 4 % of all breast cancers diagnosed in the United States. Despite the efforts of several investigators to identify the molecular factors driving the aggressive phenotype of IBC, a great deal is still unknown about the molecular underpinnings of the disease. In the present study, we investigated the role of interferon-induced transmembrane protein 1 (IFITM1), a well-known interferon-stimulated gene (ISG), in promoting the aggressiveness of SUM149 IBC cells.Methods: Western blot and real-time polymerase chain reaction analyses were performed to assess the protein and messenger RNA (mRNA) levels of IFITM1 and other ISGs in three IBC cell lines: SUM149, MDA-IBC-3, and SUM190. IFITM1 expression and cellular localization were assessed by using immunofluorescence, while the tumorigenic potential was assessed by performing cell migration, invasion, and colony formation assays. Small interfering RNA and short hairpin RNA knockdowns, enzyme-linked immunosorbent assays, and luciferase assays were performed to determine the functional significance of IFITM1 and signal transducers and activators of transcription 1 and 2 (STAT1/2) in SUM149 cells.Results: We found that IFITM1 was constitutively overexpressed at the mRNA and protein levels in triple-negative SUM149 IBC cells, but that it was not expressed in SUM190 and MDA-IBC-3 IBC cells, and that suppression of IFITM1 or blockade of the IFNα signaling pathway significantly reduced the aggressive phenotype of SUM149 cells. Additionally, we found that knockdown of STAT2 abolished IFITM1 expression and IFITM1 promoter activity in SUM149 cells and that loss of STAT2 significantly inhibited the ability of SUM149 cells to proliferate, migrate, invade, and form 2-D colonies. Notably, we found that STAT2-mediated activation of IFITM1 was particularly dependent on the chromatin remodeler brahma-related gene 1 (BRG1), which was significantly elevated in SUM149 cells compared with SUM190 and MDA-IBC-3 cells.Conclusions: These findings indicate that overexpression of IFITM1 enhances the aggressive phenotype of triple-negative SUM149 IBC cells and that this effect is dependent on STAT2/BRG1 interaction. Further studies are necessary to explore the potential of IFITM1 as a novel therapeutic target and prognostic marker for some subtypes of IBCs. [ABSTRACT FROM AUTHOR]

The family of interferon-inducible transmembrane proteins (IFITMs) plays a crucial role in inhibiting proliferation, promoting homotypic cell adhesion and mediating germ cell development. In the present study, the full-length cDNAs of zebrafish ifitm1 (744 bp) and ifitm3 (702 bp) were obtained by rapid amplification of cDNA ends (RACE). Reverse transcription polymerase chain reaction (RT-PCR) analysis showed that ifitm1 mRNA was expressed in the ovary, testis, brain, muscle, liver and kidney, while ifitm3 mRNA was only detected in the ovary. Based on in situ hybridization, ifitm1 mRNA was found to be strongly expressed in the ooplasm from stage I to stage II and ifitm3 mRNA was also strongly expressed in the ooplasm from stage I to stage II, furthermore ifitm3 expression ultimately localized to the cortex region beneath the plasma membrane of stage IV oocytes. During development, ifitm1 expression was initially detected in the enveloping layer cells and deep layer cells of shield stage embryos. Then, throughout the segmentation phase (10.25–24 hours post-fertilization (hpf)), ifitm1 expression was mainly detected in the head, trunk and tail regions. Unlike ifitm1, ifitm3 expression was initially detected in sphere stage embryos and was then broadly expressed throughout the embryo from the 70% epiboly stage to 24 hpf. Interestingly, ifitm3 was also expressed in primordial germ cells (PGCs) from the bud stage to 24 hpf. This expression analysis indicates that zebrafish ifitm1 may play a critical role in early organogenesis and may perform immune or hematopoietic functions and ifitm3 might be necessary for PGC migration and the formation of female germ cells. [ABSTRACT FROM PUBLISHER]

• Expression patterns of 10 DEGs were diametrically opposite in Z8R and Z8S group. • DHAV-3 infection results in cell growth suppression may be associated with IFITM1. • Conserved regions of IFITM1 (213–317 bp) could affected the cell cycle of DEF cells. Duck viral hepatitis (DVH) has a significant economic impact on duck industry, and duck hepatitis A virus genotype 3 (DHAV-3) is the most prevalent pathogen of DVH in Asian duck industry. The detailed study connecting differentially expressed genes (DEGs) and the differential resistance to DHAV-3 have not been accurately described, although a large numbers of DEGs have been identified by transcriptomic studies. Here, a resistant Pekin duck line (Z8R) and a susceptible Pekin duck line (Z8S) as models, high mortality and dramatically increased aspartate aminotransferase (AST), alanine aminotransferase (ALT) and the expression of immune-related genes of Z8S group were shown to be noticeable signs of cases caused by DHAV-3 infection. Compared with the control (Con) group, 1117 down-regulated DEGs and 612 up-regulated DEGs were found in the Z8S group and 37 down-regulated DEGs and 82 up-regulated DEGs were found in the Z8R group. Ultimately, the expression patterns of 10 DEGs were found to be diametrically opposite in Z8R and Z8S group. Functional analysis revealed that IFITM1 was associated with cell growth suppression, which was considered a key candidate gene. Results of flow cytometry showed that the conserved regions of IFITM1 (213–317 bp) could affected the cell cycle of duck embryo fibroblast (DEF) cells after infection with DHAV-3. Transcriptome and western blot analysis suggested that the CCND1, CCNE1 and CDK6 were significantly up-regulated in susceptible ducks by comparing with Con group. The hepatic injury and pathogenic outcomes caused by DHAV-3 infection were more severe in Z8S group compared to Z8R. Results of transcriptomics analysis and flow cytometry suggested that DHAV-3 infection can induce cell cycle changes that may be associated with IFITM1 expression level. These data will greatly enhance our understanding of the pathogenesis of DHAV-3 infection in ducklings and have implications for development of resistance breeding. [ABSTRACT FROM AUTHOR]