RESUMEN
By analyzing the expression patterns of inner root sheath (IRS) specific genes during different developmental stages of hair follicle (HF) in Tan sheep embryos and at birth, this study aims to reveal the influence of the IRS on crimped wool. Skin tissues from the scapular region of male Tan sheep were collected at 85 days (E85) and 120 days (E120) of fetal development, and at 0 days (D0), 35 days (D35), and 60 days (D60) after birth, with four samples at each stage. Real-time quantitative polymerase chain reaction (RT-qPCR) was employed to determine the relative expression levels of IRS type I keratin genes (KRT25, KRT26, KRT27, KRT28), type II keratin genes (KRT71, KRT72, KRT73, KRT74), and the trichohyalin gene (TCHH) in the skin of Tan sheep at different stages. Results showed that the expression levels of all IRS-specific genes peaked at D0, with the expression of all genes significantly higher than at E85 (P < 0.01), except for KRT73 and TCHH. The expression levels of KRT25, KRT26, and KRT72 were also significantly higher than at E120 (P < 0.01). Furthermore, the expression levels of KRT27, KRT28, KRT71, and KRT74 were significantly higher than both at E120 and D35 (P < 0.01). The expression levels of other genes at different stages showed no significant difference (P > 0.05). Conclusion: The IRS-specific genes exhibit the highest expression levels in Tan sheep at the neonatal stage. The expression levels of KRT71, KRT72, and TCHH, which are consistent with the pattern of wool crimp, may influence the morphology of the IRS and thereby affect the crimp of Tan sheep wool.
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Regulación del Desarrollo de la Expresión Génica , Folículo Piloso , Animales , Folículo Piloso/metabolismo , Folículo Piloso/crecimiento & desarrollo , Ovinos/genética , Ovinos/crecimiento & desarrollo , Masculino , Lana/metabolismo , Lana/crecimiento & desarrollo , Queratinas Tipo II/genética , Queratinas Tipo II/metabolismo , Queratinas/genética , Queratinas/metabolismo , Queratinas Tipo I/genética , Queratinas Tipo I/metabolismo , Proteínas de Filamentos IntermediariosRESUMEN
Keratins are the main structural protein components of wool fibres, and variation in them and their genes (KRTs) is thought to influence wool structure and characteristics. The PCR-single strand conformation polymorphism technique has been used previously to investigate genetic variation in selected coding and intron regions of the type II sheep keratin gene KRT81, but no variation was identified. In this study, we used the same technique to explore the 5' untranslated region of KRT81 and detected three sequence variants (A, B and C) that contain four single nucleotide polymorphisms. Among the 389 Merino × Southdown cross sheep investigated, variant B was linked to a reduction in clean fleece weight, while C was associated with an increase in both greasy fleece weight and clean fleece weight. No discernible effects on staple length or mean-fibre-diameter-related traits were observed. These findings suggest that variation in ovine KRT81 might influence wool growth by changing the density of wool follicles in the skin, the density of individual fibres, or the area of the skin producing fibre, as opposed to changing the rate of extrusion of fibres or their diameter.
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Polimorfismo de Nucleótido Simple , Fibra de Lana , Lana , Animales , Ovinos/genética , Ovinos/crecimiento & desarrollo , Lana/crecimiento & desarrollo , Queratinas Tipo II/genética , Queratinas Tipo II/metabolismo , Queratinas/genética , Queratinas/metabolismo , Oveja Doméstica/genética , Oveja Doméstica/crecimiento & desarrolloRESUMEN
Keratin 80 (KRT80) is a filament protein that makes up one of the major structural fibers of epithelial cells, and involved in cell differentiation and epithelial barrier integrity. Here, KRT80 mRNA expression was found to be higher in esophageal cancer than normal epithelium by RT-PCR and bioinformatics analysis (p < .05), opposite to KRT80 methylation (p < .05). There was a negative relationship between promoter methylation and expression level of KRT80 gene in esophageal cancer (p < .05). KRT80 mRNA expression was positively correlated with the differentiation, infiltration of immune cells, and poor prognosis of esophageal cancer (p < .05). KRT80 mRNA expression was positively linked to no infiltration of immune cells, the short survival time of esophageal cancers (p < .05). The differential genes of KRT80 mRNA were involved in fat digestion and metabolism, peptidase inhibitor, and intermediate filament, desosome, keratinocyte differentiation, epidermis development, keratinization, ECM regulator, complement cascade, metabolism of vitamins and co-factor (p < .05). KRT-80-related genes were classified into endocytosis, cell adhesion molecule binding, cadherin binding, cell-cell junction, cell leading edge, epidermal cell differentiation and development, T cell differentiation and receptor complex, plasma membrane receptor complex, external side of plasma membrane, metabolism of amino acids and catabolism of small molecules, and so forth (p < .05). KRT80 knockdown suppressed anti-apoptosis, anti-pyroptosis, migration, invasion, chemoresistance, and lipogenesis in esophageal cancer cells (p < .05), while ACC1 and ACLY overexpression reversed the inhibitory effects of KRT80 on lipogenesis and chemoresistance. These findings indicated that up-regulated expression of KRT80 might be involved in esophageal carcinogenesis and subsequent progression, aggravate aggressive phenotypes, and induced chemoresistance by lipid droplet assembly and ACC1- and ACLY-mediated lipogenesis.
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Resistencia a Antineoplásicos , Neoplasias Esofágicas , Queratinas Tipo II , Humanos , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Resistencia a Antineoplásicos/genética , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Regulación Neoplásica de la Expresión Génica , Lipogénesis/genética , ARN Mensajero , Queratinas Tipo II/genética , Queratinas Tipo II/metabolismoRESUMEN
Long non-coding RNAs (lncRNAs) are important in tumorigenesis and the development of multiple malignant human tumors, including colorectal cancer (CRC). We aimed to determine the regulatory mechanism of LINC01485 and its biological function in CRC. We estimated the expression of miR-383-5p, KRT80, and LINC01485 in CRC cells and tissues using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. The results were confirmed using RNA immunoprecipitation (RIP) and dual-luciferase assays. Binding relationships among miR-383-5p, LINC01485, and KRT80 were assessed. We explored the molecular mechanisms and functions of the LINC01485/miR-383-5p/KRT80 axis using CCK-8 and colony formation assays. Expression of the apoptotic markers Bcl-2 and Bax was quantified by western blotting, and the effects of LINC01485 on tumor development in vivo were investigated using xenograft tumors. Both LINC01485 and KRT80 were upregulated, whereas miR-383-5p was downregulated in CRC cells and tissues. Knockdown of LINC01485 attenuated CRC cell growth and xenograft tumor formation in vivo, whereas LINC01485 enhanced the proliferative capacity of CRC cells but inhibited apoptosis by sponging miR-383-5p to increase KRT80 expression in CRC cells. The regulatory molecular mechanism of the LINC01485/miR-383-5p/KRT80 axis plays a crucial role in CRC progression. Our findings highlight novel pathways and promising biomarkers for diagnostic and therapeutic application to patients with CRC.
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Neoplasias Colorrectales , Queratinas Tipo II , MicroARNs , ARN Largo no Codificante , Humanos , Carcinogénesis/genética , Carcinogénesis/patología , Línea Celular Tumoral , Proliferación Celular/genética , Neoplasias Colorrectales/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , Queratinas Tipo II/genéticaRESUMEN
INTRODUCTION: Fine-wool sheep are the most common breed used by the wool industry worldwide. Fine-wool sheep have over a three-fold higher follicle density and a 50% smaller fiber diameter than coarse-wool sheep. OBJECTIVES: This study aims to clarify the underlying genetic basis for the denser and finer wool phenotype in fine-wool breeds. METHOD: Whole-genome sequences of 140 samples, Ovine HD630K SNP array data of 385 samples, including fine, semi-fine, and coarse wool sheep, as well as skin transcriptomes of nine samples were integrated for genomic selection signature analysis. RESULTS: Two loci at keratin 74 (KRT74) and ectodysplasin receptor (EDAR) were revealed. Fine-scale analysis in 250 fine/semi-fine and 198 coarse wool sheep narrowed this association to one C/A missense variant of KRT74 (OAR3:133,486,008, P = 1.02E-67) and one T/C SNP in the regulatory region upstream of EDAR (OAR3:61,927,840, P = 2.50E-43). Cellular over-expression and ovine skin section staining assays confirmed that C-KRT74 activated the KRT74 protein and specifically enlarged cell size at the Huxley's layer of the inner root sheath (P < 0.01). This structure enhancement shapes the growing hair shaft into the finer wool than the wild type. Luciferase assays validated that the C-to-T mutation upregulated EDAR mRNA expression via a newly created SOX2 binding site and potentially led to the formation of more hair placodes. CONCLUSIONS: Two functional mutations driving finer and denser wool production were characterized and offered new targets for genetic breeding during wool sheep selection. This study not only provides a theoretical basis for future selection of fine wool sheep breeds but also contributes to improving the value of wool commodities.
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Receptor Edar , Queratinas Tipo II , Mutación Missense , Lana , Animales , Receptor Edar/genética , Ovinos/genética , Queratinas Tipo II/genéticaRESUMEN
The role of desmoglein-3 (DSG3) in oncogenesis is unclear. This study aimed to uncover molecular mechanisms through comparative transcriptome analysis in oral cancer cells, defining potential key genes and associated biological processes related to DSG3 expression. Four mRNA libraries of oral squamous carcinoma H413 cell lines were sequenced, and 599 candidate genes exhibited differential expression between DSG3-overexpressing and matched control lines, with 12 genes highly significantly differentially expressed, including 9 upregulated and 3 downregulated. Genes with known implications in cancer, such as MMP-13, KRT84, OLFM4, GJA1, AMOT and ADAMTS1, were strongly linked to DSG3 overexpression. Gene ontology analysis indicated that the DSG3-associated candidate gene products participate in crucial cellular processes such as junction assembly, focal adhesion, extracellular matrix formation, intermediate filament organisation and keratinocyte differentiation. Validation of RNA-Seq was performed through RT-qPCR, Western blotting and immunofluorescence analyses. Furthermore, using transmission electron microscopy, we meticulously examined desmosome morphology and revealed a slightly immature desmosome structure in DSG3-overexpressing cells compared to controls. No changes in desmosome frequency and diameter were observed between the two conditions. This study underscores intricate and multifaceted alterations associated with DSG3 in oral squamous carcinoma cells, implying a potential oncogenic role of this gene in biological processes that enable cell communication, motility and survival.
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Carcinoma de Células Escamosas , Neoplasias de la Boca , Humanos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Desmogleína 3/genética , Desmogleína 3/análisis , Desmogleína 3/metabolismo , Desmosomas/metabolismo , Perfilación de la Expresión Génica , Queratinocitos/metabolismo , Queratinas Específicas del Pelo/análisis , Queratinas Específicas del Pelo/genética , Queratinas Específicas del Pelo/metabolismo , Queratinas Tipo II/análisis , Queratinas Tipo II/genética , Queratinas Tipo II/metabolismo , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Oncogenes , TranscriptomaRESUMEN
Epidermolytic palmoplantar keratoderma (EPPK), a highly penetrant autosomal dominant genodermatosis, is characterized by diffuse keratoses on palmplantar epidermis. The keratin 9 gene (KRT9) is responsible for EPPK. To date, phenotypic therapy is the primary treatment for EPPK. Because KRT9 pairs with a type II keratin-binding partner to function in epidermis, identifying the interaction partner is an essential first step in revealing EPPK pathogenesis and its fundamental treatment. In this study, we proved that keratin 6C (KRT6C) is a probable hereterodimer partner for KRT9. In silico model for KRT6C/KRT9 shows a typical coiled-coil structure in their 2B domains. Proteomics analysis shows that KRT6C/KRT9 pair is in a densely connected protein-protein interaction network, where proteins participate jointly in regulating cytoskeleton organization and keratinization. This study shows that co-immunoprecipitation coupled with mass spectroscopy and proteomics analysis provide a sensitive approach, which compensates for inevitable inadequacies of anti-keratin 6C antibody and helps discover the probable hereterodimer partner KRT6C for KRT9. The acknowledgement of KRT6C/KRT9 pairwise relationship may help re-classify EPPK and PC-K6c (a milder form of pachyonychia congenita, caused by KRT6C) as a group of hereditary defects at a molecular-based level, and lay foundation for deciphering the keratin network contributing to EPPK and PC-K6c. SIGNIFICANCE OF THE STUDY: What is already known about this topic? KRT9 and KRT6C are disease-causing factors for epidermolytic palmoplantar keratoderma (EPPK) and a milder form of pachyonychia congenita (PC-K6c), respectively. EPPK and PC-K6c have some symptom similarities. Keratins are the major structural proteins in epithelial cells. Each of the type I keratin is matched by a particular type II keratin to assemble a coiled-coil heterodimer. The hereterodimer partner for KRT9 is unknown. What does this study add? We discovered and proved that KRT6C is a probable hereterodimer partner for KRT9 in palmplantar epidermis in a native endogenous environment by using co-immunoprecipitation coupled with mass spectroscopy and proteomics analysis, etc. The proteomics analysis shows that KRT6C/KRT9 keratin pair is in a densely connected protein-protein interaction network, where proteins participate jointly in regulating intermediate filament-based cytoskeleton organization and keratinization processes. What are the implications of this work? The new understanding of probable KRT6C/KRT9 pairwise correlation may help re-classify the genetic cutaneous disorders EPPK and PC-K6c as a group of hereditary defects at a molecular-based level, and lay foundation for pathogenic mechanism research in EPPK and PC-K6c. The densely related network components derived from the proteomic data using Metascape in the study and pairwise regulation fashion of specific keratin pairs should attract more attention in the further explorations when investigators concern the physiological functions of keratins and the pathogenesis of related skin diseases.
Asunto(s)
Queratodermia Palmoplantar Epidermolítica , Paquioniquia Congénita , Humanos , Queratodermia Palmoplantar Epidermolítica/genética , Queratodermia Palmoplantar Epidermolítica/patología , Proteómica , Epidermis , Queratinas/genética , Queratinas Tipo II/genética , Mutación , Linaje , Queratina-9/genéticaRESUMEN
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a model of a diverse spectrum of cancers because it is induced by well-known etiologies, mainly hepatitis C virus (HCV) and hepatitis B virus. Here, we aimed to identify HCV-specific mutational signatures and explored the link between the HCV-related regional variation in mutations rates and HCV-induced alterations in genome-wide chromatin organization. METHODS: To identify an HCV-specific mutational signature in HCC, we performed high-resolution targeted sequencing to detect passenger mutations on 64 HCC samples from 3 etiology groups: hepatitis B virus, HCV, or other. To explore the link between the genomic signature and genome-wide chromatin organization we performed chromatin immunoprecipitation sequencing for the transcriptionally permissive H3K4Me3, H3K9Ac, and suppressive H3K9Me3 modifications after HCV infection. RESULTS: Regional variation in mutation rate analysis showed significant etiology-dependent regional mutation rates in 12 genes: LRP2, KRT84, TMEM132B, DOCK2, DMD, INADL, JAK2, DNAH6, MTMR9, ATM, SLX4, and ARSD. We found an enrichment of C->T transversion mutations in the HCV-associated HCC cases. Furthermore, these cases showed regional variation in mutation rates associated with genomic intervals in which HCV infection dictated epigenetic alterations. This signature may be related to the HCV-induced decreased expression of genes encoding key enzymes in the base excision repair pathway. CONCLUSIONS: We identified novel distinct HCV etiology-dependent mutation signatures in HCC associated with HCV-induced alterations in histone modification. This study presents a link between cancer-causing mutagenesis and the increased predisposition to liver cancer in chronic HCV-infected individuals, and unveils novel etiology-specific mechanisms leading to HCC and cancer in general.
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Carcinoma Hepatocelular , Hepatitis C , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/patología , Carcinoma Hepatocelular/patología , Hepatitis C/complicaciones , Hepatitis C/genética , Mutación/genética , Hepacivirus/genética , Virus de la Hepatitis B/genética , Epigénesis Genética/genética , Cromatina , Genómica , Proteínas Tirosina Fosfatasas no Receptoras/genética , Queratinas Tipo II/genética , Queratinas Específicas del Pelo/genéticaRESUMEN
Alopecia areata is a complex genetic disease that results in hair loss due to the autoimmune-mediated attack of the hair follicle. We previously defined a role for both rare and common variants in our earlier GWAS and linkage studies. Here, we identify rare variants contributing to Alopecia Areata using a whole exome sequencing and gene-level burden analyses approach on 849 Alopecia Areata patients compared to 15,640 controls. KRT82 is identified as an Alopecia Areata risk gene with rare damaging variants in 51 heterozygous Alopecia Areata individuals (6.01%), achieving genome-wide significance (p = 2.18E-07). KRT82 encodes a hair-specific type II keratin that is exclusively expressed in the hair shaft cuticle during anagen phase, and its expression is decreased in Alopecia Areata patient skin and hair follicles. Finally, we find that cases with an identified damaging KRT82 variant and reduced KRT82 expression have elevated perifollicular CD8 infiltrates. In this work, we utilize whole exome sequencing to successfully identify a significant Alopecia Areata disease-relevant gene, KRT82, and reveal a proposed mechanism for rare variant predisposition leading to disrupted hair shaft integrity.
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Alopecia Areata/genética , Alopecia Areata/metabolismo , Secuenciación del Exoma , Queratinas Específicas del Pelo/genética , Queratinas Tipo II/genética , Predisposición Genética a la Enfermedad , Variación Genética , Cabello/metabolismo , Folículo Piloso/metabolismo , Humanos , Piel/metabolismoRESUMEN
KRT81 is involved in carcinogenesis and progression of many types of human cancers. However, little is known about the role of KRT81 in melanoma. In this study, we identified that KRT81 expression is upregulated in melanoma tissues compared with corresponding adjacent nontumor tissues. Overexpression of KRT81 was also found in human melanoma cell lines. Cell functional studies have shown that KRT81 knockdown could inhibit proliferation, colony formation, migration, invasion, and promote apoptosis of A375 cells. Consistently, in vivo tumorigenesis experiments showed that KRT81 knockdown significantly suppressed the growth of xenograft tumors. Moreover, KRT81 knockdown increased the chemosensitivity of A375 cells to DDP. Mechanical exploration revealed that KRT81 knockdown mediated the downregulation of inflammatory cytokine interleukin-8 (IL-8). In conclusion, these findings indicate that downregulation of KRT81 could inhibit progression of melanoma by regulating IL-8. Therefore, KRT81 represents a potential therapeutic target for melanoma therapy.
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Queratinas Específicas del Pelo/genética , Queratinas Tipo II/genética , Melanoma/genética , Neoplasias Cutáneas/genética , Anciano , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Línea Celular Tumoral , Femenino , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Queratinas Específicas del Pelo/metabolismo , Queratinas Tipo II/metabolismo , Masculino , Melanoma/metabolismo , Melanoma/patología , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patologíaRESUMEN
In human hair follicles, the hair-forming cells express 16 hair keratin genes depending on the differentiation stages. K85 and K35 are the first hair keratins expressed in cortical cells at the early stage of the differentiation. Two types of mutations in the gene encoding K85 are associated with ectodermal dysplasia of hair and nail type. Here, we transfected cultured SW-13 cells with human K85 and K35 genes and characterized filament formation. The K85-K35 pair formed short filaments in the cytoplasm, which gradually elongated and became thicker and entangled around the nucleus, indicating that K85-K35 promotes lateral association of short intermediate filaments (IFs) into bundles but cannot form IF networks in the cytoplasm. Of the K85 mutations related to ectodermal dysplasia of hair and nail type, a two-nucleotide (C1448 T1449 ) deletion (delCT) in the protein tail domain of K85 interfered with the K85-K35 filament formation and gave only aggregates, whereas a missense mutation (233A>G) that replaces Arg78 with His (R78H) in the head domain of K85 did not interfere with the filament formation. Transfection of cultured MCF-7 cells with all the hair keratin gene combinations, K85-K35, K85(R78H)-K35 and K85(delCT)-K35, as well as the individual hair keratin genes, formed well-developed cytoplasmic IF networks, probably by incorporating into the endogenous cytokeratin IF networks. Thus, the unique de novo assembly properties of the K85-K35 pair might play a key role in the early stage of hair formation.
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Quinasa 8 Dependiente de Ciclina/genética , Queratinas Específicas del Pelo/genética , Queratinas Tipo II/genética , Secuencia de Aminoácidos/genética , Línea Celular , Quinasa 8 Dependiente de Ciclina/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Cabello/metabolismo , Humanos , Filamentos Intermedios/genética , Queratinas/genética , Queratinas/metabolismo , Queratinas Específicas del Pelo/metabolismo , Queratinas Tipo II/metabolismo , Células MCF-7 , TransfecciónRESUMEN
Single nucleotide polymorphisms in miRNA binding sites (miR-SNPs) are associated with cancer risk. We assessed the relationship between five miR-SNPs in the 3' untranslated region (3'-UTR) of RYR3 (rs1044129), KIAA0423 (rs1053667), C14orf101 (rs4901706), GOLGA7 (rs11337), and KRT81 (rs3660) and the risk of breast cancer (BC). The CC genotype of rs3660 located in the 3'-UTR of KRT81 was identified for its association with lower BC risk (odds ratio, 0.093; 95% confidence interval, 0.045-0.193; p = 0.000). Immunnochemical analysis and Renilla luciferase reporter assays indicated that the CC genotype of KRT81 was associated with lower expression of KRT81 (p < 0.05). The subsequently functional analysis showed that knockdown the KRT81 could inhibit proliferation and promote apoptosis of the MDA-MB-231 BC cells (p < 0.05) with monocyte chemotactic protein-1 (MCP-1) deregulation. Meanwhile, KRT81 overexpression could promote the proliferation and inhibit the apoptosis of MCF-7 BC cells (p < 0.05). Our data demonstrated that the KRT81 expressional change modulated by rs3660 miR-SNP could modify the carcinogenesis of BC, thereby KRT81 would be a new target for BC treatment.
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Regiones no Traducidas 3' , Neoplasias de la Mama/genética , Queratinas Específicas del Pelo/genética , Queratinas Tipo II/genética , MicroARNs/metabolismo , Polimorfismo de Nucleótido Simple , Apoptosis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Quimiocina CCL2/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Queratinas Específicas del Pelo/metabolismo , Queratinas Tipo II/metabolismo , Células MCF-7RESUMEN
Skin lesions in dermatomyositis (DM) are common, are frequently refractory, and have prognostic significance. Histologically, DM lesions appear similar to cutaneous lupus erythematosus (CLE) lesions and frequently cannot be differentiated. We thus compared the transcriptional profile of DM biopsies with CLE lesions to identify unique features. Type I IFN signaling, including IFN-κ upregulation, was a common pathway in both DM and CLE; however, CLE also exhibited other inflammatory pathways. Notably, DM lesions could be distinguished from CLE by a 5-gene biomarker panel that included IL18 upregulation. Using single-cell RNA-sequencing, we further identified keratinocytes as the main source of increased IL-18 in DM skin. This study identifies a potentially novel molecular signature, with significant clinical implications for differentiating DM from CLE lesions, and highlights the potential role for IL-18 in the pathophysiology of DM skin disease.
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Dermatomiositis/genética , Interleucina-18/genética , Lupus Eritematoso Cutáneo/genética , Biopsia , Estudios de Cohortes , Proteínas Ricas en Prolina del Estrato Córneo/genética , Dermatomiositis/metabolismo , Dermatomiositis/patología , Femenino , Humanos , Interferones/genética , Interferones/metabolismo , Queratinas Tipo II/genética , Lupus Eritematoso Cutáneo/metabolismo , Lupus Eritematoso Cutáneo/patología , Masculino , Persona de Mediana Edad , Proteínas de Resistencia a Mixovirus/metabolismo , Transcriptoma , Tropomiosina/genéticaRESUMEN
BACKGROUND: Gastric cancer (GC) has been regarded as a kind of the most common cancers in gastrointestinal malignant tumors. Circular RNA (circRNA) is a newly discovered category of non-coding RNAs and plays a significant role in the initiation or development of human cancers. Nevertheless, the role of circPIP5K1A in GC remains unclear. METHODS: The relative expression level and the circular structure of circPIP5K1A were confirmedby RT-qPCR. The biological function of circPIP5K1A in GC was evaluated by colony formation, transwell and western blot assays. The binding capacity between miR-671-5p and circPIP5K1A (or KRT80) was assessed by luciferase reporter and Ago2-RIP assays. Protein levels of PI3K/AKT pathway were measured by western blot assay. RESULTS: CircPIP5K1A was up-regulated in GC tissues and cells with a circular structure. Functionally, circPIP5K1A silence limited cell proliferation, invasion, migration and EMT process. Mechanistically, circPIP5K1A directly interacted with miR-671-5p to modulate KRT80 expression. Either miR-671-5p inhibitor or KRT80 overexpression could offset the inhibitory effect of circPIP5K1A depletion on GC development. Besides, circPIP5K1A played its oncogenic role in GC through regulating PI3K/AKT pathway. At last, circPIP5K1A promoted GC tumor growth in vivo. CONCLUSIONS: CircPIP5K1A/miR-671-5p/KRT80 axis contributes to GC progression through PI3K/AKT pathway, implying this axis may be a potential therapeutic target for the treatment of GC patients.
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Queratinas Tipo II/metabolismo , MicroARNs/metabolismo , ARN Circular/metabolismo , Neoplasias Gástricas/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Queratinas Tipo II/genética , MicroARNs/genética , ARN Circular/genética , Neoplasias Gástricas/genética , Regulación hacia ArribaRESUMEN
BACKGROUND: Uterine receptivity is one of the determinants of embryo implantation, which is responsible for pregnancy success. Aberrant embryo implantation due to disrupted uterine receptivity is usually found in ovarian hyperstimulation induced hyperoestrogen patients. RESULTS: This study identified keratin 86 (KRT86), a fibrous structural protein, which was upregulated in uterine endometrium during peri-implantation. Using a hyperoestrogen mouse model established in a previous study, we found abnormal oestradiol (E2) levels during pre-implantation could trigger high expression of Krt86 in the uterine epithelium. In an ovariectomised mouse model, combining oestrogen receptors ERα and ERß knockout mice models, uterine Krt86 was found to be up-regulated after E2 treatment, mediated by nuclear ERα. Furthermore, we found progesterone (P4) could ameliorate Krt86 expression, induced by abnormal E2. CONCLUSIONS: These results revealed the dynamic expression and regulation of Krt86, especially in hyperoestrogen treated mice, indicating it might act as a marker for non-receptive uterus.
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Implantación del Embrión/fisiología , Estradiol/farmacología , Queratinas Tipo II/metabolismo , Útero/citología , Animales , Receptor alfa de Estrógeno/metabolismo , Femenino , Queratinas Tipo II/genética , Ratones Noqueados , Progesterona/farmacología , Útero/metabolismoRESUMEN
Approximately 30% of ERα breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epigenetic reprogramming in aromatase inhibitors (AI)-resistant cells, leading to Keratin-80 (KRT80) upregulation. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion and cellular stiffening, collectively promoting cancer cell invasion. Shearwave elasticity imaging performed on prospectively recruited patients confirms KRT80 levels correlate with stiffer tumors. Immunohistochemistry showed increased KRT80-positive cells at relapse and, using several clinical endpoints, KRT80 expression associates with poor survival. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.
Asunto(s)
Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/patología , Citoesqueleto/patología , Queratinas Tipo II/genética , Recurrencia Local de Neoplasia/patología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Antineoplásicos Hormonales/uso terapéutico , Inhibidores de la Aromatasa/farmacología , Inhibidores de la Aromatasa/uso terapéutico , Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Citoesqueleto/genética , Resistencia a Antineoplásicos/genética , Elementos de Facilitación Genéticos/genética , Epigénesis Genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Queratinas Tipo II/metabolismo , Células MCF-7 , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/mortalidad , Pronóstico , Dominios Proteicos/genética , Regulación hacia ArribaRESUMEN
The purpose of this review is to discuss the disease process and wide variety of treatment options for psuedofolliculitis barbae (PFB), or razor bumps. PFB is caused by hair follicles penetrating the skin and causing an inflammatory response. PFB can occur to anyone who shaves, and is more likely in those with curly hair. PFB can cause significant hyperpigmentation and scarring, more noticeable in darker skin types. PFB can be treated with a variety of topical, systemic, or light/laser therapies. Minimal progress has been made in treating PFB in recent years, partially due to the success of well-established current treatments discussed in this review. The most effective treatments involve a multifaceted approach including behavioral changes in shaving habits as well as the use of topical therapies. J Drugs Dermatol. 2019;18(3):246-250.