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1.
Cell Death Dis ; 13(8): 708, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35970845

RESUMO

Breast cancer, the most common cancer in women, usually exhibits intrinsic insensitivity to drugs, even without drug resistance. MUC1 is a highly glycosylated transmembrane protein, overexpressed in breast cancer, contributing to tumorigenesis and worse prognosis. However, the molecular mechanism between MUC1 and drug sensitivity still remains unclear. Here, natural flavonoid apigenin was used as objective due to the antitumor activity and wide availability. MUC1 knockout (KO) markedly sensitized breast cancer cells to apigenin cytotoxicity in vitro and in vivo. Both genetical and pharmacological inhibition significantly enhanced the chemosensitivity to apigenin and clinical drugs whereas MUC1 overexpression conversely aggravated such drug resistance. Constitutively re-expressing wild type MUC1 in KO cells restored the drug resistance; however, the transmembrane domain deletant could not rescue the phenotype. Notably, further investigation discovered that membrane-dependent drug resistance relied on the extracellular glycosylated modification since removing O-glycosylation via inhibitor, enzyme digestion, or GCNT3 (MUC1 related O-glycosyltransferase) knockout markedly reinvigorated the chemosensitivity in WT cells, but had no effect on KO cells. Conversely, inserting O-glycosylated sites to MUC1-N increased the drug tolerance whereas the O-glycosylated deletant (Ser/Thr to Ala) maintained high susceptibility to drugs. Importantly, the intracellular concentration of apigenin measured by UPLC and fluorescence distribution firmly revealed the increased drug permeation in MUC1 KO and BAG-pretreated cells. Multiple clinical chemotherapeutics with small molecular were tested and obtained the similar conclusion. Our findings uncover a critical role of the extracellular O-glycosylation of MUC1-N in weakening drug sensitivity through acting as a barrier, highlighting a new perspective that targeting MUC1 O-glycosylation has great potential to promote drug sensitivity and efficacy.


Assuntos
Neoplasias da Mama , Mucina-1 , Apigenina/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Resistência a Medicamentos , Tolerância a Medicamentos , Feminino , Glicosilação , Humanos , Mucina-1/genética , Mucina-1/metabolismo
2.
Arch Oral Biol ; 142: 105525, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36027639

RESUMO

OBJECTIVES: The aim of this study was to assess the MUC1 expression in the oral epithelium of normal, oral epithelial dysplasia (OED), oral squamous cell carcinoma (OSCC), and irradiated oral epithelium (IROE) and its association with smoking habits in non-smokers and smokers. DESIGN: Oral mucosal biopsies from controls, OED, OSCC, and IROE groups were obtained and categorized based on the smoking history as non-smokers, smoker I (25 pack-years), and smoker II (>25 pack-years). Immunohistochemical staining of MUC1 using human milk fat globule 1 (HMFG 1) antibody was performed, and the MUC1 score was calculated. The relation between MUC1 expression and clinicopathological findings was examined. RESULTS: MUC1 staining of superficial oral epithelial cells with mild MUC1 score was detected in all control samples. The MUC1 staining extended from superficial to basal cell layer of oral epithelium with the increase in MUC1 score from moderate to strong in OED, OSCC, and IROE, and the difference was significant (p < 0.004, p < 0.002 and p < 0.004, respectively) compared to controls. A positive association between smoking and MUC1 score was observed within groups (p < 0.05). CONCLUSION: The depolarization of MUC1 protein expression is associated with smoking habits in OED and OSCC. In the IROE, the radiation causes subcellular and molecular changes, observed as altered MUC1 expression and accelerated by smoking, furthermore, complicating the oral mucosal adaptation and progress to radiation-induced lesions as a delayed effect.


Assuntos
Carcinoma de Células Escamosas , Mucina-1 , Fumar , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Epitélio/metabolismo , Epitélio/patologia , Epitélio/efeitos da radiação , Humanos , Mucosa Bucal/metabolismo , Mucosa Bucal/patologia , Mucosa Bucal/efeitos da radiação , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Mucina-1/metabolismo , Fumar/efeitos adversos
3.
Anal Chim Acta ; 1223: 340193, 2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-35999001

RESUMO

Mucin 1(MUC1) is an effective marker of breast cancer, so it is of great significance to develop a simple, sensitive and highly selective MUC1 detection sensor. Herein, we constructed a label-free nanopore biosensor for rapid and highly sensitive detection of MUC1. The presence of MUC1 triggered the modification of the DNAzyme walking chain on the surface of Fe3O4 nanoparticles and separation from the aptamer. In the presence of Zn2+, DNAzyme catalyzed hydrolytic cleavage of the hairpin substrate at the scissile rA. The DNAzyme was divided into two fragments and ssDNA was released. ssDNA products from the hairpin substrate can generate a current blocking signal during α-hemolysin nanopore testing. The frequency of signature events showed a linear response toward the concentration of MUC1 in the range of 0.01 nM-100 nM. The sensing system also exhibited high selectivity against other protein and can be used for the detection of real sample.


Assuntos
Técnicas Biossensoriais , DNA Catalítico , Nanoporos , DNA , DNA Catalítico/metabolismo , DNA de Cadeia Simples , Proteínas Hemolisinas , Limite de Detecção , Mucina-1/metabolismo
4.
ACS Appl Mater Interfaces ; 14(35): 39727-39735, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36000701

RESUMO

Hydrogels of cross-linked mucin glycoproteins (Muc-gel) have shown strong immune-modulating properties toward macrophages in vitro, which are translated in vivo by the dampening of the foreign body response to implantation in mice. Beyond mucin hydrogels, other biomaterials such as sensors, electrodes, and other long-term implants would also benefit from such immune-modulating properties. In this work, we aimed to transfer the bioactivity observed for three-dimensional Muc-gels to the surface of two model materials by immobilizing mucin into thin films (Muc-film) using covalent layer-by-layer assembly. We tested how the surface immobilization of mucins affects macrophage responses compared to Muc-gels. We showed that Muc-films on soft polyacrylamide gels mimic Muc-gel in their modulation of macrophage responses with activated gene expression of inflammatory cytokines on day 1 and then dampening them on day 3. Also, the markers of polarized macrophages, M1 and M2, were expressed at the same level for macrophages on Muc-film-coated soft polyacrylamide gels and Muc-gel. In contrast, Muc-film-coated hard polystyrene led to a different macrophage response compared to Muc-gel, having no activated expression of inflammatory cytokines and a different M1 marker expression. This suggested that the substrate mechanical properties and mucin molecular configuration determined by substrate-mucin interactions affect mucin immune-modulating properties. We conclude that mucin immune-modulating properties can be transferred to materials by mucin surface immobilization but will be dependent on the substrate chemical and mechanical properties.


Assuntos
Hidrogéis , Mucinas , Animais , Materiais Biocompatíveis/metabolismo , Biomarcadores/metabolismo , Citocinas/metabolismo , Glicoproteínas/metabolismo , Hidrogéis/química , Macrófagos/metabolismo , Camundongos , Mucina-1/metabolismo , Mucinas/metabolismo
5.
Oxid Med Cell Longev ; 2022: 2405943, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35910848

RESUMO

Background: Ferroptosis is a nonapoptotic form of programmed cell death, which may be related to the occurrence and development of sepsis-induced acute respiratory distress syndrome (ARDS)/acute lung injury (ALI). Mucin 1 (MUC1) is a kind of macromolecule transmembrane glycoprotein. Previous studies have shown that MUC1 could relieve ALI in sepsis and predict whether sepsis patients would develop into ARDS. However, the role of MUC1 in the ferroptosis of sepsis-induced ALI/ARDS remains unclear. Materials and Methods: Sera samples from 50 patients with sepsis/septic shock were used to detect iron metabolism-related markers. Western blot and qRT-PCR were conducted to detect the expression levels of ferroptosis-related genes. Enzyme-linked immunosorbent assay (ELISA) was performed to evaluate inflammatory factors. Transmission electron microscopy (TEM) was used to assess morphological changes of cells. Results: The results showed that the iron metabolism-related indicators in sepsis-induced ARDS patients changed significantly, suggesting the iron metabolism disorder. The expression levels of ferroptosis-related genes in lung tissues of sepsis had marked changes, and the lipid peroxidation levels increased, while Ferrostatin-1 (Fer-1) could reverse the above results, which confirmed the occurrence of ferroptosis. In terms of mechanism studies, inhibition of MUC1 dimerization could increase the expression level of Keap1, reduce the phosphorylation level of GSK3ß, inhibit the entry of Nrf2 into the nucleus, further inhibit the expression level of GPX4, enhance the lipid peroxidation level of lung tissues, trigger ferroptosis, and aggravate lung injury. Besides, inhibiting MUC1 reversed the alleviating effect of vitamin E on ALI caused by sepsis, increased the aggregation of inflammatory cells in lung tissues, and aggravated alveolar injury and edema. Conclusions: Our study was the first to explore the changes of iron metabolism indicators in ALI/ARDS of sepsis, clarify the important role of ferroptosis in ALI/ARDS induced by sepsis, and reveal the effects and specific mechanisms of MUC1 in regulating ferroptosis, as well as the sensitization on vitamin E.


Assuntos
Lesão Pulmonar Aguda , Ferroptose , Mucina-1 , Sepse , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Ferroptose/genética , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Ferro/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Mucina-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Síndrome do Desconforto Respiratório , Sepse/complicações , Sepse/tratamento farmacológico , Vitamina E/metabolismo
6.
Int J Mol Sci ; 23(14)2022 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-35887202

RESUMO

Anti-mucin1 (MUC1) antibodies have been widely used for breast cancer diagnosis and treatment. This is based on the fact that MUC1 undergoes aberrant glycosylation upon cancer progression, and anti-MUC1 antibodies differentiate changes in glycan structure. MY.1E12 is a promising anti-MUC1 antibody with a distinct specificity toward MUC1 modified with an immature O-glycan (NeuAcα(2-3)Galß(1-3)GalNAc) on a specific Thr. However, the structural basis for the interaction between MY.1E12 and MUC1 remains unclear. The aim of this study is to elucidate the mode of interaction between MY.1E12 and MUC1 O-glycopeptide by NMR, molecular dynamics (MD) and docking simulations. NMR titration using MUC1 O-glycopeptides suggests that the epitope is located within the O-linked glycan and near the O-glycosylation site. MD simulations of MUC1 glycopeptide showed that the O-glycosylation significantly limits the flexibility of the peptide backbone and side chain of the O-glycosylated Thr. Docking simulations using modeled MY.1E12 Fv and MUC1 O-glycopeptide, suggest that VH mainly contributes to the recognition of the MUC1 peptide portion while VL mainly binds to the O-glycan part. The VH/VL-shared recognition mode of this antibody may be used as a template for the rational design and development of anti-glycopeptide antibodies.


Assuntos
Glicopeptídeos , Simulação de Dinâmica Molecular , Anticorpos Monoclonais , Glicopeptídeos/química , Espectroscopia de Ressonância Magnética , Mucina-1/metabolismo , Polissacarídeos/química
7.
Int J Mol Sci ; 23(15)2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35897789

RESUMO

Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options. TNBC progression is associated with expansion of cancer stem cells (CSCs). Few insights are available regarding druggable targets that drive the TNBC CSC state. This review summarizes the literature on TNBC CSCs and the compelling evidence that they are addicted to the MUC1-C transmembrane protein. In normal epithelia, MUC1-C is activated by loss of homeostasis and induces reversible wound-healing responses of inflammation and repair. However, in settings of chronic inflammation, MUC1-C promotes carcinogenesis. MUC1-C induces EMT, epigenetic reprogramming and chromatin remodeling in TNBC CSCs, which are dependent on MUC1-C for self-renewal and tumorigenicity. MUC1-C-induced lineage plasticity in TNBC CSCs confers DNA damage resistance and immune evasion by chronic activation of inflammatory pathways and global changes in chromatin architecture. Of therapeutic significance, an antibody generated against the MUC1-C extracellular domain has been advanced in a clinical trial of anti-MUC1-C CAR T cells and in IND-enabling studies for development as an antibody-drug conjugate (ADC). Agents targeting the MUC1-C cytoplasmic domain have also entered the clinic and are undergoing further development as candidates for advancing TNBC treatment. Eliminating TNBC CSCs will be necessary for curing this recalcitrant cancer and MUC1-C represents a promising druggable target for achieving that goal.


Assuntos
Neoplasias de Mama Triplo Negativas , Carcinogênese/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Inflamação/patologia , Mucina-1/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
8.
Biomolecules ; 12(7)2022 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-35883508

RESUMO

Breast cancer (BRCA) is the leading cause of death from malignant tumors among women. Fortunately, however, immunotherapy has recently become a prospective BRCA treatment with encouraging achievements and mild safety profiles. Since the overexpression and aberrant glycosylation of MUC1 (human mucin) are closely associated with BRCA, it has become an ideal target for BRCA immunotherapies. In this review, the structure and function of MUC1 are briefly introduced, and the main research achievements in different kinds of MUC1-mediated BRCA immunotherapy are highlighted, from the laboratory to the clinic. Afterward, the future directions of MUC1-mediated BRCA immunotherapy are predicted, addressing, for example, urgent issues in regard to how efficient immunotherapeutic strategies can be generated.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/terapia , Feminino , Glicosilação , Humanos , Fatores Imunológicos , Imunoterapia , Mucina-1/metabolismo , Mucinas , Estudos Prospectivos
9.
BMC Urol ; 22(1): 114, 2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35879749

RESUMO

BACKGROUND: MUC1 is a type I transmembrane protein that plays an important role in tumor cell signal transduction. Although current studies have shown that MUC1 is upregulated in bladder cancer (BC), the specific mechanism is still unclear. METHODS: We performed expression analysis, gene set enrichment analysis, survival analysis, immune infiltration analysis, drug sensitivity analysis, and metabolism-related gene expression analysis on TCGA-BLCA, GES31684 and GSE13507. RESULTS: The expression of MUC1 in the tumor and lymphatic metastasis positive samples was significantly increased. Genes related to MUC1 expression were significantly enriched in immune response, ribosomes, exosomes, and energy metabolism. The results of the immune infiltration analysis showed that M1 macrophages in BC with high MUC1 expression were significantly decreased. Expression of MUC1 increases drug resistance in BC patients. In addition, MUC1 increases glycolysis, glucose uptake, and lactate production by inducing metabolic reprogramming. CONCLUSION: MUC1 has a significant effect on the metabolism and immune cell infiltration of BC, which may be the cause of increased drug resistance, and can be used as a molecular target for the diagnosis and treatment of BC.


Assuntos
Neoplasias da Bexiga Urinária , Biologia Computacional , Resistência a Medicamentos , Glicólise , Humanos , Mucina-1/genética , Mucina-1/metabolismo , Prognóstico , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética
10.
mBio ; 13(4): e0105522, 2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-35699372

RESUMO

Influenza A virus (IAV) causes significant morbidity and mortality in the human population. Tethered mucin 1 (MUC1) is highly expressed in airway epithelium, the primary site of IAV replication, and also by other cell types that influence IAV infection, including macrophages. MUC1 has the potential to influence infection dynamics through physical interactions and/or signaling activity, yet MUC1 modulation and its impact during viral pathogenesis remain unclear. Thus, we investigated MUC1-IAV interactions in an in vitro model of human airway epithelium (HAE). Our data indicate that a recombinant IAV hemagglutinin (H3) and H3N2 virus can bind endogenous HAE MUC1. Notably, infection of HAE with H1N1 or H3N2 IAV strains does not trigger MUC1 shedding but instead stimulates an increase in cell-associated MUC1 protein. We observed a similar increase after type I or III interferon (IFN) stimulation; however, inhibition of IFN signaling during H1N1 infection only partially abrogated this increase, indicating that multiple soluble factors contribute to MUC1 upregulation during the antiviral response. In addition to HAE, primary human monocyte-derived macrophages also upregulated MUC1 protein in response to IFN treatment and conditioned media from IAV-infected HAE. Then, to determine the impact of MUC1 on IAV pathogenesis, we developed HAE genetically depleted of MUC1 and found that MUC1 knockout cultures exhibited enhanced viral growth compared to control cultures for several IAV strains. Together, our data support a model whereby MUC1 inhibits productive uptake of IAV in HAE. Infection then stimulates MUC1 expression on multiple cell types through IFN-dependent and -independent mechanisms that further impact infection dynamics. IMPORTANCE Influenza A virus (IAV) targets airway epithelial cells for infection. Large, heavily glycosylated molecules known as tethered mucins extend from the airway epithelial cell surface and may physically restrict pathogen access to underlying cells. Additionally, tethered mucin 1 (MUC1) can be differentially phosphorylated based on external stimuli and can influence inflammation. Given MUC1's multifunctional capability, we sought to define its role during IAV infection. Here, we demonstrate that IAV directly interacts with MUC1 in a physiologically relevant model of human airway epithelium (HAE) and find that MUC1 protein expression is elevated throughout the epithelium and in primary human monocyte-derived macrophages in response to antiviral signals produced during infection. Using CRISPR/Cas9-modified HAE, we demonstrated more efficient IAV infection when MUC1 is genetically ablated. Our data suggest that MUC1 physically restricts IAV uptake and represents a dynamic component of the host response that acts to inhibit viral spread, yielding new insight into mucin-mediated antiviral defense.


Assuntos
Vírus da Influenza A , Influenza Humana , Mucina-1 , Antivirais/farmacologia , Epitélio , Interações Hospedeiro-Patógeno , Humanos , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Vírus da Influenza A/fisiologia , Influenza Humana/metabolismo , Interferons/farmacologia , Mucina-1/genética , Mucina-1/metabolismo , Mucosa Respiratória/metabolismo , Mucosa Respiratória/virologia , Replicação Viral
11.
Oncogene ; 41(27): 3511-3523, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35688945

RESUMO

Merkel cell carcinoma (MCC) is an aggressive malignancy with neuroendocrine (NE) features, limited treatment options, and a lack of druggable targets. There is no reported involvement of the MUC1-C oncogenic protein in MCC progression. We show here that MUC1-C is broadly expressed in MCCs and at higher levels in Merkel cell polyomavirus (MCPyV)-positive (MCCP) relative to MCPyV-negative (MCCN) tumors. Our results further demonstrate that MUC1-C is expressed in MCCP, as well as MCCN, cell lines and regulates common sets of signaling pathways related to RNA synthesis, processing, and transport in both subtypes. Mechanistically, MUC1-C (i) interacts with MYCL, which drives MCC progression, (ii) is necessary for expression of the OCT4, SOX2, KLF4, MYC, and NANOG pluripotency factors, and (iii) induces the NEUROD1, BRN2 and ATOH1 NE lineage dictating transcription factors. We show that MUC1-C is also necessary for MCCP and MCCN cell survival by suppressing DNA replication stress, the p53 pathway, and apoptosis. In concert with these results, targeting MUC1-C genetically and pharmacologically inhibits MCC self-renewal capacity and tumorigenicity. These findings demonstrate that MCCP and MCCN cells are addicted to MUC1-C and identify MUC1-C as a potential target for MCC treatment.


Assuntos
Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Mucina-1 , Neoplasias Cutâneas , Carcinoma de Célula de Merkel/tratamento farmacológico , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/virologia , Humanos , Mucina-1/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/virologia
12.
Am J Dermatopathol ; 44(10): 718-727, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-35642978

RESUMO

ABSTRACT: This study sought to reveal the clinicopathologic characteristics of large cell neuroendocrine carcinoma (LCNEC) of the skin/conjunctiva. The retrieved patients included 3 men and 3 women with a median age of 85 (63-95) years. All lesions occurred on the face, including the ears, with a median tumor size of 11.5 (7-65) mm. Lymph node metastasis was observed in 5 (83%) of 6 cases, and distant metastasis was noted in 2 (33%). One patient (17%) who had a 13-mm-sized tumor died of the tumor 13 months after excision. All tumors were mainly located in the dermis, and one of them also exhibited intraepithelial spreading. The cytology resembled that of an LCNEC in other organs. No adnexal differentiation was observed. Five cases were of the pure type, but one had a component of squamous cell carcinoma. Immunoreactivities for CAM5.2, CK7, CK19, BerEP4, epithelial membrane antigen, neuron-specific enolase, synaptophysin, c-KIT, GATA3, and bcl-2 were frequently present, but CK20, neurofilament, Merkel cell polyomavirus large T antigen, mammaglobin, estrogen receptor, HER2, and TTF1 were completely negative in all cases. Mutant-pattern immunostaining of p53, PTEN, and Rb was frequently observed. The Ki67 rate exceeded 70% in all cases. LCNEC of the skin/conjunctiva is a morphologically-defined group of primary cutaneous/conjunctival neuroendocrine neoplasm, although it may be heterogeneous similar to other-site LCNEC or Merkel cell carcinoma. This study highlighted the predominant location for the face, high metastatic and lethal potential, possible combination with other tumor components, and frequent mutant-type immunoexpressions of p53, PTEN, and Rb in this tumor group.


Assuntos
Carcinoma de Célula de Merkel , Carcinoma Neuroendócrino , Carcinoma de Células Escamosas , Neoplasias Cutâneas , Idoso de 80 Anos ou mais , Antígenos Virais de Tumores , Biomarcadores Tumorais/metabolismo , Carcinoma de Célula de Merkel/patologia , Carcinoma Neuroendócrino/patologia , Túnica Conjuntiva/metabolismo , Túnica Conjuntiva/patologia , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Masculino , Mucina-1/metabolismo , Fosfopiruvato Hidratase/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores de Estrogênio , Neoplasias Cutâneas/patologia , Sinaptofisina/metabolismo , Proteína Supressora de Tumor p53
13.
Sci Rep ; 12(1): 8564, 2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35595812

RESUMO

Disease progression (DP) is an important parameter for the prognosis of idiopathic pulmonary fibrosis (IPF). This study aimed to evaluate the baseline serum biomarkers for predicting the DP in IPF. Seventy-four patients who were diagnosed with IPF and had their serum Krebs von den Lungen-6 (KL-6) and monocyte count, which might be associated with prognosis of IPF, checked more than twice were included. KL-6 ≥ 1000 U/mL and monocyte ≥ 600/µL were arbitrarily set as the cut-off values for DP. The DP was defined as a 10% reduction in forced vital capacity, a 15% reduction in diffusing capacity of the lung for carbon monoxide relative to the baseline, or disease-related mortality. Of the 74 patients, 18 (24.3%) were defined as having DP. The baseline KL-6 level was significantly increased in the DP group compared to the stable disease group (median, 1228.0 U/mL vs. 605.5 U/mL, P = 0.019). Multivariate Cox analyses demonstrated that a high KL-6 level (KL-6 ≥ 1000 U/mL; hazard ratio, 2.761 or 2.845; P = 0.040 or 0.045) was independently associated with DP in each model. The baseline serum KL-6 level might be a useful biomarker for DP in IPF.


Assuntos
Progressão da Doença , Fibrose Pulmonar Idiopática , Mucina-1 , Biomarcadores , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/patologia , Mucina-1/metabolismo , Capacidade Vital
14.
Mol Cancer Res ; 20(9): 1379-1390, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-35612556

RESUMO

Small cell lung cancer (SCLC) is a recalcitrant malignancy defined by subtypes on the basis of differential expression of the ASCL1, NEUROD1, and POU2F3 transcription factors. The MUC1-C protein is activated in pulmonary epithelial cells by exposure to environmental carcinogens and promotes oncogenesis; however, there is no known association between MUC1-C and SCLC. We report that MUC1-C is expressed in classic neuroendocrine (NE) SCLC-A, variant NE SCLC-N and non-NE SCLC-P cells and activates the MYC pathway in these subtypes. In SCLC cells characterized by NE differentiation and DNA replication stress, we show that MUC1-C activates the MYC pathway in association with induction of E2F target genes and dysregulation of mitotic progression. Our studies further demonstrate that the MUC1-C→MYC pathway is necessary for induction of (i) NOTCH2, a marker of pulmonary NE stem cells that are the proposed cell of SCLC origin, and (ii) ASCL1 and NEUROD1. We also show that the MUC1-C→MYC→NOTCH2 network is necessary for self-renewal capacity and tumorigenicity of NE and non-NE SCLC cells. Analyses of datasets from SCLC tumors confirmed that MUC1 expression in single SCLC cells significantly associates with activation of the MYC pathway. These findings demonstrate that SCLC cells are addicted to MUC1-C and identify a potential new target for SCLC treatment. IMPLICATIONS: This work uncovers addiction of SCLC cells to MUC1-C, which is a druggable target that could provide new opportunities for advancing SCLC treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Células Neuroendócrinas , Carcinoma de Pequenas Células do Pulmão , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Mucina-1/genética , Mucina-1/metabolismo , Células Neuroendócrinas/patologia , Proteínas Oncogênicas/genética , Carcinoma de Pequenas Células do Pulmão/genética
15.
Oncogene ; 41(22): 3064-3078, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35461328

RESUMO

Aberrant overexpression of mucin 1 (MUC1) and human epidermal growth factor receptor 2 (HER2) are often observed in breast cancer. However, the role of concomitant MUC1/HER2 in the development of breast cancer has not been fully illustrated. Following analysis of public microarray datasets that revealed a correlation between double MUC1 and HER2 positivity and a worse clinical outcome, we generated a mouse model overexpressing both Her2 and MUC1 cytoplasmic domain (MUC1-CD) to investigate their interaction in mammary carcinogenesis. Coexpression of Her2 and MUC1-CD conferred a growth advantage and promoted the development of spontaneous mammary tumors. Genomic analysis revealed that enforced expression of MUC1-CD and Her2 induces mammary tumor lineage plasticity, which is supported by gene reprogramming and mammary stem cell enrichment. Through gain- and loss-of-function strategies, we show that coexpression of Her2 and MUC1-CD is associated with downregulation of tricarboxylic acid (TCA) cycle genes in tumors. Importantly, the reduction in TCA cycle genes induced by MUC1-CD was found to be significantly connected to poor prognosis in HER2+ breast cancer patients. In addition, MUC1 augments the Her2 signaling pathway by inducing Her2/Egfr dimerization. These findings collectively demonstrate the vital role of MUC1-CD/Her2 collaboration in shaping the mammary tumor landscape and highlight the prognostic and therapeutic implications of MUC1 in patients with HER2+ breast cancer.


Assuntos
Neoplasias da Mama , Neoplasias Mamárias Animais , Mucina-1/metabolismo , Animais , Neoplasias da Mama/patologia , Transformação Celular Neoplásica , Feminino , Humanos , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/metabolismo , Camundongos , Mucina-1/genética , Receptor ErbB-2/metabolismo , Transdução de Sinais
16.
J Dent Res ; 101(8): 983-991, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35259994

RESUMO

Current treatments for xerostomia/dry mouth are palliative and largely ineffective. A permanent clinical resolution is being developed to correct hyposalivation using implanted hydrogel-encapsulated salivary human stem/progenitor cells (hS/PCs) to restore functional salivary components and increase salivary flow. Pluripotent epithelial cell populations derived from hS/PCs, representing a basal stem cell population in tissue, can differentiate along either secretory acinar or fluid-transporting ductal lineages. To develop tissue-engineered salivary gland replacement tissues, it is critical to reliably identify cells in tissue and as they enter these alternative lineages. The secreted protein α-amylase, the transcription factor MIST1, and aquaporin-5 are typical markers for acinar cells, and K19 is the classical ductal marker in salivary tissue. We found that early ductal progenitors derived from hS/PCs do not express K19, and thus earlier markers were needed to distinguish these cells from acinar progenitors. Salivary ductal cells express distinct polarity complex proteins that we hypothesized could serve as lineage biomarkers to distinguish ductal cells from acinar cells in differentiating hS/PC populations. Based on our studies of primary salivary tissue, both parotid and submandibular glands, and differentiating hS/PCs, we conclude that the apical marker MUC1 along with the polarity markers INADL/PATJ and SCRIB reliably can identify ductal cells in salivary glands and in ductal progenitor populations of hS/PCs being used for salivary tissue engineering. Other markers of epithelial maturation, including E-cadherin, ZO-1, and partition complex component PAR3, are present in both ductal and acinar cells, where they can serve as general markers of differentiation but not lineage markers.


Assuntos
Proteínas de Membrana , Mucina-1 , Glândulas Salivares , Proteínas Supressoras de Tumor , Xerostomia , Células Acinares/metabolismo , Biomarcadores/metabolismo , Diferenciação Celular , Células Cultivadas , Células Epiteliais , Humanos , Proteínas de Membrana/metabolismo , Mucina-1/metabolismo , Glândulas Salivares/metabolismo , Proteínas de Junções Íntimas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Xerostomia/terapia
17.
Theranostics ; 12(3): 999-1011, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35154471

RESUMO

Mucin 1 (MUC1) is a heterodimeric transmembrane glycoprotein that protects epithelial cells in mammals. The transmembrane C-terminal subunit (MUC1-C) plays a crucial role in oncogenesis. As an oncoprotein, MUC1-C regulates a number of proteins that are associated with tumorigenesis by interacting with oncoproteins, transcription factors, coactivators, etc., inducing proliferation, epithelial-mesenchymal transition (EMT), invasion, stemness, immune evasion, and drug resistance. Moreover, MUC1-C modulates the expression of non-coding RNAs (ncRNAs), which further regulate carcinogenesis by directly binding to specific proteins. ncRNAs can also affect MUC1 protein expression by targeting the MUC1 mRNA 3' untranslated region (UTR). A series of ncRNAs can modulate cancer development by regulating MUC1-C. This review focuses on the interaction of MUC1-C with proteins and ncRNAs in cancer progression. We also summarize the recent advances in immunotherapy with a focus on therapeutic approaches based on MUC1-C and nanocarrier complexes for cancer treatment.


Assuntos
MicroRNAs , Neoplasias , Animais , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Mamíferos/genética , Mamíferos/metabolismo , MicroRNAs/metabolismo , Mucina-1/metabolismo , Neoplasias/genética , Neoplasias/terapia , Proteínas Oncogênicas , RNA não Traduzido/genética
18.
Mol Carcinog ; 61(4): 417-432, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35040191

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common primary malignancies. Drug resistance has significantly prevented the clinical application of sorafenib (SF), a first-line targeted medicine for the treatment of HCC. Solamargine (SM), a natural alkaloid, has shown potential antitumor activity, but studies about antitumor effect of SM are obviously insufficient in HCC. In the present study, we found that SM significantly inhibited the growth of HCC and enhanced the anticancer effect of SF. In brief, SM significantly inhibited the growth of HepG2 and Huh-7 cells. The combination of SM and SF showed a synergistic antitumor effect. Mechanistically, SM downregulated the expression of long noncoding RNA HOTTIP and TUG1, followed by increasing the expression of miR-4726-5p. Moreover, miR-4726-5p directly bound to the 3'-UTR region of MUC1 and decreased the expression of MUC1 protein. Overexpression of MUC1 partially reversed the inhibitory effect of SM on HepG2 and Huh-7 cells viability, which suggested that MUC1 may be the key target in SM-induced growth inhibition of HCC. More importantly, the combination of SM and SF synergistically restrained the expression of MUC1 protein. Taken together, our study revealed that SM inhibited the growth of HCC and enhanced the anticancer effect of SF through HOTTIP-TUG1/miR-4726-5p/MUC1 signaling pathway. These findings will provide potential therapeutic targets and strategies for the treatment of HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , RNA Longo não Codificante , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Mucina-1/genética , Mucina-1/metabolismo , Mucina-1/uso terapêutico , RNA Longo não Codificante/genética , Alcaloides de Solanáceas , Sorafenibe/farmacologia
19.
Food Chem Toxicol ; 161: 112820, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35033595

RESUMO

Acute inhalation toxicity testing for chemical classification and labeling has been performed using animal models, however, these models have limited predictibility of the toxicity on the respiratory system. Thus, non-animal models have been emerging as alternatives for preclinical assessment of respiratory toxicity of chemicals, comprising in chemico, in vitro, ex vivo, and in silico approaches. In this study, we characterized and evaluated the applicability of a new ex vivo bovine bronchial model for addressing key aspects of pulmonary toxicity. Standardized bronchial fragments were cultured at an air-liquid interface for seven days showing cell viability, morphology, and function during the ex vivo time of cultivation. Different exposure ways, liquid or aerosol exposure, were also studied using paraformaldehyde (PFA) as a positive control. In a concentration-dependent manner, a decrease in tissue viability was observed for aerosols instead of direct liquid exposure upon tissue surface. Moreover, PFA exposure allowed the addressment of several damage biomarkers, including epithelium thickness, mitochondrial activity, ROS production, and caspase-3 activation. Besides, the bronquial tissue was exposed to chemicals from different UN GHS inhalation toxicity categories and presented a concentration-dependent response for most of the evaluated materials. The proposed airway ex vivo model represents a low-cost and reproducible tool applicable for pulmonary toxicity assessment of chemicals.


Assuntos
Fixadores/toxicidade , Formaldeído/toxicidade , Pulmão/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Polímeros/toxicidade , Testes de Toxicidade/métodos , Animais , Biomarcadores/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Bovinos , Sobrevivência Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Mucina-1/genética , Mucina-1/metabolismo , Espécies Reativas de Oxigênio
20.
Mol Cancer Res ; 20(4): 556-567, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35022313

RESUMO

The oncogenic MUC1-C protein promotes dedifferentiation of castrate-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC) cells. Chromatin remodeling is critical for the cancer stem cell (CSC) state; however, there is no definitive evidence that MUC1-C regulates chromatin accessibility and thereby expression of stemness-associated genes. We demonstrate that MUC1-C drives global changes in chromatin architecture in the dedifferentiation of CRPC and TNBC cells. Our results show that MUC1-C induces differentially accessible regions (DAR) across their genomes, which are significantly associated with differentially expressed genes (DEG). Motif and cistrome analysis further demonstrated MUC1-C-induced DARs align with genes regulated by the JUN/AP-1 family of transcription factors. MUC1-C activates the BAF chromatin remodeling complex, which is recruited by JUN in enhancer selection. In studies of the NOTCH1 gene, which is required for CRPC and TNBC cell self-renewal, we demonstrate that MUC1-C is necessary for (i) occupancy of JUN and ARID1A/BAF, (ii) increases in H3K27ac and H3K4me3 signals, and (iii) opening of chromatin accessibility on a proximal enhancer-like signature. Studies of the EGR1 and LY6E stemness-associated genes further demonstrate that MUC1-C-induced JUN/ARID1A complexes regulate chromatin accessibility on proximal and distal enhancer-like signatures. These findings uncover a role for MUC1-C in chromatin remodeling that is mediated at least in part by JUN/AP-1 and ARID1A/BAF in association with driving the CSC state. IMPLICATIONS: These findings show that MUC1-C, which is necessary for the CRPC and TNBC CSC state, activates a novel pathway involving JUN/AP-1 and ARID1A/BAF that regulates chromatin accessibility of stemness-associated gene enhancers.


Assuntos
Montagem e Desmontagem da Cromatina , Regulação Neoplásica da Expressão Gênica , Carcinogênese/genética , Cromatina/genética , Cromatina/metabolismo , Humanos , Masculino , Mucina-1/metabolismo , Células-Tronco Neoplásicas/metabolismo , Oncogenes
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