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Breast cancer patients with lymphatic metastasis suffer from poor prognoses. There is an urgent need for controlling lymph node metastasis, but it has proven challenging so far. Here, we implemented LASSO analysis of The Cancer Genome Atlas database to identify genes related to lymph node metastasis and prognosis, and 15 genes were selected. We constructed a functional protein association network and univariate Cox regression to identify significant genes. The results showed that BAHD1 could be predictive of lymph node metastasis as well as prognosis. In vitro studies demonstrated that BAHD1 exerted appreciable effects on the proliferation, migration, and invasion capacity of breast cancer cells. Furthermore, downregulation of BAHD1 induced cell cycle arrest in G1 phase. Additionally, the mRNA levels of CCND1, CDK1 and YWHAZ were decreased upon BAHD1 silencing. These findings indicate that the expression of BAHD1 is essential in the progression of breast cancer, which may provide novel therapeutic and diagnostic clues and insights into the prevention of lymph node metastasis in breast cancer.
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Neoplasias da Mama , Neoplasias da Mama/patologia , Proliferação de Células/genética , Proteínas Cromossômicas não Histona , Feminino , Humanos , Metástase Linfática , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Bioaugmented biotrickling filter (BTF) seeded with Piscinibacter caeni MQ-18, Pseudomonas oleovorans DT4, and activated sludge was established to investigate the treatment performance and biodegradation kinetics of the gaseous mixtures of tetrahydrofuran (THF) and methyl tert-butyl ether (MTBE). Experimental results showed an enhanced startup performance with a startup period of 9 d in bioaugmented BTF (25 d in control BTF seeded with activated sludge). The interaction parameter I2,1 of control (7.462) and bioaugmented BTF (3.267) obtained by the elimination capacity-sum kinetics with interaction parameter (EC-SKIP) model indicated that THF has a stronger inhibition of MTBE biodegradation in the control BTF than in the bioaugmented BTF. Similarly, the self-inhibition EC-SKIP model quantified the positive effects of MTBE on THF biodegradation, as well as the negative effects of THF on MTBE biodegradation and the self-inhibition of MTBE and THF. Metabolic intermediate analysis, real-time quantitative polymerase chain reaction, biofilm-biomass determination, and high-throughput sequencing revealed the possible mechanism of the enhanced treatment performance and biodegradation interactions of MTBE and THF.
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Éteres Metílicos , Pseudomonas oleovorans , Biodegradação Ambiental , Burkholderiales , Furanos , Éteres Metílicos/análiseRESUMO
Given the heterogeneity of solid tumors, single-target CAR-T cell therapy often leads to recurrence, especially in ovarian cancer (OV). Here, we constructed a Tandem-CAR targeting two antigens with secretory activity (IL-12) to improve the effects of CAR-T cell therapy. Twenty coexpressed upregulated genes were identified from the GEO database, and we found FOLR1 (folate receptor 1) and MSLN (mesothelin) were specifically and highly expressed in cancer tissues and only 11.25% of samples were negative for both antigens. We observed an increased proliferation rate for these three CAR-T cells, and Tandem CAR-T cells could efficiently lyse antigen-positive OV cells in vitro and secrete higher levels of cytokines than single-target CAR-T cells. More importantly, in vivo experiments indicated that Tandem CAR-T cells markedly decreased tumor volume, exhibited enhanced antitumor activity, and prolonged mouse survival. Furthermore, the infiltration and persistence of T cells in the Tandem-CAR group were higher than those in the MSLN-CAR and Control-T groups but comparable to those in the FOLR1-CAR group. Collectively, this study demonstrated that Tandem CAR-T cells secreting IL-12 could enhance immunotherapeutic effects by reducing tumor antigen escape and increasing T cell functionality, which could be a promising therapeutic strategy for OV and other solid tumors.
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Terapia Baseada em Transplante de Células e Tecidos/métodos , Receptor 1 de Folato/metabolismo , Mesotelina/metabolismo , Neoplasias Ovarianas/terapia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Citocinas/genética , Citocinas/metabolismo , Bases de Dados Genéticas , Feminino , Receptor 1 de Folato/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-12/metabolismo , Mesotelina/genética , Camundongos , Camundongos Nus , Transcriptoma , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
SITSH (syndrome of inappropriate secretion of thyrotropin) is a rare clinical state defined as uninhibited serum thyroid stimulating hormone in the presence of elevated thyroid hormone. This state is complicated and mainly caused by the abnormal feedback of hypothalamus-pituitary thyroid axis. The TSH adenoma (TSH-oma) and resistance to thyroid hormones (RTH) are the main etiologies of SITSH. As is well known that the treatment strategies of RTH and TSH-oma are apparently different, thus identifying the difference between RTH and TSH-oma is of great significance for the diagnosis and treatment of SITSH. CASE DESCRIPTION: A 62-year-old man with a state of elevated thyroid hormones and inappropriate elevated serum TSH level was hospitalized in 2016. Results of the pituitary enhanced magnetic resonance imaging and the somatostatin test respectively demonstrated a space-occupying lesion of pituitary and an elevated serum sex hormone binding globulin (SHBG) and inhibited TSH secretion, which indicated the occurrence of TSH-oma. In 2019, a 23-year-old girl with a state of elevated thyroid hormones and inappropriate normal serum TSH was hospitalized. Interestingly, whole exome sequencing detection suggested a pathogenic mutation in thyroid hormone receptor ß (THRB) gene, which has been shown to be associated with RTH. CONCLUSIONS: The difference between TSH-oma and RTH ought to be clarified for their accurate diagnose and treatment. The clinical experiences of the two cases reported here suggest that more detail information such as family medical history, serum SHBG level, and THRB gene test is helpful for the diagnose and treatment of TSH-oma and RTH. Additionally, we also summarized the identification points, diagnosis process, and treatment strategies for these two rare diseases.
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Adenoma , Neoplasias Hipofisárias , Síndrome da Resistência aos Hormônios Tireóideos , Adenoma/diagnóstico por imagem , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/diagnóstico por imagem , Síndrome da Resistência aos Hormônios Tireóideos/genética , Hormônios Tireóideos , Tireotropina , Adulto JovemRESUMO
Lysosomes are an important component of the inner membrane system and participate in numerous cell biological processes, such as macromolecular degradation, antigen presentation, intracellular pathogen destruction, plasma membrane repair, exosome release, cell adhesion/migration and apoptosis. Thus, lysosomes play important roles in cellular activity. In addition, previous studies have shown that lysosomes may play important roles in cancer development and progression through the abovementioned biological processes and that the functional status and spatial distribution of lysosomes are closely related to cancer cell proliferation, energy metabolism, invasion and metastasis, immune escape and tumor-associated angiogenesis. Therefore, identifying the factors and mechanisms that regulate the functional status and spatial distribution of lysosomes and elucidating the relationship between lysosomes and the development and progression of cancer can provide important information for cancer diagnosis and prognosis prediction and may yield new therapeutic targets. This study briefly reviews the above information and explores the potential value of lysosomes in cancer therapy.
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Triple-negative breast cancer (TNBC) has a greater risk of recurrence and metastasis along with a worse prognosis compared with other subtypes of breast cancer. Studies have revealed that mitogenic estrogen signaling is involved in the malignant proliferation of TNBC cells through a novel variant of the estrogen receptor, estrogen receptor α-36 (ER-α36). The results of the present study demonstrated that knockdown of ER-α36 expression in TNBC cells using short hairpin RNA inhibited rapid estrogen signaling bypass activation of the PI3K/AKT signaling pathway. Moreover, the ER-α36 modulator icaritin inhibited the proliferation of TNBC cells both in vitro and in vivo. Here, it was revealed that the combination of icaritin and cetuximab, a therapeutic epidermal growth factor receptor (EGFR) neutralizing antibody, induced apoptosis and inhibited cell proliferation synergistically in TNBC cells. The results of the present study improved the understanding of the underlying mechanisms of TNBC progression and supported the therapeutic potential of combined treatment targeting the ER-α36 and EGFR.
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Although Wilms' tumor gene 1 (WT1) was first cloned and identified as a tumor suppressor gene in nephroblastoma, subsequent studies have demonstrated that it can also play an oncogenic role in leukemia and various solid tumors. WT1 exerts biological functions with high tissue- and cell-specificity. This article reviews the relationship between WT1 and breast cancer from two aspects: (1) clinical application of WT1, including the relationship between expression of WT1 and prognosis of breast cancer patients, and its effectiveness as a target for comprehensive therapy of breast cancer; (2) the biological effects and molecular mechanisms of WT1 in the development and progression of breast cancer, including proliferation, apoptosis, invasion, and metastasis of breast cancer cells.
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Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas WT1/genética , Proteínas WT1/metabolismo , Apoptose/genética , Apoptose/fisiologia , Neoplasias da Mama/genética , Proliferação de Células/genética , Proliferação de Células/fisiologia , Feminino , Humanos , PrognósticoRESUMO
MYCN-amplified neuroblastoma (NB) is characterized by poor prognosis, and directly targeting MYCN has proven challenging. Here, we showed that aldehyde dehydrogenase family 18 member A1 (ALDH18A1) exerts profound impacts on the proliferation, self-renewal, and tumorigenicity of NB cells and is a potential risk factor in patients with NB, especially those with MYCN amplification. Mechanistic studies revealed that ALDH18A1 could both transcriptionally and posttranscriptionally regulate MYCN expression, with MYCN reciprocally transactivating ALDH18A1 and thus forming a positive feedback loop. Using molecular docking and screening, we identified an ALDH18A1-specific inhibitor, YG1702, and demonstrated that pharmacological inhibition of ALDH18A1 was sufficient to induce a less proliferative phenotype and confer tumor regression and prolonged survival in NB xenograft models, providing therapeutic insights into the disruption of this reciprocal regulatory loop in MYCN-amplified NB.
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Aldeído Desidrogenase/genética , Proteína Proto-Oncogênica N-Myc , Células-Tronco Neurais , Neuroblastoma , Linhagem Celular Tumoral , Retroalimentação , Humanos , Simulação de Acoplamento Molecular , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genéticaRESUMO
The original and corrected figures are shown in the accompanying Author Correction.
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Early invasive growth along specific anatomical structures, especially the white matter tract, is regarded as one of the main causes of poor therapeutic outcome of people with gliomas. We show that some glioma stem cells (GSCs) are preferentially located along white matter tracts, which exhibit a demyelinated phenotype, at the invasive frontier of glioma tissues. These GSCs are CD133+Notch1+, whereas the nerve fibers express the Notch ligand Jagged1. The Notch-induced transcription factor Sox9 promotes the transcription of SOX2 and the methylation level of the NOTCH1 promoter is attenuated by the upregulation of SOX2 to reinforce NOTCH1 expression in GSCs. This positive-feedback loop in a cohort of glioma subjects is correlated with a poor prognosis. Inhibition of Notch signaling attenuates the white-matter-tract tropism of GSCs. These findings provide evidence indicating that the NOTCH1-SOX2 positive-feedback loop controls GSC invasion along white matter tracts.
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Neoplasias Encefálicas/metabolismo , Retroalimentação Fisiológica/fisiologia , Glioma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Receptor Notch1/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Substância Branca/metabolismo , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Imagem de Tensor de Difusão , Glioma/diagnóstico por imagem , Glioma/patologia , Humanos , Proteína Jagged-1/metabolismo , Invasividade Neoplásica/patologia , Células-Tronco Neoplásicas/patologia , Substância Branca/patologiaRESUMO
PURPOSE: Cancer stem-like cells (CSCs) contribute to bladder cancer chemotherapy resistance and progression, but the associated mechanisms have not been elucidated. This study determined whether blocking an autocrine signaling loop in CSCs improves the therapeutic effects of cis-platinum on bladder cancer. EXPERIMENTAL DESIGN: The expression of the epithelial marker OV6 and other markers in human bladder cancer specimens was examined by IHC. The CSC properties of magnetic-activated cell sorting (MACS)-isolated OV6+ and OV6- bladder cancer cells were examined. Molecular mechanisms were assessed through RNA-Seq, cytokine antibody arrays, co-immunoprecipitation (co-IP), chromatin immunoprecipitation (ChIP) and other assays. An orthotopic bladder cancer mouse model was established to evaluate the in vivo effects of a YAP inhibitor (verteporfin) and a PDGFR inhibitor (CP-673451) on the cis-platinum resistance of OV6+ CSCs in bladder cancer. RESULTS: Upregulated OV6 expression positively associated with disease progression and poor prognosis for bladder cancer patients. Compared with OV6- cells, OV6+ bladder cancer cells exhibited strong CSC characteristics, including self-renewal, tumor initiation in NOD/SCID mice, and chemotherapy resistance. YAP, which maintains the stemness of OV6+ CSCs, triggered PDGFB transcription by recruiting TEAD1. Autocrine PDGF-BB signaling through its receptor PDGFR stabilized YAP and facilitated YAP nuclear translocation. Furthermore, blocking the YAP/TEAD1/PDGF-BB/PDGFR loop with verteporfin or CP-673451 inhibited the cis-platinum resistance of OV6+ bladder cancer CSCs in an orthotopic bladder cancer model. CONCLUSIONS: OV6 could be a helpful indicator of disease progression and prognosis for patients with bladder cancer, and targeting the autocrine YAP/TEAD1/PDGF-BB/PDGFR loop might serve as a remedy for cis-platinum resistance in patients with advanced bladder cancer.
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Comunicação Autócrina/genética , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/metabolismo , Quinolinas/farmacologia , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Verteporfina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Proteínas de Sinalização YAPRESUMO
Purpose: Cancer stem-like cells (CSC) contribute to the progression and androgen deprivation therapy (ADT) resistance of prostate cancer. As CSCs depend on their specific niche, including tumor-associated macrophages (TAM), elucidating the network between CSCs and TAMs may help to effectively inhibit the progression and ADT resistance of prostate cancer.Experimental Design: The underlying intracellular mechanism that sustains the stem-like characteristics of CSCs in prostate cancer was assessed via RNA sequencing, co-immunoprecipitation, chromatin immunoprecipitation, and other assays. A coculture system and cytokine antibody arrays were used to examine the interaction network between CSCs and TAMs. In addition, an orthotopic prostate cancer model was established to evaluate the in vivo effects of the combined targeting of CSCs and their interaction with TAMs on ADT resistance.Results: Autophagy-related gene 7 (ATG7) facilitated the transcription of OCT4 via ß-catenin, which binds to the OCT4 promoter, promoting CSC characteristics in prostate cancer, including self-renewal, tumor initiation, and drug resistance. In addition, CSCs remodeled their specific niche by educating monocytes/macrophages toward TAMs, and the CSC-educated TAMs reciprocally promoted the stem-like properties of CSCs, progression and ADT resistance of prostate cancer via IL6/STAT3. Furthermore, the combined targeting of CSCs and their interaction with TAMs by inhibiting ATG7/OCT4 and IL6 receptor effectively ameliorated ADT resistance in an orthotopic prostate cancer model.Conclusions: Targeting CSCs and their niche may prove to be a more powerful strategy than targeting CSCs alone, providing a rational approach to ameliorating ADT resistance in prostate cancer. Clin Cancer Res; 24(18); 4612-26. ©2018 AACR.
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Antagonistas de Androgênios/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Adulto , Idoso , Antagonistas de Androgênios/efeitos adversos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologiaRESUMO
A rational treatment strategy for glioma, the most common primary central nervous system tumor, should focus on early invasive growth and resistance to current therapeutics. Connexin 43 (Cx43), a gap junction protein, plays important roles not only in the development of the central nervous system and but also in the progression of glioma. The different structural domains of Cx43, including extracellular loops, transmembrane domains, and an intracellular carboxyl terminal, have distinct functions in the invasion and proliferation of gliomas. Targeting these domains of Cx43, which is expressed in distinct patterns in the heterogeneous glioma cell population, can inhibit tumor cell invasion and new tumor formation. Thus, this review summarizes the structural characteristics of Cx43, the effects of regulating different Cx43 domains on the biological characteristics of glioma cells, intervention strategies targeting different domains of Cx43, and future research directions.
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Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Conexinas/antagonistas & inibidores , Glioma/tratamento farmacológico , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioma/metabolismo , Glioma/patologia , Humanos , Terapia de Alvo Molecular , Prognóstico , Domínios ProteicosRESUMO
Quantitation of chromatographically coeluting compounds with partially overlapping mass profiles is a challenging task, especially if only a low-resolution mass spectrometer is available. To examine whether theoretical predictions can be utilized to determine the appropriate concentration ranges of the coeluting compounds that satisfy the non-interfering condition, we utilized an algorithm based upon a two-component model to compare the experimentally measured and predicted quantitation errors. Selected unlabeled and 13C-labeled polychlorinated biphenyl (PCB) congeners were investigated as model compounds. Standard solutions containing various concentration ratios of the unlabeled and 13C-labeled PCB congeners were analyzed, and the data were used to compare with theoretical predictions derived from the chlorine isotopic distributions (35Cl and 37Cl). Good agreements between experimental predictions and theoretical predictions were found on the magnitude of interferences for quantitation of 13C-labeled PCB congeners, as well as on the variability of the quantitation errors with the concentration ratio of 13C-labeled and unlabeled PCB counterparts. In addition, the magnitude of interferences considered in the present study was highly dependent upon the number of coexisting ions included for quantitation and their relative abundances in the mass spectrum. All these results suggest that the magnitude of interferences in quantifying a pair of coeluting compounds with partially overlapping mass spectral profiles can be effectively determined and minimized by carefully selecting the concentration ratio of the coeluting compounds and/or the number of quantitation ions. Finally, the selection of the experimental parameters to satisfy the non-interfering condition can be made purely on the basis of theoretical considerations.