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The focal adhesion kinase (FAK) tyrosine kinase is activated and upregulated in multiple cancer types including small cell lung cancer (SCLC). However, FAK inhibitors have shown limited efficacy in clinical trials for cancer treatment. With the aim of identifying potential therapeutic strategies to inhibit FAK for cancer treatment, we investigated long non-coding RNAs (lncRNAs) that potentially regulate FAK in SCLC. In this study, we identified a long non-coding RNA LINC01089 that binds and inhibits FAK phosphorylation (activation). Expression analysis revealed that LINC01089 was downregulated in SCLC tissues and negatively correlated with chemoresistance and survival in SCLC patients. Functionally, LINC01089 inhibited chemoresistance and progression of SCLC in vitro and in vivo. Mechanistically, LINC01089 inhibits FAK activation by blocking binding with Src and talin kinases, while FAK negatively regulates LINC01089 transcription by activating the ERK signaling pathway to recruit the REST transcription factor. Furthermore, LINC01089-FAK axis mediates the expression of drug resist-related genes by modulating YBX1 phosphorylation, leading to drug resistance in SCLC. Intriguingly, the FAK-LINC01089 interaction depends on the co-occurrence of the novel FAK variant and the non-conserved region of LINC01089 in primates. In Conclusion, our results indicated that LINC01089 may serve as a novel high-efficiency FAK inhibitor and the FAK-LINC01089 axis represents a valuable prognostic biomarker and potential therapeutic target in SCLC.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Quinase 1 de Adesão Focal , Neoplasias Pulmonares , RNA Longo não Codificante , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , RNA Longo não Codificante/genética , Animais , Camundongos , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Progressão da Doença , Linhagem Celular Tumoral , Feminino , Fosforilação , Camundongos Nus , MasculinoRESUMO
[This corrects the article DOI: 10.3389/fphar.2019.01287.].
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Immunomodulatory drugs (e.g. thalidomide, lenalidomide and pomalidomide) have been proven highly successful in clinical treatment of multiple myeloma. However, systematic degradation of zinc finger transcriptional factors induced by these drugs could lead to severe systematic toxicity in patients. Previous reports of NVOC caged pomalidomide attempted to regulate its activity using UVA irradiation, but their application was limited by high cytotoxicity and low tissue penetration. Here, we reported red-shifted BODIPY caged lenalidomide and pomalidomide that enabled red-light controlled protein degradation with spatiotemporal precision.
Assuntos
Mieloma Múltiplo , Talidomida , Humanos , Talidomida/farmacologia , Talidomida/uso terapêutico , Lenalidomida/farmacologia , Proteólise , Mieloma Múltiplo/tratamento farmacológicoRESUMO
Insufficient delivery of therapeutic agents into solid tumors by systemic administration remains a major challenge in cancer treatment. Secreted protein acidic and rich in cysteine (SPARC) has high binding affinity to albumin and has been shown to enhance the penetration and uptake of albumin-based drug carriers in tumors. Here, we developed a strategy to alter the tumor microenvironment (TME) by upregulating SPARC to enhance the delivery efficiency of albumin-based drug carriers into tumors. We prepared albumin nanoparticles encapsulating an NF-κB controllable CRISPR activation system (SP-NPs). SP-NPs achieved tumor-selective SPARC upregulation by responding to the highly activated NF-κB in tumor cells. Whereas a single dose of SP-NPs only modestly upregulated SPARC expression, serial administration of SP-NPs created a positive feedback loop that induced progressive increases in SPARC expression as well as tumor cell uptake and tumor penetration of the nanoparticles in vitro, in organoids, and in subcutaneous tumors in vivo. Additionally, pre-treatment with SP-NPs significantly enhanced the anti-tumor efficacy of Abraxane, a commercialized albumin-bound paclitaxel nanoformulation. Our data provide evidence that modulating SPARC in the TME can enhance the efficiency of albumin-based drug delivery to solid tumors, which may result in new strategies to increase the efficacy of nanoparticle-based cancer drugs.
Assuntos
NF-kappa B , Neoplasias , Humanos , Osteonectina , Albuminas , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Portadores de Fármacos , Paclitaxel Ligado a Albumina , Microambiente TumoralRESUMO
Nuclear factor kappa-B (NF-κB), a pivotal transcriptional regulator, plays a crucial role in modulating downstream genes implicated in tumor drug resistance. We establish a programmable system within bladder cancer cells to tailor drug responses by employing a synthetic clustered regularly interspaced short palindromic repeats (CRISPR)-based expression strategy that emulates natural transcriptional regulators. Our investigation uncovers the functional significance of Opa-interacting protein 5 (OIP5), upregulated upon NF-κB activation, as a key regulator governing drug-resistance to vincristine (VCR) treatment in bladder cancer. Through engineered guide RNAs (sgRNAs) targeting OIP5 to integrate NF-κB aptamers, we construct a modular scaffold RNA that encodes both the target locus and regulatory functionality. This engineered CRISPR scaffold RNA effectively responds to VCR stimulus by binding with activated NF-κB. Intriguingly, it redirects NF-κB to attenuate OIP5 expression-a reversal of its original role-while concurrently obstructing multiple NF-κB-mediated drug resistance pathways. This dual action thwarts drug resistance development. Further enhancing therapeutic potential, we develop a versatile nanoparticle system capable of co-delivering CRISPR scaffold RNAs and VCR. This synergistic approach demonstrates potent anti-tumor effects in both in vitro and in vivo settings. Our nanoparticle-mediated combination presents a compelling proof-of-concept, showcasing the utility of engineered CRISPR-based synthetic expression programs to reconfigure cellular drug responses and heighten tumor cell susceptibility to chemotherapy.
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NF-kappa B , Neoplasias da Bexiga Urinária , Humanos , NF-kappa B/genética , RNA Guia de Sistemas CRISPR-Cas , Neoplasias da Bexiga Urinária/tratamento farmacológico , Vincristina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
[This corrects the article DOI: 10.7150/jca.16438.].
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The development of biosensors mediated by synergistic quenching effect is of great significance for rapid and accurate clinical diagnosis. Hence, we prepared a cyan-emitting fluorescent Si dots for alkaline phosphatase (ALP) detection through the synergistic quenching effect of inner filter effect (IFE) and photo-induced electron transfer (PET). Si dots were prepared by microwave-assisted method, which displayed high quantum yield (28.7%), as well as good physiochemical properties, such as photo-stability, pH stability, and chemical stability. As the hydrolysate of 4-nitrophenyl phosphate disodium salt hexahydrate catalyzed by ALP, both IFE and PET of 4-nitrophenyl to Si dots were used for the turn-off mode detection of ALP. The linear relationships were established between the change of fluorescence intensity and ALP concentration in the range of 0.05 U L-1 to 5.0 U L-1, and 5.0 U L-1 to 80.0 U L-1, respectively. The detection limit was 0.01 U L-1. The synergistic quenching effect caused the turn-off mode detection to be more sensitive, and it can also be used for the accurate detection of ALP in human serum, thereby showing great anti-interference ability in complex environments.
Assuntos
Fosfatase Alcalina , Pontos Quânticos , Humanos , Fosfatase Alcalina/química , Fluorescência , Pontos Quânticos/química , Limite de Detecção , Corantes Fluorescentes/química , Espectrometria de Fluorescência/métodosRESUMO
Chemotherapy resistance and treatment failure hinder clinical cancer treatment. Src, the first mammalian proto-oncogene to be discovered, is a valuable anti-cancer therapeutic target. Although several c-Src inhibitors have reached the clinical stage, drug resistance remains a challenge during treatment. Herein, a positive feedback loop between a previously uncharacterized long non-coding RNA (lncRNA), which the authors renamed lncRNA-inducing c-Src tumor-promoting function (LIST), and c-Src is uncovered. LIST directly binds to and regulates the Y530 phosphorylation activity of c-Src. As a c-Src agonist, LIST promotes tumor chemoresistance and progression in vitro and in vivo in multiple cancer types. c-Src can positively regulate LIST transcription by activating the NF-κB signaling pathway and then recruiting the P65 transcription factor to the LIST promoter. Interestingly, the LIST/c-Src interaction is associated with evolutionary new variations of c-Src. It is proposed that the human-specific LIST/c-Src axis renders an extra layer of control over c-Src activity. Additionally, the LIST/c-Src axis is of high physiological relevance in cancer and may be a valuable prognostic biomarker and potential therapeutic target.
Assuntos
Neoplasias , RNA Longo não Codificante , Animais , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Retroalimentação , RNA Longo não Codificante/genética , Transdução de Sinais , Neoplasias/tratamento farmacológico , Mamíferos/metabolismoRESUMO
Recent studies have demonstrated that hypertension correlates with tumorigenesis and prognosis of clear-cell renal cell carcinoma (ccRCC); however, the underlying molecular mechanisms remain unclear. By analyzing bulk and single-cell RNA sequencing data and experimental examining of surgical excised ccRCC samples, we found that tissue inhibitors of metalloproteinases 3 (TIMP3), a pivotal paracrine factor in suppressing tumor progression, was significantly reduced in the tumor endothelial cells of patients with hypertensive ccRCC. Besides, in tumor xenograft of NCG mouse model, compared with saline normotensive group the expression of TIMP3 was significantly decreased in the angiotensin II-induced hypertension group. Treating human umbilical vein endothelial cells (HUVEC) with the plasma of patients with hypertensive ccRCC and miR-21-5p, elevated in the plasma of patients with hypertensive ccRCC, reduced the expression of TIMP3 compared with normotensive and control littermates. We also found that the inhibition of TIMP3 expression by miR-21-5p was not through directly targeting at 3'UTR of TIMP3 but through suppressing the expression of TGFß receptor 2 (TGFBR2). In addition, the knockout of TGFBR2 reduced TIMP3 expression in HUVECs through P38/EGR1 (early growth response protein 1) signaling axis. Moreover, via coculture of ccRCC cell lines with HUVECs and mouse tumor xenograft model, we discovered that the TIMP3 could suppress the proliferation and migration of ccRCC. IMPLICATIONS: Overall, our findings shed new light on the role of hypertension in promoting the progression of ccRCC and provide a potential therapeutic target for patients with ccRCC with hypertension.
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Carcinoma de Células Renais , Hipertensão , Neoplasias Renais , MicroRNAs , Humanos , Animais , Camundongos , Carcinoma de Células Renais/genética , Neoplasias Renais/patologia , MicroRNAs/genética , Regulação para Baixo , Células Endoteliais/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Linhagem Celular Tumoral , Proliferação de Células , Hipertensão/genética , Regulação Neoplásica da Expressão Gênica , Inibidor Tecidual de Metaloproteinase-3/genética , Inibidor Tecidual de Metaloproteinase-3/metabolismoRESUMO
Over recent years, with the advances in image recognition technology for deep learning, researchers have devoted continued efforts toward importing anomaly detection technology into the production line of automatic optical detection. Although unsupervised learning helps overcome the high costs associated with labeling, the accuracy of anomaly detection still needs to be improved. Accordingly, this paper proposes a novel deep learning model for anomaly detection to overcome this bottleneck. Leveraging a powerful pre-trained feature extractor and the skip connection, the proposed method achieves better feature extraction and image reconstructing capabilities. Results reveal that the areas under the curve (AUC) for the proposed method are higher than those of previous anomaly detection models for 16 out of 17 categories. This indicates that the proposed method can realize the most appropriate adjustments to the needs of production lines in order to maximize economic benefits.
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Indústrias , Tecnologia , Área Sob a Curva , Reconhecimento Psicológico , RegistrosRESUMO
BACKGROUND: Kidney cancer is one of the most common solid tumors. The advancement of human kidney cancer research and treatment has been hindered by a lack of research models that faithfully recapitulate the diversity of the disease. METHODS: We established an effective three-dimensional culture system for generating kidney cancer organoids from clinical renal cell carcinoma samples. Renal cell carcinoma (RCC) organoids were characterized by H&E staining, immunofluorescence, whole-exome sequencing, RNA sequencing and single-cell RNA sequencing. The use of RCC organoids in personalized cancer therapy was assessed by testing their responses to treatment drugs and chimeric antigen receptor T cells. RESULTS: Using this organoid culture system, 33 kidney cancer organoid lines from common kidney cancer subtypes, including clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), and chromophobe renal cell carcinoma (chRCC), were generated. RCC organoids preserved the histological architectures, mutational landscapes, and transcriptional profile of the parental tumor tissues. Single-cell RNA-sequencing revealed inter- and intra-tumoral heterogeneity in RCC organoids. RCC organoids allowed for in vitro drug screening and provided a tool for assessing the efficacy of chimeric antigen receptor T cells. CONCLUSIONS: Patient-derived RCC organoids are valuable pre-clinical models for academic research and personalized medicine.
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Carcinoma de Células Renais , Neoplasias Renais , Receptores de Antígenos Quiméricos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/terapia , Humanos , Rim/metabolismo , Rim/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Organoides/metabolismo , Organoides/patologiaRESUMO
Cancer represents a leading cause of death, despite the rapid progress of cancer research, leading to urgent need for accurate preclinical model to further study of tumor mechanism and accelerate translational applications. Cancer cell lines cannot fully recapitulate tumors of different patients due to the lack of tumor complexity and specification, while the high technical difficulty, long time, and substantial cost of patient-derived xenograft model makes it unable to be used extensively for all types of tumors and large-scale drug screening. Patient-derived organoids can be established rapidly with a high success rate from many tumors, and precisely replicate the key histopathological, genetic, and phenotypic features, as well as therapeutic response of patient tumor. Therefore, they are extensively used in cancer basic research, biobanking, disease modeling and precision medicine. The combinations of cancer organoids with other advanced technologies, such as 3D bio-printing, organ-on-a-chip, and CRISPR-Cas9, contributes to the more complete replication of complex tumor microenvironment and tumorigenesis. In this review, we discuss the various methods of the establishment and the application of patient-derived organoids in diverse tumors as well as the limitations and future prospects of these models. Further advances of tumor organoids are expected to bridge the huge gap between bench and bedside and provide the unprecedented opportunities to advance cancer research.
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Neoplasias , Organoides , Bancos de Espécimes Biológicos , Humanos , Neoplasias/patologia , Organoides/patologia , Medicina de Precisão/métodos , Microambiente TumoralRESUMO
Many studies have confirmed the important roles of nutritional status and micronutrients in the COVID-19 pandemic. Magnesium is a vital essential trace element that is involved in oxidative stress, inflammation, and many other immunological functions and has been shown to be associated with the outcome of COVID-19 infection. Here, we conducted a nationwide retrospective cohort study in the United States involving 1150 counties, 287,326,503 individuals, and 5,401,483 COVID-19 confirmed cases as of 30 September 2020 to reveal the infection risk of the populations distributed in low-magnesium areas in the early transmission of COVID-19. Our results indicate that the average county-level COVID-19 cumulative incidence in low-magnesium areas was significantly higher than in the control areas. Additionally, a significant negative nonlinear association was found between environmental magnesium concentration and the county-level COVID-19 cumulative incidence. Furthermore, the populations distributed in low environmental magnesium areas faced a higher COVID-19 infection risk (RR: 1.066; CI: 1.063-1.068), among which females (RR: 1.07; CI: 1.067-1.073), the 0-17 years subgroup (RR: 1.125; CI: 1.117-1.134), the 65+ years subgroup (RR: 1.093; CI: 1.087-1.098), black people (RR: 1.975; CI: 1.963-1.986), populations outside metro areas, and counties with a smaller population experienced higher risk of infection by COVID-19 than other subgroups. Considering that the magnesium intake of about half the population of the United States is below the daily required dose, our study will contribute to the creation of long-term public health strategies to help protect against COVID-19.
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COVID-19 , Magnésio , COVID-19/epidemiologia , Feminino , Humanos , Pandemias , Estudos Retrospectivos , SARS-CoV-2 , Estados Unidos/epidemiologiaAssuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Desmetilação do DNA , Neoplasias da Bexiga Urinária/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/fisiologia , Progressão da Doença , Humanos , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/fisiopatologiaRESUMO
Upper tract urothelial carcinomas (UTUCs) are rare entities that are usually diagnosed at advanced stages. Research on UTUC pathobiology and clinical management has been hampered by the lack of models accurately reflecting disease nature and diversity. In this study, a modified organoid culture system is used to generate a library of 25 patient-derived UTUC organoid lines retaining the histological architectures, marker gene expressions, genomic landscapes, and gene expression profiles of their parental tumors. The study demonstrates that the responses of UTUC organoids to anticancer drugs can be identified and the model supports the exploration of novel treatment strategies. This work proposes a modified protocol for generating patient-derived UTUC organoid lines that may help elucidate UTUC pathophysiology and assess the responses of these diseases to various drug therapies in personalized medicine.