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Dual blocker therapy (DBT) has the enhanced antitumor benefits than the monotherapy. Yet, few effective biomarkers are developed to monitor the therapy response. Herein, we investigate the DBT longitudinal plasma proteome profiling including 113 longitudinal samples from 22 patients who received anti-PD1 and anti-CTLA4 DBT therapy. The results show the immune response and cholesterol metabolism are upregulated after the first DBT cycle. Notably, the cholesterol metabolism is activated in the disease non-progressive group (DNP) during the therapy. Correspondingly, the clinical indicator prealbumin (PA), free triiodothyronine (FT3) and triiodothyronine (T3) show significantly positive association with the cholesterol metabolism. Furthermore, by integrating proteome and radiology approach, we observe the high-density lipoprotein partial remodeling are activated in DNP group and identify a candidate biomarker APOC3 that can reflect DBT response. Above, we establish a machine learning model to predict the DBT response and the model performance is validated by an independent cohort with balanced accuracy is 0.96. Thus, the plasma proteome profiling strategy evaluates the alteration of cholesterol metabolism and identifies a panel of biomarkers in DBT.
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Colesterol , Proteoma , Humanos , Colesterol/sangue , Colesterol/metabolismo , Proteoma/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Antígeno CTLA-4/sangue , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/sangue , Biomarcadores/sangue , Idoso , Tri-Iodotironina/sangue , Aprendizado de Máquina , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/sangue , Neoplasias/metabolismo , Proteômica/métodosRESUMO
Exosomal PD-L1 has been increasingly considered a noninvasive and accurate predictive marker for immunotherapy treatment response. However, the clinical monitoring of exosomal PD-L1 expression is still limited by its complex biological environment as well as the lack of a robust isolation strategy. Here, a Tim4-functionalized magnetic core-shell metal-organic framework (denoted as Fe3O4@SiO2-ILI-01@Tim4) was facilely constructed via layer-by-layer assembly. Owing to the strongly hydrophilic organic ligand of 1,3-bis(4-carboxybutyl)imidazolium bromide (ILI), magnetic Fe3O4@SiO2-ILI-01@Tim4 was endowed with the merits of low nonspecific adsorption and quick, easy, and convenient isolation of exosomes. The capture efficiency of Fe3O4@SiO2-ILI-01@Tim4 reached as high as 90.3 ± 0.5% and the recovery rate for exosomes was up to 93.0 ± 6.1%. The purity of the isolated exosomes was 7.5 times higher than that via the ultracentrifugation (UC) method. By further combination with immunofluorescence assay, high throughput and noninvasive exosomal PD-L1 detection for accurate immunotherapy response prediction was achieved. The prognosis accuracy of the developed Fe3O4@SiO2-ILI-01@Tim4-based strategy reached 85.7%, whereas the prognosis accuracy of the clinical gold standard, the PD-L1 combined positive score (CPS) test, was only 57.1%. Most interestingly, the developed method is especially suitable for those patients receiving false negative results in the CPS test. The proposed Fe3O4@SiO2-ILI-01@Tim4 is a highly efficient and robust technique showing great potential in high throughput and noninvasive exosomal PD-L1 detection for accurately predicting immunotherapy efficacy.
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Exossomos , Estruturas Metalorgânicas , Humanos , Antígeno B7-H1 , Dióxido de Silício , Imunoterapia , Fenômenos MagnéticosRESUMO
Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC). Chemotherapy resistance is the main cause of chemotherapy failure. Cullin7 (Cul7) is highly expressed in LUAD and is associated with poor prognosis. Moreover, Cul7 is abnormally overexpressed in docetaxel-resistant LUAD cells. Therefore, further exploration of the role and molecular mechanism of Cul7 in LUAD docetaxel resistance is necessary. Methods: We established docetaxel-resistant cell lines (A549DTX and H358DTX cell lines) by exposing cells to gradually increasing concentrations of docetaxel. Cell (A549, A549DTX, H358, and H358DTX cell lines) sensitivity to docetaxel was determined via a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymmethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. And then quantitative polymerase chain reaction (qPCR) and Western blotting were performed to measure the expression of Cul7 and Survivin in A549, A549DTX, H358, and H358DTX cell lines. Subsequently, we knocked down Cul7 in docetaxel-resistant cells and overexpressed Cul7 in parental cells via lentiviral transduction to further validate the correlation between Cul7 and docetaxel resistance, while exploring the molecular mechanism of docetaxel resistance it caused. Immunofluorescence and immunohistochemical (IHC) staining were also used to evaluate the expression and cellular localization of Cul7. To confirm the effect of Cul7 expression on cell apoptosis, we used flow cytometry to detect the apoptosis rate of A549 and A549DTX cells with the same drug concentration. Results: Cul7 was highly expressed in A549DTX and H358DTX cells. However, when Cul7 expression was knocked down in A549DTX and H358DTX cells, cell sensitivity to docetaxel was significantly increased. In addition, we found that Cul7 was coexpressed with Survivin. Silencing Survivin reversed the docetaxel insensitivity caused by Cul7 overexpression. High expression of Cul7 and Survivin in docetaxel-resistant LUAD cells inhibited the intrinsic apoptosis pathway and promoted cell proliferation. Therefore, the Cul7/Survivin axis may play a role in inducing LUAD docetaxel chemoresistance. Conclusions: Cul7 and Survivin were both highly expressed in docetaxel-resistant LUAD cells. Our results suggest that Cul7 may inhibit apoptosis and promote the proliferation of LUAD cells by increasing the Survivin protein level, which in turn contributes to docetaxel chemoresistance in LUAD.
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Virtual Touch Tissue Quantification (VTQ) offers several advantages in the diagnosis of various lung diseases. Chemokine expression levels, such as CXCL13, play a vital role in the occurrence and development of tumors and aid in the diagnosis process. The purpose of this study was to evaluate the combined value of VTQ and changes in CXCL13 expression levels for the diagnosis of lung tumors. A total of 60 patients with thoracic nodules and pleural effusion were included, with 30 of them having malignant pleural effusion (based on pathology) and the remaining 30 having benign thoracic nodules and pleural effusion. The relative expression level of CXCL13 was measured in the collected pleural effusions using Enzyme-Linked Immunosorbent Assay (ELISA). The relationship between CXCL13 expression levels and various clinical features was analyzed. A Receiver Operating Characteristic (ROC) curve analysis was conducted on the VTQ results and relative expression levels of CXCL13, and the areas under the curve, critical values, sensitivity, and specificity were calculated. Multivariate analysis incorporating multiple indicators was performed to determine the accuracy of lung tumor diagnosis. The results showed that the expression levels of CXCL13 and VTQ were significantly higher in the lung cancer group compared to the control group (P < 0.05). In the Non-Small Cell Lung Cancer (NSCLC) group, CXCL13 expression levels increased with later TNM staging and poorer tumor differentiation. The expression level of CXCL13 in adenocarcinoma was higher than that in squamous cell carcinoma. The ROC curve analysis revealed that CXCL13 had an area under the curve (AUC) of 0.74 (0.61, 0.86) with an optimal cut-off value of 777.82 pg/ml for diagnosing lung tumors. The ROC curve analysis of VTQ showed an AUC of 0.67 (0.53, 0.82) with a sensitivity of 60.0% and a specificity of 83.3%, and an optimal diagnostic cut-off of 3.33 m/s. The combination of CXCL13 and VTQ for diagnosing thoracic tumors had an AUC of 0.842 (0.74, 0.94), which was significantly higher than either factor alone. The results of the study demonstrate the strong potential of combining VTQ results with chemokine CXCL13 expression levels for lung tumor diagnosis. Additionally, the findings suggest that elevated relative expression of CXCL13 in cases of malignant pleural effusion caused by non-small cell lung cancer may indicate a poor prognosis. This provides promising potential for using CXCL13 as a screening tool and prognostic indicator for patients with advanced lung cancer complicated by malignant pleural effusion.
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Small extracellular vesicles (sEVs) have been increasingly recognized as circulating biomarkers and prognosticators for disease diagnosis. However, the clinical applications of sEVs are seriously limited by the lack of a robust and easy scale-up isolation technique. Herein, the feasibility of a polyphenol-metal three-dimensional (3D) network for label-free sEV isolation was explored. As a proof-of-concept, with tannic acid (TA) as the polyphenolic ligand and Fe(III) as the coordinated metal, the TA-Fe(III) 3D network coating mesoporous silica beads (SiO2@BSA@Fe-TA6) was designed and fabricated via a coordination-driven layer-by-layer self-assembly approach. The successful fabrication of SiO2@BSA@Fe-TA6 was validated by Fourier transform infrared spectroscopy, scanning electron microscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis. With the low-cost TA (as low as US$ 0.18/g) as the probe, SiO2@BSA@Fe-TA6 achieved universal capture toward sEVs in different cells and plasma samples. The capture efficiency reached 85.4 ± 1.5%, which is comparable to the antibody-based capture techniques and significantly higher than the ultracentrifugation (UC) method. The purity of sEVs isolated by SiO2@BSA@Fe-TA6 from the H1299 cell culture supernatant was measured as (1.07 ± 0.14) × 1011 particles/µg, which is 3.1 times higher than that via the UC method. Another important superiority of SiO2@BSA@Fe-TA6 is the facile self-assembly approach, which can harvest a yield of up to grams, allowing simultaneous processing of more than 500 plasma samples. The SiO2@BSA@Fe-TA6-based strategy was further successfully employed to distinguish nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC) with an accuracy of 87.1%. The developed SiO2@BSA@Fe-TA6 is a label-free, universal, low cost, and easy scale-up technique for sEV-based liquid biopsy in lung cancer diagnosis and typing.
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Carcinoma Pulmonar de Células não Pequenas , Vesículas Extracelulares , Neoplasias Pulmonares , Humanos , Dióxido de Silício/química , Polifenóis , Compostos Férricos/química , Neoplasias Pulmonares/diagnóstico , Metais , TaninosRESUMO
BACKGROUND: Small cell ovarian neuroendocrine (NE) carcinoma is a rare NE tumor with a low incidence, poor prognosis, and no standardized treatment. To date, there have been no clear reports on the efficacy or prognosis of combined immunological and chemotherapy-based approaches in patients with this type of tumor. METHODS: We administered the immune checkpoint inhibitor tirelizumab (PD-1 mab), in combination with etoposide and cisplatin chemotherapy (EP), to a patient with small cell ovarian NE carcinoma to examine its efficacy and safety. RESULTS: The evaluation of efficacy was PR for every 2 courses of application, and immunomaintenance therapy was administered after 6 courses of treatment. CONCLUSION: Our studies indicate that tirelizumab combined with EP, may be an effective treatment for small cell ovarian NE carcinoma.
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Carcinoma Neuroendócrino , Carcinoma de Células Pequenas , Neoplasias Ovarianas , Humanos , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologiaRESUMO
Background: Acquired resistance is inevitable in non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). The emergence of EGFR exon 20 C797S is one of the major resistance mechanisms to osimertinib as a third-generation EGFR-TKI. To date, there is no standard of care for NSCLC patients after acquiring EGFR C797S. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various types of cancers in the last decade. Whether NSCLC patients with acquired EGFR C797S could benefit from ICIs remains elusive. Case Description: Herein, we reported two cases of EGFR-mutant NSCLC patients who acquired a tertiary EGFR mutation C797S benefited from ICIs. A 28-year-old woman presented with anepithymia and nausea. Chest computed tomography (CT) revealed a mass in the right lung. She was diagnosed with stage IV lung adenocarcinoma (LUAD) with EGFR exon 19 deletion (19del) based on imaging and next-generation sequencing (NGS) findings. She received icotinib followed by osimertinib, then acquired EGFR T790M-cis-C797S. She had low tumor mutation burden (TMB) and achieved partial response (PR) to a programmed cell death-1 (PD-1) inhibitor sintilimab combined with platinum-based doublet chemotherapy as late-line treatment lasting more than 5 months. A 66-year-old man complained with chest tightness, hemoptysis, and back pain. CT scans revealed a mass in the right lung and metastases to the bilateral lungs, liver, adrenal gland, mediastinal lymph nodes, and bone. He was also diagnosed with EGFR 19del-positive LUAD and treated with icotinib followed by osimertinib. He also acquired EGFR T790M-cis-C797S. The patient had low TMB also and benefited from a PD-1 inhibitor camrelizumab combined with platinum-based doublet chemotherapy as late-line treatment with a progression-free survival (PFS) of 8 months. Two cases had no treatment-related adverse events leading to discontinuation of PD-1 inhibitors. Conclusions: Our study provides the first clinical evidence that ICIs combined with platinum-based doublet chemotherapy may be effective treatment options for overcoming resistance mediated by EGFR T790M-cis-C797S. Clinical trials are needed to evaluate the efficacy and safety of PD-1 inhibitors in the treatment of NSCLC patients harboring EGFR T790M-cis-C797S.
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Objective: To analyze the transmission and blocking intervention scheme of emotional disorders between cancer patients and their families. Methods: About 150 patients with cancer and 150 family members with mood disorders treated in a tertiary hospital in North China from March 2021 to Octobor2021 were enrolled. The patients were randomly assigned into control group and study group. The control group received routine intervention, and the study group received the diagnosis, intervention, and treatment strategies of doctor-patient-affective disorder. The factors related to the transmission of emotional disorders between cancer patients and their families were analyzed, and the alterations of anxiety, depression, social support, and satisfaction of the two groups were compared under different blocking intervention schemes. Results: (1) Univariate analysis indicated that there were significant differences in family age, family income, sex, location of tumor, course of disease, TNM stage, somatic symptoms, and the incidence of anxiety and depression. There exhibited no significant difference between the gender of the family, the years of education of the family, the occupational status of the family, the relationship between the family and the patient, the mode of payment of the patient's medical expenses, the age of the patient, the mode of treatment of the patient, the degree of knowledge of the disease, and the incidence of anxiety and depression (P > 0.05). The anxiety and depression status of relatives were taken as dependent variables, and the age of family members, family income status, sex of patients, location of tumor, course of disease, TNM stage, and physical symptoms of patients were taken as independent variables, and the data were analyzed by Logistic regression analysis. Logistic regression analysis indicated that family income, tumor location, disease course, TNM stage, and somatic symptoms were the risk factors of anxiety and depression in relatives. (2) Comparison of social support status and intergroup, the objective support, subjective support, support utilization, and total score of social support in the study group were higher compared to the control group. In terms of the depression score before intervention, there exhibited no significant difference (P > 0.05), but after intervention, the depression score of the two groups decreased, and the depression score of the study group was lower compared to the control group before intervention, 1 week, 2 weeks, 3 weeks, and 4 weeks after intervention (P < 0.05). In terms of the anxiety score before intervention, there exhibited no significant difference (P > 0.05), but after intervention, the anxiety score of the two groups decreased, and the anxiety score of the study group was lower compared to the control group before intervention, 1 week, 2 weeks, 3 weeks, and 4 weeks after intervention (P < 0.05). Comparison of the satisfaction between the two groups and the study group was very satisfied in 56 cases, satisfactory in 14 cases, and general in 5 cases, and the satisfaction rate was 100.00%. The control group was very satisfied in 35 cases, satisfactory in 23 cases, general in 12 cases, and dissatisfied in 5 cases, and the satisfaction rate was 93.33%. The satisfaction of the study group was higher compared to the control group (P < 0.05). Conclusion: Family income, tumor location, course of disease, TNM stage, and somatic symptoms are the risk factors of anxiety and depression in relatives. After establishing the diagnosis, intervention and treatment strategies of doctor-patient-affective disorder, the emotional disorder of family members of cancer patients, is significantly promoted, and the intervention satisfaction is high, so the scheme is worth promoting.
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Sintomas Inexplicáveis , Neoplasias , Ansiedade/epidemiologia , Depressão/epidemiologia , Família/psicologia , Humanos , Transtornos do Humor , Neoplasias/epidemiologiaRESUMO
BACKGROUND: Lung adenocarcinoma (LUAD) is the most common subtype of nonsmall-cell lung cancer (NSCLC) and has a high incidence rate and mortality. The survival of LUAD patients has increased with the development of targeted therapeutics, but the prognosis of these patients is still poor. Long noncoding RNAs (lncRNAs) play an important role in the occurrence and development of LUAD. The purpose of this study was to identify novel abnormally regulated lncRNA-microRNA (miRNA)-messenger RNA (mRNA) competing endogenous RNA (ceRNA) networks that may suggest new therapeutic targets for LUAD or relate to LUAD prognosis. METHODS: We used the SBC human ceRNA array V1.0 to screen for differentially expressed (DE) lncRNAs and mRNAs in four paired LUAD samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to annotate the DE lncRNAs and mRNAs. R bioinformatics packages, The Cancer Genome Atlas (TCGA) LUAD database, and Kaplan-Meier (KM) survival analysis tools were used to validate the microarray data and construct the lncRNA-miRNA-mRNA ceRNA regulatory network. Then, quantitative real-time PCR (qRT-PCR) was used to validate the DE lncRNAs in 7 LUAD cell lines. RESULTS: A total of 2819 DE lncRNAs and 2396 DE mRNAs (P < 0.05 and fold change ≥ 2 or ≤ 0.5) were identified in four paired LUAD tissue samples. In total, 255 of the DE lncRNAs were also identified in TCGA. The GO and KEGG analysis results suggested that the DE genes were most enriched in angiogenesis and cell proliferation, and were closely related to human cancers. Moreover, the differential expression of ENST00000609697, ENST00000602992, and NR_024321 was consistent with the microarray data, as determined by qRT-PCR validation in 7 LUAD cell lines; however, only ENST00000609697 was associated with the overall survival of LUAD patients (log-rank P = 0.029). Finally, through analysis of ENST00000609697 target genes, we identified the ENST00000609697-hsa-miR-6791-5p-RASL12 ceRNA network, which may play a tumor-suppressive role in LUAD. CONCLUSION: ENST00000609697 was abnormally expressed in LUAD. Furthermore, downregulation of ENST00000609697 and its target gene RASL12 was associated with poor prognosis in LUAD. The ENST00000609697-hsa-miR-6791-5p-RASL12 axis may play a tumor-suppressive role. These results suggest new potential prognostic and therapeutic biomarkers for LUAD.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Neoplasias Pulmonares/genética , PrognósticoRESUMO
ABSTRACT: The LIM domain only 1 (LMO1) gene belongs to the LMO family of genes that encodes a group of transcriptional cofactors. This group of transcriptional cofactors regulates gene transcription by acting as a key "connector" or "scaffold" in transcription complexes. All LMOs, including LMO1, are important players in the process of tumorigenesis. Unique biological features of LMO1 distinct from other LMO members, such as its tissue-specific expression patterns, interacting proteins, and transcriptional targets, have been increasingly recognized. Studies indicated that LMO1 plays a critical oncogenic role in various types of cancers, including T-cell acute lymphoblastic leukemia, neuroblastoma, gastric cancer, lung cancer, and prostate cancer. The molecular mechanisms underlying such functions of LMO1 have also been investigated, but they are currently far from being fully elucidated. Here, we focus on reviewing the current findings on the role of LMO1 in tumorigenesis, the mechanisms of its oncogenic action, and the mechanisms that drive its aberrant activation in cancers. We also briefly review its roles in the development process and non-cancer diseases. Finally, we discuss the remaining questions and future investigations required for promoting the translation of laboratory findings to clinical applications, including cancer diagnosis and treatment.
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Proteínas de Ligação a DNA , Proteínas com Domínio LIM , Carcinogênese/genética , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas com Domínio LIM/genética , Masculino , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Exosomes have become the most ideal analysis target for liquid biopsy since they carry a large amount of genetic materials. The study on exosomes has great significance for cancer diagnosis and prognosis. However, the extremely low concentration renders the development of a robust exosomes enrichment technique, with the merits of low nonspecific cell adhesion, high-capture efficiency, and easy nondestructive release of captured exosomes, of vital significance. We successfully designed and developed a novel Tim4@ILI-01 immunoaffinity flake material. First, a strongly hydrophilic ILI-01 MOFs matrix material was fabricated with cationic ionic liquid 1,3-bis(4-carboxybutyl)imidazolium bromide as the organic ligand. The nonspecific adsorption of the ILI-01 MOFs material was only 0.7% after two washings with a neutral buffer. Moreover, based on the inherent abundant carboxyl groups on the ILI-01 MOFs flake, they can be facilely functionalized with an anti-Tim4 antibody with the bonding efficiency of 82.4%. The capture efficiency of the developed Tim4@ILI-01 immunoaffinity material for exosomes reached 85.2%, which is 5.2 times higher than that via the gold standard ultracentrifugation method. Furthermore, based on the Ca2+-dependent characteristic of the binding between the Tim4@ILI-01 immunoaffinity material and phosphatidylserine (PS) on the surfaces of exosomes, the captured exosomes can be easily released with the addition of a chelating agent under neutral eluent conditions. Thus, the captured exosomes maintained good biological activity. The developed Tim4@ILI-01 immunoaffinity flake was successfully applied for enrichment of exosomes from serums of healthy persons and lung adenocarcinoma patients. The levels of the expressed CD44 gene significantly changed under different stages of lung adenocarcinoma cancer. All these results demonstrate that the Tim4@ILI-01 immunoaffinity flake is a robust enrichment material and has a good potential in practical clinical applications.
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Exossomos , Estruturas Metalorgânicas , Neoplasias , Humanos , Fosfatidilserinas , UltracentrifugaçãoRESUMO
As a core scaffold protein, Cullin 7 (Cul7) forms Skp1-Cullin-F-box (SCF) E3 ubiquitin ligase complexes with the regulator of cullins-1 (ROC1), S-phase kinase associated protein 1 (Skp1) and F-Box, and WD repeat domain containing 8 (Fbxw8). Alternatively, Cul7 can form a CRL7SMU1 complex with suppressor of Mec-8 and Unc-52 protein homolog (SMU1), damage-specific DNA binding protein 1 (DDB1), and ring finger protein 40 (RNF40), to promote cell growth. The mutations of Cul7 cause the 3-M dwarf syndrome, indicating Cul7 plays an important role in growth and development in humans and mice. Moreover, Cul7 regulates cell transformation, tumor protein p53 activity, cell senescence, and apoptosis, mutations in Cul7 are also involved in the development of tumors, indicating the characteristics of an oncogene. Cul7 is highly expressed in breast cancer, lung cancer, hepatocellular carcinoma, pancreatic cancer, ovarian cancer, and other malignant tumors where Cul7 promotes tumor development, cell transformation, and cell survival by regulating complex signaling pathways associated with protein degradation. In this review, we discuss the roles of Cul7 in malignant tumor development and its involvement in oncogenic signaling. We finally discuss the potential of Cul7 as a potential significant anti-cancer target.
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Proteínas Culina , Neoplasias Pancreáticas , Animais , Proliferação de Células , Proteínas Culina/genética , Proteínas Culina/metabolismo , Camundongos , Proteólise , Transdução de SinaisRESUMO
The factor that binds to the inducer of short transcripts-1 (FBI-1) is a transcription suppressor and an important proto-oncogene that plays multiple roles in carcinogenesis and therapeutic resistance. In the present work, our results indicated that FBI-1 enhanced the resistance of triple-negative breast cancer (TNBC) cells to chemotherapeutic agents by repressing the expression of micoRNA-30c targeting the pregnane X receptor (PXR). The expression of FBI-1 was positively related to PXR and its downstream drug resistance-related genes in TNBC tissues. FBI-1 enhanced the expression of PXR and enhanced the activation of the PXR pathway. The miR-30c decreased the expression of PXR by targeting the 3'-UTR of PXR, and FBI-1 increased the expression of PXR by repressing miR-30c's expression. Through the miR-30c/PXR axis, FBI-1 accelerated the clearance or elimination of antitumor agents in TNBC cells (the TNBC cell lines or the patients derived cells [PDCs]) and induced the resistance of cells to antitumor agents. Therefore, the results indicated that the miR-30c/PXR axis participates in the FBI-1-mediated drug-resistance of TNBC cells.
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Proteínas de Ligação a DNA/metabolismo , MicroRNAs/metabolismo , Ftalazinas/farmacologia , Piperazinas/farmacologia , Fatores de Transcrição/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , MicroRNAs/biossíntese , MicroRNAs/genética , Ftalazinas/farmacocinética , Piperazinas/farmacocinética , Proto-Oncogene Mas , Transdução de Sinais , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Aim: This review aims to systematically describe the biogenesis and degradation of circular RNAs (circRNAs), discusses the major functions of circRNAs, introduces the mechanisms by which circRNAs play a role in cancer, comprehensively summarize the relationship between circRNAs and anticarcinogen resistance as well as underlying specific mechanisms in multiple cancers. Materials & methods: We screened and analyzed large quantity of scientific papers which associated with circRNAs, noncoding RNAs, function, cancer, drug resistance and chemoresistance, and then summarized in Figures 1 & 2 & Table 1. Results & conclusion: The biogenesis, degradation and function of circRNAs are specially compared with other noncoding RNAs, it can affect cancer pathogenesis and progression and are implicated in mediating resistance to various anticarcinogens in various types of cancer.
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Anticarcinógenos/farmacologia , Resistencia a Medicamentos Antineoplásicos , RNA Circular/genética , Transcrição Gênica , Humanos , Estabilidade de RNARESUMO
Lung adenocarcinoma (LUAD) is the most common form of malignant tumor and closely correlated with high risk of death worldwide. Accumulating researches have manifested that long noncoding RNAs (lncRNAs) are deeply involved in the progression of multiple cancers. LncRNA LOXL1 antisense RNA 1 (LOXL1-AS1) was identified as an oncogene in several cancers, nonetheless, its biological effect and regulatory mechanism have not been explained in LUAD. Our present study suggested that LOXL1-AS1 expression was considerably increased in LUAD tissues and cells. Moreover, LOXL1-AS1 deficiency notably hampered cell proliferation and migration as well as dramatically facilitated cell apoptosis. Through molecular mechanism assays, LOXL1-AS1 was identified as a cytoplasmic RNA and acted as a sponge of miR-423-5p. Furthermore, MYBL2 was targeted and negatively modified by miR-423-5p. Rescue experiments revealed that MYBL2 knockdown could counteract miR-423-5p repression-mediated enhancement on the progression of LOXL1-AS1 downregulated LUAD cells. More importantly, MYBL2 was discovered to interact with LOXL1-AS1 promoter, indicating a positive feedback loop of LOXL1-AS1/miR-423-5p/MYBL2 in LUAD. These findings manifested the carcinogenic role of LOXL1-AS1 and LOXL1-AS1/miR-423-5p/MYBL2 feedback loop in LUAD, which could be helpful to explore effective therapeutic strategy for LUAD patients.
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Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/metabolismo , Proteínas de Ciclo Celular/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Transativadores/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Aminoácido Oxirredutases/antagonistas & inibidores , Aminoácido Oxirredutases/genética , Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular/genética , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Oligonucleotídeos Antissenso/genética , Prognóstico , Transativadores/genética , Células Tumorais CultivadasRESUMO
Polo-like kinase 1 (PLK1) has been suggested to serve as oncogene in most human cancers. The aim of our study is to present more evidence about the clinical and prognostic value of PLK1 in lung squamous cell carcinoma patients. The status of PLK1 was observed in lung adenocarcinoma, lung squamous cell carcinoma and normal lung tissues through analyzing microarray data set (GEO accession number: GSE1213 and GSE 3627). PLK1 mRNA and protein expressions were detected in lung squamous cell carcinoma and normal lung tissues by using qRT-PCR and immunohistochemistry. In our results, the levels of PLK1 in lung squamous cell carcinoma tissues were higher than that in lung adenocarcinoma tissues. Compared with paired adjacent normal lung tissues, the PLK1 expression was increased in lung squamous cell carcinoma tissues. Furthermore, high-expression of PLK1 protein was correlated with differentiated degree, clinical stage, tumor size, lymph node metastasis, and distant metastasis. The univariate and multivariate analyses showed PLK1 protein high-expression was an unfavorable prognostic biomarker for lung squamous cell carcinoma patients. In conclusion, High-expression of PLK1 is associated with the aggressive progression and poor prognosis in lung squamous cell carcinoma patients.
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BACKGROUND: Accumulating evidence supports the hypothesis that cancer stem cells (CSCs) are essential for cancer initiation, metastasis and drug resistance. However, the functional association of gastric CSC markers with stemness and epithelial-mesenchymal transition (EMT) signature genes is unclear. METHODS: qPCR was performed to measure the expression profiles of stemness and EMT signature genes and their association with putative CSC markers in gastric cancer tissues, cancer cell lines and sphere cells. Western blot analysis was used to confirm the results of the transcript analysis. Cell proliferation, cell migration, drug resistance and sphere cell growth assays were conducted to measure the expansion and invasion abilities of the cells. Tumor xenograft experiments were performed in NOD/SCID mice to test cell stemness in vivo. Flow cytometry and immunofluorescence staining were used to analyze cell subpopulations. RESULTS: The expression of LGR5 was strikingly up-regulated in sphere cells but not in cancer tissues or parental adherent cells. The up-regulation of LGR5 was also positively associated with stemness regulators (NANOG, OCT4, SOX2, and AICDA) and EMT inducers (PRRX1, TWIST1, and BMI1). In addition, sphere cells exhibited up-regulated vimentin and down-regulated E-cadherin expression. Using gene-specific primers, we found that the NANOG expression primarily originates from the retrogene NANOGP8. Western blot analysis showed that the expression of both LGR5 and NANOG is significantly higher in sphere cells. LGR5 over-expression significantly enhanced sphere cell growth, cell proliferation, cell migration and drug resistance in MGC803 cells. Tumor xenografts in nude mice showed that sphere cells are at least 10 times more efficient at tumor initiation than adherent cells. Flow cytometry analysis showed that ~20% of sphere cells are LGR5+/CD54+, but only ~3% of adherent cells are Lgr5+/CD54+. Immunofluorescence staining supports the above results. CONCLUSION: The LGR5-expressing fraction of CD54+ cells represents gastric cancer CSCs, in which LGR5 is closely associated with stemness and EMT core genes, and NANOG expression is mainly contributed by the retrogene NANOGP8. Sphere cells are the best starting materials for the characterization of CSCs.
Assuntos
Biomarcadores Tumorais/metabolismo , Transição Epitelial-Mesenquimal/genética , Células-Tronco Neoplásicas/patologia , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Animais , Biomarcadores Tumorais/deficiência , Biomarcadores Tumorais/genética , Caderinas/genética , Carcinogênese/genética , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Proteína Quinase 7 Ativada por Mitógeno/genética , Proteína Homeobox Nanog/genética , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/genética , Neoplasias Gástricas/metabolismo , Proteína 1 Relacionada a Twist/genética , Regulação para Cima , Vimentina/genéticaRESUMO
BACKGROUND: The aim of this study was to evaluate the effects of targeted silencing of forkhead box C1 (FOXC1) gene with small interfering RNA (siRNA) on the proliferation and in vitro migration of human non-small-cell lung carcinoma (NSCLC) A549 and NCIH460 cells, and to explore the molecular mechanism. METHODS: These cells were divided into FOXC1 siRNA groups and negative control groups. RESULTS: Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) showed that compared with normal cells and paracancerous tissues, FOXC1 mRNA expressions in NSCLC cells and tissues were significantly higher (P<0.05). qRT-PCR and Western blot showed that FOXC1 siRNA effectively silenced FOXC1 gene expression in NSCLC cells. EdU labeling assay revealed that the proliferative capacity significantly decreased compared with that of normal control group after FOXC1 silencing (P<0.05). Significantly fewer cells in the transfected group migrated than those in negative control group did. After FOXC1 silencing, NSCLC cells were arrested in the G0/G1 phase, which were significantly different from those in negative control group (P<0.05). Compared with negative control group, the expression of cyclin D1 decreased and that of E-cadherin increased. Meanwhile, vimentin and MMP-2 expressions significantly reduced (P<0.05). FOXC1 siRNA effectively silenced FOXC1 gene expressions in NSCLC cells, inhibited their proliferation and invasion, and arrested them in the G0/G1 phase, suggesting that FOXC1 affected proliferation probably by regulating the expression of cell cycle-related protein cyclin D1. CONCLUSION: Silencing FOXC1 may evidently inhibit the migration of these cells by reversing the EMT process through suppressing cadherin, being associated with the expressions of extracellular MMPs.
RESUMO
Genistein is a soybean isoflavone; in its aglycone it has various biological activities. Animal experiments, clinical studies and epidemiological investigations suggest that genistein has preventative and curative functions for a number of diseases, particularly in cancer. The present study explored the potential anti-cancer effect of genistein by observing its role in inhibiting A549 human lung cancer cell proliferation and investigating the possible mechanism. A549 cells were exposed to various concentrations of genistein (0, 10, 25, 50, 100 and 200 µM; dissolved in physiological saline) for 1, 2 and 3 days. Subsequently, the viability of A549 cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell apoptosis was examined using a flow cytometer, caspase 3/9 activity was measured using commercial kits, reverse transcription quantitative polymerase chain reaction was used to analyze the miR-27a expression and western blotting was used to investigate MET protein expression. The results suggested a significant inhibition of A549 cell growth following treatment with genistein in a time- and dose-dependent manner. The current study also indicated that treatment with genistein significantly induces cell apoptosis and promotes caspase-3/9 activation of A549 cells in a dose-dependent manner. Further functional assays revealed that the anti-cancer effect of genistein activated microRNA-27a (miR-27a) expression levels and reduced MET protein expression in A549 cells. In conclusion, the present study demonstrates that genistein inhibits A549 human lung cancer cell proliferation. Furthermore, this study reports, for the first time, a correlation between the anti-cancer effect of genistein and miR-27a-mediated MET signaling.