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Enhancing the intrinsic stability of perovskite and through encapsulation to isolate water, oxygen, and UV-induced decomposition are currently common and most effective strategies in perovskite solar cells. Here, the atomic layer deposition process is employed to deposit a nanoscale (≈100 nm), uniform, and dense Al2O3 film on the front side of perovskite devices, effectively isolating them from the erosion caused by water and oxygen in the humid air. Simultaneously, nanoscale (≈100 nm) TiO2 films are also deposited on the glass surface to efficiently filter out the ultraviolet (UV) light in the light source, which induces degradation in perovskite. Ultimately, throughthe collaborative effects of both aspects, the stability of the devices is significantly improved under conditions of humid air and illumination. As a result, after storing the devices in ambient air for 1000 h, the efficiency only declines to 95%, and even after 662 h of UV exposure, the efficiency remains at 88%, far surpassing the performance of comparison devices. These results strongly indicate that the adopted Al2O3 and TiO2 thin films play a significant role in enhancing the stability of perovskite solar cells, demonstrating substantial potential for widespread industrial applications.
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This study first optimized the processing technology for Zhangbang vinegar-processed Olibanum and investigated its in vitro anticoagulant activity. A multi-index-response surface methodology was used, with yield, powder yield, and the relative percentage of the content of six non-volatile components [11-keto-boswellic acid(KBA), 3-acetyl-11-keto-boswellic acid(AKBA), ß-elemonic acid, α-boswellic acid(α-BA), ß-boswellic acid(ß-BA), and α-acetyl-boswellic acid(α-BA)] and three volatile components(octyl acetate, incensole, and incensole acetate) as evaluation indicators. Analytical hierarchy process(AHP) combined with coefficient of variation method was used to calculate the weight of each indicator and calculate the comprehensive score(OD). Furthermore, response surface methodology was used to investigate the effects of frying temperature(A), burning time(B), rice vinegar dosage(C), and steaming time(D) on the processing technology of vinegar-processed Olibanum. Vinegar-steamed Olibanum was prepared according to the optimal processing technology for in vitro anticoagulant experiments. The results showed that the weights of octyl acetate, incensole, incensole acetate, KBA, AKBA, ß-elemonic acid, α-BA, ß-BA, α-ABA, yield, and powder yield were 0.358 2, 0.104 5, 0.146 4, 0.032 9, 0.123 7, 0.044 4, 0.022 1, 0.042 2, 0.110 1, 0.012 2, and 0.0032, respectively. The optimal processing technology for Zhangbang vinegar-processed Olibanum was as follows. Olibanum(50 g) with a particle size of 1-5 mm was continuously stir-fried at a low heat of 150-180 â until in a gel-like state, ignited for burning for 15 s, sprayed with 7.5 g of rice vinegar(15%), and steamed for 3 min without fire. Subsequently, the cover was removed, and the product was continuously stir-fried at 150-180 â until in a soft lump shape, removed, cooled, and crushed. The results of the in vitro anticoagulant experiments showed that compared with the blank group, both Olibanum and vinegar-processed Olibanum significantly prolonged the activated partial thromboplastin time(APTT), thrombin time(TT), and prothrombin time(PT) of rat platelet-poor plasma(PPP), and the effect of vinegar-processed Olibanum was significantly better than that of Olibanum(P<0.05). The optimized processing technology for Zhangbang vinegar-processed Olibanum is stable, feasible, and beneficial for the further development and utilization of Olibanum slices. At the same time, using the content of volatile and non-volatile components, yield, and powder yield as indicators, and verifying through pharmacological experiments, the obtained results are more reasonable and credible, and have positive guiding significance for the clinical application of characteristic processed Olibanum products.
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Franquincenso , Triterpenos , Ratos , Animais , Ácido Acético , Pós , Anticoagulantes/farmacologia , TecnologiaRESUMO
OBJECTIVE: The aim of the study is to systematically review the effects of leg-driven treadmill-based exoskeleton robot training on balance and walking ability in poststroke patients. DESIGN: The PubMed, Cochrane Library, Embase, Web of Science, Medline, CNKI, VIP, and Wanfang databases were searched from inception to August 2021. The literature quality was evaluated using Cochrane Handbook. Primary outcomes include the Functional Ambulation Category Scale and Berg Balance Scale, and secondary outcomes include the 10 meter walk test, 6 minute walk test, and gait assessment cadence were analyzed. RESULTS: Seventeen randomized controlled trials were included in the systematic review, 15 studies in meta-analysis. Primary outcomes showed no significant difference in the Functional Ambulation Category Scale score; subgroup with the exoskeleton robot + conventional therapy of the Berg Balance Scale score was significantly increased; secondary outcomes showed no significance in 6 minute walk test or 10 meter walk test. The cadence score increased for the subgroup with an onset of more than 6 mos in the treatment group. The control group performed better than the subgroup with an onset of less than 6 mos. CONCLUSIONS: Leg-driven treadmill-based exoskeleton robot training can improve balance function in poststroke patients and is beneficial for patients with an onset of greater than 6 mos. However, there is no evidence to support the efficacy of walking ability.
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Exoesqueleto Energizado , Robótica , Reabilitação do Acidente Vascular Cerebral , Humanos , Perna (Membro) , Caminhada , Marcha , Terapia por ExercícioRESUMO
Hematological and neurological expressed 1 like (HN1L) is a newly identified oncogene in lung cancer and hepatocellular carcinoma recently identified by our team, but its roles in the development and treatment of esophageal squamous cell carcinoma (ESCC) remain incompletely cataloged. Here, using ESCC tissue array and public database analysis, we demonstrated that HN1L was highly expressed in ESCC tissues, which was associated with tumor tissue invasion, poor clinical stage and short survival for ESCC patients. Loss- and gain-of-function studies in ESCC cells revealed that HN1L enhances ESCC cell metastasis and proliferation in vitro and in mice models. Moreover, high level of HN1L reduces the sensibility of ESCC cells to chemotherapeutic drugs, such as Docetaxel. Mechanism studies revealed that HN1L activated the transcription of polo-like kinase 1 (PLK1) by interacting with transcription factor AP-2γ, which increased the expression of malignancy related proteins Cyclin D1 and Slug in ESCC cells. Blocking PLK1 with inhibitor BI-2356 abrogated the oncogenic function of HN1L and significantly suppressed ESCC progression by combining with chemotherapy. Therefore, this study demonstrates the vital pro-tumor role of HN1L/AP-2γ/PLK1 signaling axis in ESCC, offering a potential therapeutic strategy for ESCC patients with high HN1L by blocking PLK1.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Animais , Camundongos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , Fator de Transcrição AP-2 , Humanos , Quinase 1 Polo-LikeRESUMO
To elucidate the mechanism of Euodiae Fructus stir-fried with water decoction of Coptidis Rhizoma in the treatment of chronic colitis, this study employed ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS), network pharmacology, and experimental verification to predict the involved targets and signaling pathways. The chronic colitis mouse model was constructed to verify the core targets. A total of 48 compounds in the herbal medicine were identified by UPLC-Q-TOF-MS. SwissTargetPrediction was used to screen the potential active components and drug targets. GeneCards, OMIM, PharmGKB, and TDD were used to search for the disease targets. A total of 31 active ingredients, 453 targets of the herbal medicine, and 3 960 targets of chronic colitis were obtained. The common targets shared by the herbal medicine and chronic colitis were introduced into STRING to construct the protein-protein interaction(PPI) network, and CytoNCA plug-in was used to screen the key targets. A total of 90 key targets were obtained, and the key active components included isorhamnetin, quercetin, limonin, and oxyberberine. GO annotation and KEGG pathway enrichment for the key targets were carried out via DAVID. The targets were mainly involved in the positive regulation of protein phosphorylation, positive regulation of nitric oxide biosynthetic process, and negative regulation of apoptotic process. The medicine may treat chronic colitis through PI3 K-Akt, VEGF, HIF-1, and TNF signaling pathways. A mouse model of chronic colitis was established and then treated with Euodiae Fructus stir-fried with the water decoction of Coptidis Rhizoma. The experimental results demonstrated that the medicine can alleviate the pathological damage of colon, significantly reduce the levels of IL-1ß, IL-6, and TNF-α, inhibit the activation of PI3 K/Akt pathway, and down-regulate the expression of VEGFA in the treatment of chronic colitis.
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Colite , Medicamentos de Ervas Chinesas , Animais , Camundongos , Água , Medicamentos de Ervas Chinesas/farmacologia , Farmacologia em Rede , Proteínas Proto-Oncogênicas c-akt , Colite/tratamento farmacológico , Doença Crônica , Simulação de Acoplamento MolecularRESUMO
BACKGROUND: Esophageal cancer is currently the eighth most common tumor in the world and a leading cause of cancer death. SULT2B1 plays crucial roles in tumorigenesis. The purpose of this study is to explore the role of SULT2B1 in esophageal squamous cell carcinoma (ESCC). METHODS: The expression of SULT2B1 and its clinicopathological characteristics were evaluated in ESCC cohorts. Bisulfite genomic sequencing and methylation specific PCR were used to detect the promoter hypermethylation of the SULT2B1 gene. The effects of SULT2B1 on the biological characters of ESCC cells were identified on functional assays. Subcutaneous xenograft models revealed the role of SULT2B1 in vivo with tumor growth. RNA-Seq analysis and qRT-PCR were performed to recognize the targeted effect of SULT2B1 on PER1. RESULTS: SULT2B1 was not expressed or at a low level in most patients with ESCC or in ESCC cell lines, and this was accompanied by poor clinical prognosis. Furthermore, the downregulation of SULT2B1 occurred in promoter hypermethylation. According to the functional results, overexpression of SULT2B1 could inhibit tumoral proliferation in vitro and retard tumor growth in vivo, whereas SULT2B1 knockdown could accelerate ESCC progression. Mechanistically, SULT2B1 targeted PER1 at the mRNA level during post-transcriptional regulation. Finally, PER1 was verified as a suppressor and poor-prognosis factor in ESCC. CONCLUSIONS: SULT2B1 loss is a consequence owing to its ability to promote hypermethylation. In addition, it serves as a suppressor and poor-prognosis factor because of the post-transcriptional regulation of PER1 in ESCC.
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Carcinogênese/genética , Metilação de DNA/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Proteínas Circadianas Period/genética , Sulfotransferases/genética , Idoso , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: By using integrative RNA sequencing analysis, we identified a novel tumor suppressor, serpin family A member 11 (SERPINA11), which is a serine proteinase inhibitor that belongs to the serpin superfamily. However, the function of SERPINA11 in hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to investigate the role and molecular mechanism of SERPINA11 in HCC. METHODS: Gene expression patterns of SERPINA11 were analyzed in tissue samples of HCC patients by qRT-PCR. In vitro and in vivo experiments were performed to characterize the function and molecular mechanism of SERPINA11 in the tumor metastasis capacity. RESULTS: SERPINA11 was downregulated in approximately 50% of HCC and significantly associated with metastasis and poor outcome of patients. Functional study demonstrated that SERPINA11 could inhibit cell growth, cell migration and tumor metastasis. Mechanistic investigations suggested that SERPINA11 accelerated urokinase-type plasminogen activator (uPA) degradation to suppress extracellular signal-regulated kinase (ERK1/2) phosphorylation, and thereby subdued metastatic capabilities of HCC cells. CONCLUSION: SERPINA11 plays an important tumor suppressive role in HCC, with possible use as a biomarker and an intervention point for new therapeutic strategies.
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PD-1/PD-L1 blockade therapies provide notable clinical benefits for patients with advanced cancers, but the factors influencing the effectiveness of the treatment remain incompletely cataloged. Here, the up-regulation of laminin γ2 (Ln-γ2) predicted the attenuated efficacy of anti-PD-1 drugs and was associated with unfavorable outcomes in patients with lung cancer or esophageal cancer. Furthermore, Ln-γ2 was transcriptionally activated by transforming growth factor-ß1 (TGF-ß1) secreted from cancer-associated fibroblasts via JNK/AP1 signaling, which blocked T cell infiltration into the tumor nests by altering the expression of T cell receptors. Coadministration of the TGF-ß receptor inhibitor galunisertib and chemotherapy drugs provoked vigorous antitumor activity of anti-PD-1 therapy in mouse tumor models. Therefore, Ln-γ2 may represent a useful biomarker to optimize clinical decisions and predict the response of cancer patients to treatment with anti-PD-1 drugs.
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Hepatocellular carcinoma (HCC) is one of the common malignancy and lacks effective therapeutic targets. Here, we demonstrated that ectopic expression of trophinin-associated protein (TROAP) dramatically drove HCC cell growth assessed by foci formation in monolayer culture, colony formation in soft agar and orthotopic liver transplantation in nude mice. Inversely, silencing TROAP expression with short-hairpin RNA attenuated the malignant proliferation of HCC cells in vitro and in vivo. Next, mechanistic investigation revealed that TROAP directly bound to dual specificity tyrosine phosphorylation regulated kinase 1A/B (DYRK1A/B), resulting in the cytoplasmic retention of proteins DYRK1A/B and promoting cell cycle process via activation of Akt/GSK-3ß signaling. Combination of cisplatin with an inhibitor of DYRK1 AZ191 effectively inhibited tumor growth in mouse model for HCC cells with high level of TROAP. Clinically, TROAP was significantly upregulated by miR-142-5p in HCC tissues, which predicted the poor survival of patients with HCC. Therefore, TROAP/DYRK1/Akt axis may be a promising therapeutic target and prognostic indicator for patients with HCC.
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Carcinoma Hepatocelular/metabolismo , Moléculas de Adesão Celular/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Animais , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Moléculas de Adesão Celular/genética , Proliferação de Células , Progressão da Doença , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Transfecção , Quinases DyrkRESUMO
Gynecologic cancers, including endometrial, ovarian, and cervical cancers, are the leading causes of cancer-related mortality in women worldwide. Mitochondrial transcription factor A (TFAM) has been demonstrated playing critical roles in the development of tumors. However, the clinical relationship of TFAM expression in gynecologic cancers requires further clarification. Our results showed gynecologic cancer cells are highly expressed TFAM in both protein and RNA levels compared to normal cells. The TCGA dataset revealed that TFAM gene expression is higher in most of the solid tumors than the expression of the known oncogenes (e.g., TP53, BRCA1, and BRCA2). The dataset also suggested a high expression of TFAM in primary and recurrent tumor sites in gynecologic cancers compared to the adjacent normal tissues. Besides, the subcellular fractionation results indicated that the main form of TFAM in cells is chromatin-binding proteins. Further immunohistochemistry study showed that the overexpression of TFAM in tumor tissues is associated with the patient's advanced clinicopathological parameters. The Kaplan-Meier analysis demonstrated that high TFAM expression is a potential prognostic prediction marker for the patient's survival. Furthermore, we observed that downregulated TFAM expression with siRNA suppresses cell proliferation, colony formation, migration, and invasion ability. Taken together, our findings demonstrated that TFAM is highly expressed in cancer cell lines and tumor tissues of gynecologic cancers. The majority of TFAM protein is binding to chromatin in cells, and downregulation of TFAM suppresses cell proliferation, colony formation, migration, and invasion. High level of TFAM in tumor tissues is related to an unfavorable overall survival and disease-free survival in patients with endometrial, ovarian, and cervical cancers, which can serve as a promising prognostic predictive biomarker and a potential therapeutic target.
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T-cell exhaustion was initially identified in chronic infection in mice and was subsequently described in humans with cancer. Although the distinct signature of exhausted T (TEX) cells in cancer has been well investigated, the molecular mechanism of T-cell exhaustion in cancer is not fully understood. Using single-cell RNA sequencing, we report here that TEX cells in esophageal cancer are more heterogeneous than previously clarified. Sprouty RTK signaling antagonist 1 (SPRY1) was notably enriched in two subsets of exhausted CD8+ T cells. When overexpressed, SPRY1 impaired T-cell activation by interacting with CBL, a negative regulator of ZAP-70 tyrosine phosphorylation. Data from the Tumor Immune Estimation Resource revealed a strong correlation between FGF2 and SPRY1 expression in esophageal cancer. High expression of FGF2 was evident in fibroblasts from esophageal cancer tissue and correlated with poor overall survival. In vitro administration of FGF2 significantly upregulated expression of SPRY1 in CD8+ T cells and attenuated T-cell receptor-triggered CD8+ T-cell activation. A mouse tumor model confirmed that overexpression of FGF2 in fibroblasts significantly upregulated SPRY1 expression in TEX cells, impaired T-cell cytotoxic activity, and promoted tumor growth. Thus, these findings identify FGF2 as an important regulator of SPRY1 expression involved in establishing the dysfunctional state of CD8+ T cells in esophageal cancer. SIGNIFICANCE: These findings reveal FGF2 as an important regulator of SPRY1 expression involved in establishing the dysfunctional state of CD8+ T cells and suggest that inhibition of FGF2 has potential clinical value in ESCC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/24/5583/F1.large.jpg.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linfócitos T CD8-Positivos/imunologia , Fibroblastos Associados a Câncer/metabolismo , Neoplasias Esofágicas/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Proteínas de Membrana/metabolismo , Fosfoproteínas/metabolismo , Animais , Modelos Animais de Doenças , Neoplasias Esofágicas/patologia , Feminino , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Células Jurkat , Ativação Linfocitária , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteína Oncogênica v-cbl/genética , Proteína Oncogênica v-cbl/metabolismo , Fosfoproteínas/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , TransfecçãoRESUMO
AIM: Our previous transcriptome sequencing analysis detected that retinol dehydrogenase 16 (RDH16) was dramatically downregulated in hepatocellular carcinoma (HCC). RDH16 belongs to the short-chain dehydrogenases/reductases super family, and its role in HCC remains unknown. This study aimed to investigate the expression and function of RDH16 in HCC. METHODS: The mRNA and protein level of RDH16 in HCC samples were detected by quantitative real-time polymerase chain reaction and immunohistochemistry analyses, respectively. The role of RDH16 in HCC was determined by in vitro and in vivo functional studies. RESULTS: Downregulation of RDH16 has been detected in approximately 90% of primary HCCs, which was significantly associated with high serum alpha-fetoprotein level, tumor size, microsatellite formation, thrombus, and poor overall survival of HCC patients. Compared with non-tumor tissues, higher density of methylation was identified in HCC samples. In addition, RDH16 increases the level of retinoic acid and blocks the de novo synthesis of fatty acid in HCC cells. Functional study shows that ectopic expression of RDH16 in HCC cells suppresses cell growth, clonogenicity, and cell motility. CONCLUSIONS: RDH16 might be a prognostic biomarker and intervention point for new therapeutic strategies in HCC.
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To solve the problem of soil acidification in the cultivation of Codonopsis tangshen, laboratory experiments were carried out to investigate C. tangshen seed germination, seedling growth and soil exchangeable acid, microbial community structure after applying quicklime (QL) and calcium magnesium phosphate fertilizer (CMP). The results showed that QL and CMP treatments significantly improved the survival rate of C. tangshen seedlings from 147.7% to 326.7% and from 270.1% to 311.2%, respectively. The maximum increase rates of the height of C. tangshen seedlings were 516.7% and 546.3%, and that of root length were 798.0% and 679.2% in the treatments of QL and CMP, respectively. 1-4 QL or CMP treatments increased the relative chlorophyll content, antioxidant enzyme activity and the content of soluble protein of C. tangshen seedlings, decreased the content of malondialdehyde and superoxide anion radical of seedlings, increased soil pH by 0.88-2.02 units and 0.23-1.19 units, and decreased the exchangeable aluminum content in soil by 53.0%-95.3% and 17.6%-81.3%, respectively. Soil bacterial and actinomycetic abundances were significantly higher in 2-4 QL or CMP treatments than that in the control. Soil fungal abundance was significantly lower in the QL treatment of 2 and CMP treatment of 4. 1-4 QL or CMP treatments significantly increased fresh weight of C. tangshen tubers by 40.5%-78.5% and 28.4%-78.8%, respectively. In conclusion, the suitable quantity of QL and CMP for acidified soil (pH=4.12, ρb=1.15 g·cm-3, tillage layer=15 cm) amendment were 1.73-3.45 t·hm-2 and 3.45-6.90 t·hm-2, and QL and CMP amendment could fit the optimum soil pH (5.5-6.5) for the growth of C. tangshen seedlings.
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Codonopsis/crescimento & desenvolvimento , Fertilizantes , Fosfatos , Compostos de Cálcio , Medicamentos de Ervas Chinesas , Óxidos , SoloRESUMO
Sirtuin 1 (SIRT1) is a protein deacetylase, which regulates various physiological activities by deacetylating different protein substrates. An increasing number of studies have revealed critical roles of SIRT1 in different aspects of cancers including metabolism, proliferation, genomic instability, and chemotherapy resistance. Depending on the protein targets in a certain oncogenic context, SIRT1 may play a unique role in each individual blood cancer subtype. Our previous work showed that activation of SIRT1 in primitive leukemia cells of acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML) promotes disease maintenance. On the other hand, an SIRT1 agonist was shown to disrupt maintenance of myelodysplastic syndrome (MDS) stem cells and holds promise as a potential therapeutic approach. Herein, we present a concise summary of the different functions of SIRT1 in hematologic malignancies.
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Resistencia a Medicamentos Antineoplásicos , Neoplasias Hematológicas/metabolismo , Sirtuína 1/metabolismo , Proliferação de Células , Sobrevivência Celular , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mieloide Aguda/metabolismo , Linfoma/metabolismo , Síndromes Mielodisplásicas/metabolismo , Fenótipo , Microambiente TumoralRESUMO
Background and Aims: Cancer cells prefer aerobic glycolysis to maintain growth advantages, but the role of long non-coding RNAs (lncRNAs) in glycometabolism still remains unclear. Here we identified one cytoplasmic lncRNA LINC01554 as a significantly downregulated lncRNA in hepatocellular carcinoma (HCC) and aimed to investigate its role in cellular glucose metabolism in the development and progression of HCC. Methods: Quantitative real-time PCR was used to determine the expression level of LINC01554. Downregulation of LINC01554 by miR-365a at transcriptional level was assessed by luciferase reporter assay. Subcellular fractionation assay and RNA fluorescence in situ hybridization were performed to detect the subcellular localization of LINC01554. RNA pull-down assay, mass spectrometry, and RNA immunoprecipitation assay were used to identify the underlying molecular mechanisms. The tumor-suppressive function of LINC01554 was determined by both in vitro assay and nude mice xenograft model. Results: LINC01554 was frequently downregulated in HCC, which was significantly associated with tumor invasion (P = 0.005), tumor size (P = 0.041), tumor staging (P = 0.023) and shorter survival (P = 0.035) of HCC patients. Luciferase reporter assay unraveled that LINC01554 was negatively regulated by miR-365a. Subcellular fractionation assay and RNA FISH revealed the cytoplasmic predominance of LINC01554 in MIHA cells and HCC clinical samples. Ectopic expression of LINC01554 inhibited HCC cell growth, colony formation in soft agar, foci formation, and tumor formation in nude mice. LINC01554 promoted the ubiquitin-mediated degradation of PKM2 and inhibited Akt/mTOR signaling pathway to abolish aerobic glycolysis in HCC cells. Further study found that LINC01554-knockout could effectively reverse the tumor-suppressive effect of LINC01554. Conclusions: Our results identify LINC01554 as a novel tumor suppressor in HCC and unravel its underlying molecular mechanism in reprogramming cellular glucose metabolism. LINC01554 could possibly serve as a novel prognostic biomarker and provide the rationale for HCC therapy.
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Carcinoma Hepatocelular/metabolismo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glucose/metabolismo , Neoplasias Hepáticas/metabolismo , Piruvato Quinase/genética , RNA Longo não Codificante/genética , Animais , Carcinoma Hepatocelular/genética , Regulação para Baixo , Feminino , Humanos , Neoplasias Hepáticas/genética , Masculino , Camundongos Endogâmicos BALB C , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies and lacks targeted therapies. Here, we reported a novel potential therapeutic target hematological and neurological expressed 1 like (HN1L) in HCC. First, HCC tissue microarray analysis showed that HN1L was frequently up-regulated in cancer tissues than that in normal liver tissues, which significantly associated with tumor size, local invasion, distant metastases, and poor prognosis for HCC patients. Functional studies demonstrated that ectopic expression of HN1L could increase cell growth, foci formation in monolayer culture, colony formation in soft agar and tumorigenesis in nude mice. In addition, HN1L could also promote HCC metastasis by inducing epithelial-mesenchymal transition. Inversely, silencing HN1L expression with shRNA could effectively attenuate its oncogenic function. We further showed that HN1L transcriptionally up-regulated methyltransferase like 13 (METTL13) gene in an AP-2γ dependent manner, which promoted cell proliferation and metastasis by up-regulating TCF3 and ZEB1. Importantly, administration of lentivirus-mediated shRNA interfering HN1L expression could inhibit tumorigenesis and metastasis in mice. Collectively, HN1L-mediated transcriptional axis AP-2γ/METTL13/TCF3-ZEB1 promotes HCC growth and metastasis representing a promising therapeutic target in HCC treatment.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Metiltransferases/metabolismo , Fator de Transcrição AP-2/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/fisiologia , Transformação Celular Neoplásica/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Metástase Neoplásica/patologia , Interferência de RNA , RNA Interferente Pequeno/genéticaRESUMO
The poorly differentiated hepatocellular carcinoma (HCC) cells are usually characterized by immature hepatic progenitor cell-like properties, such as enhanced self-renewal ability, resistance to chemotherapeutic drugs, and a loss of mature hepatocyte proteins. However, the molecular mechanisms governing this process still remain unclear. In this study, we found the lymphoid enhancer-binding factor-1 (LEF1), a transcriptional factor, was frequently overexpressed in HCCs, which was significantly associated with poor prognosis and tumor cell differentiation. Functional studies have found that LEF1 enhanced cell growth, foci formation, colony formation in soft agar, and tumor formation in nude mice. Different from its canonical roles in the WNT signaling pathway, we found that LEF1 could activate the critical members (e.g., NOTCH1 and NOTCH2) of the NOTCH signaling pathway through directly binding to their promoter regions. Further studies have found that LEF1 could enhance the self-renewal ability, drug resistance, dedifferentiation, and invasion of HCC cells. The oncogenic functions and the effects of LEF1 on cancer stemness could be effectively inhibited by NOTCH inhibitor. Further characterization of LEF1 may lead to the development of novel therapeutic strategies for HCC treatment.
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Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Diferenciação Celular/fisiologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Receptores Notch/metabolismo , Animais , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Células Hep G2 , Humanos , Camundongos , Camundongos Nus , Prognóstico , Regiões Promotoras Genéticas/fisiologia , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt/fisiologiaRESUMO
Angiogenesis is essential in the early stage of solid tumor recurrence, but how a suspensive tumor is reactivated before angiogenesis is mostly unknown. Herein, we stumble across an interesting phenomenon that s.c. xenografting human lung cancer tissues can awaken the s.c. suspensive tumor in nude mice. We further found that a high level of insulin-like growth factor 1 (IGF1) was mainly responsible for triggering the transition from suspensive tumor to progressive tumor in this model. The s.c. suspensive tumor is characterized with growth arrest, avascularity, and a steady-state level of proliferating and apoptotic cells. Intriguingly, CD133+ lung cancer stem cells (LCSCs) are highly enriched in suspensive tumor compared with progressive tumor. Mechanistically, high IGF1 initiates LCSCs self-renewal from asymmetry to symmetry via the activation of a PI3K/Akt/ß-catenin axis. Next, the expansion of LCSC pool promotes angiogenesis by increasing the production of CXCL1 and PlGF in CD133+ LCSCs, which results in lung cancer recurrence. Clinically, a high level of serum IGF1 in lung cancer patients after orthotopic lung cancer resection as an unfavorable factor is strongly correlated with the high rate of recurrence and indicates an adverse progression-free survival. Vice versa, blocking IGF1 or CXCL1/PlGF with neutralizing antibodies can prevent the reactivation of a suspensive tumor induced by IGF1 stimulation in the mouse model. Collectively, the expansion of LCSC pool before angiogenesis induced by IGF1 is a key checkpoint during the initiation of cancer relapse, and targeting serum IGF1 may be a promising treatment for preventing recurrence in lung cancer patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Antígeno AC133/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/sangue , Linhagem Celular Tumoral , Proliferação de Células , Quimiocina CXCL1/antagonistas & inibidores , Quimiocina CXCL1/metabolismo , Feminino , Humanos , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Neoplasias Pulmonares/sangue , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia/sangue , Neovascularização Patológica/sangue , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Crescimento Placentário/antagonistas & inibidores , Fator de Crescimento Placentário/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismoRESUMO
The tumor microenvironment, including stroma cells, signaling molecules, and the extracellular matrix, critically regulates the growth and survival of cancer cells. Dissecting the active molecules in tumor microenvironment may uncover the key factors that can impact cancer progression. Human NSCLC tumor tissue-conditioned medium (TCM) and adjacent nontumor tissue-conditioned medium (NCM) were used to treat two NSCLC cells LSC1 and LAC1, respectively. Cell growth and foci formation assays were applied to assess the effects of TCM and NCM on cancer cells. The active factors were identified by protein mass spectrometry. Cell growth and foci formation assays showed that 8 of 26 NCM and none of TCM could effectively lead to tumor cell lysis, which was known as tumoricidal activity. And then protein mass spectrometry analysis and functional verifications confirmed that complement component 9 (C9) played a crucial role in the complement-dependent cytotoxicity (CDC)-mediated tumoricidal activity in vitro. Furthermore, immunofluorescent staining revealed that C9 specifically expressed in most alveolar macrophages (AMs) in adjacent lung tissues and a small fraction of tumor-associated macrophages (TAMs) in NSCLC tissues. Most importantly, the percentage of C9-positive cells in AMs or TAMs was responsible for the tumoricidal activity of NCM and TCM. Herein, we found that high expression of C9 in TAMs was a significant independent prognostic factor (P = 0.029), and associated with beneficial overall survival (P = 0.012) and disease-free survival (P = 0.016) for patients with NSCLC. Finally, we unveiled that hypoxic tumor microenvironment could switch the phenotype of macrophages from M1 to M2 forms, accompanying with the downregulation of C9 in TAMs. Collectively, our findings elucidated a novel role of TAMs expressing C9 in the prognosis of NSCLC patients, which provided a promising strategy in the development of anticancer treatments based on the CDC-mediated tumoricidal activity.