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1.
J Environ Manage ; 363: 121382, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38852416

RESUMO

Vegetation restoration not only extensively reshapes spatial land use patterns but also profoundly affects the dynamics of runoff and sediment loss. However, the influence of vegetation restoration on runoff and sediment yield from a regional perspective are scarce. This study therefore focused on 85 sites within the "Grain for Green" Project (GGP) region on the Loess Plateau, to investigate the impacts of the GGP on soil erosion. The results revealed a notable reduction in sediment loss and runoff due to vegetation restoration. Since the inception of the GGP in 1999, approximately 4.1 × 106 ha of degraded lands have been converted into forestlands, shrublands, and grasslands, resulting in an average annual reduction of 1.4 × 109 m3 in runoff and a decrease of 3.6 × 108 t in annual sediment loss on the whole Loess Plateau, with the GGP contributing approximately 26.7% of the sediment reduction in the Yellow River basin. The reduced soil erosion has mainly been regulated by vegetation cover, soil properties (clay, silt, and sand), slope, and precipitation on the Loess Plateau. The insights gained offer valuable contributions to large-scale assessments of changes in soil erosion in response to vegetation reconstruction and enhance our understanding of the spatial configurations associated with soil erosion control measures.


Assuntos
Conservação dos Recursos Naturais , Erosão do Solo , Solo , Sedimentos Geológicos , China , Monitoramento Ambiental , Florestas
2.
Oncogene ; 42(32): 2456-2470, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37400530

RESUMO

Colorectal cancer (CRC) is a highly aggressive cancer in which metastasis plays a key role. However, the mechanisms underlying metastasis have not been fully elucidated. Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), a regulator of mitochondrial function, has been reported as a complicated factor in cancer. In this study, we found that PGC-1α was highly expressed in CRC tissues and was positively correlated with lymph node and liver metastasis. Subsequently, PGC-1α knockdown was shown to inhibit CRC growth and metastasis in both in vitro and in vivo studies. Transcriptomic analysis revealed that PGC-1α regulated ATP-binding cassette transporter 1 (ABCA1) mediated cholesterol efflux. Mechanistically, PGC-1α interacted with YY1 to promote ABCA1 transcription, resulting in cholesterol efflux, which subsequently promoted CRC metastasis through epithelial-to-mesenchymal transition (EMT). In addition, the study identified the natural compound isoliquiritigenin (ISL) as an inhibitor that targeted ABCA1 and significantly reduced CRC metastasis induced by PGC-1α. Overall, this study sheds light on how PGC-1α promotes CRC metastasis by regulating ABCA1-mediated cholesterol efflux, providing a basis for further research to inhibit CRC metastasis.


Assuntos
Neoplasias Colorretais , Mitocôndrias , Humanos , Mitocôndrias/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Colesterol , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética
3.
Oncogene ; 42(29): 2278-2293, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37349644

RESUMO

Cisplatin (CDDP) is the first-line drug in the clinical treatment of esophageal squamous cell carcinoma (ESCC), which has severe nephrotoxicity. Diosmetin (DIOS) can protect kidney from oxidative damage, however, its function in ESCC is unknown. This study aims to explore the effect and mechanism of DIOS on ESCC and its combined effect with CDDP. Herein, we found that DIOS significantly inhibited the progression of ESCC in vitro and in vivo. Furthermore, the anti-tumor effect of DIOS was not statistically different from that of CDDP. Mechanically, transcriptomics revealed that DIOS inhibited the E2F2/RRM2 signaling pathway. The transcriptional regulation of RRM2 by E2F2 was verified by luciferase assay. Moreover, docking model, CETSA, pull-down assay and CDK2 inhibitor assay confirmed that DIOS directly targeted CDK2, leading to significant suppression of ESCC. Additionally, the patient-derived xenografts (PDX) model showed that the combination of DIOS and CDDP significantly inhibited the growth of ESCC. Importantly, the combined treatment with DIOS and CDDP significantly reduced the mRNA expression levels of kidney injury biomarkers KIM-1 and NGAL in renal tissue, as well as the levels of blood urea nitrogen, serum creatinine and blood uric acid compared to the single treatment with CDDP. In conclusion, DIOS could be an effective drug and a potential chemotherapeutic adjuvant for ESCC treatment. Furthermore, DIOS could reduce the nephrotoxicity of CDDP to some extent.


Assuntos
Antineoplásicos , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Linhagem Celular Tumoral , Quinase 2 Dependente de Ciclina/genética , Fator de Transcrição E2F2
4.
Mol Carcinog ; 62(5): 583-597, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37014157

RESUMO

Epidemiological evidence supports that consumption of high-temperature food and beverages is an important risk factor for esophageal squamous cell carcinoma (ESCC); however, the underlying mechanism still remains unclear. Here, we established a series of animal models and found that drinking 65°C water can promote esophageal tumor progression from preneoplastic lesions to ESCC. RNA sequencing data showed that miR-132-3p was highly expressed in the heat stimulation group compared with controls. Further study verified that miR-132-3p were upregulated in human premalignant lesion tissues of the esophagus, ESCC tissues, and cells. Overexpression of miR-132-3p could promote ESCC cell proliferation and colony formation, whereas knockdown of miR-132-3p could inhibit ESCC progression in vitro and in vivo. Importantly, dual-luciferase reporter assays showed that miR-132-3p could bind with the 3'-untranslated region of KCNK2 and inhibit KCNK2 gene expression. Knockdown or overexpression of KCNK2 could promote or suppress ESCC progression in vitro. These data suggest that heat stimulation can promote ESCC progression and miR-132-3p mediated this process by directly targeting KCNK2.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , MicroRNAs , Animais , Humanos , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Regulação Neoplásica da Expressão Gênica , Temperatura Alta , MicroRNAs/genética , MicroRNAs/metabolismo
5.
Signal Transduct Target Ther ; 8(1): 96, 2023 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-36872366

RESUMO

Constitutive activation of RAS-RAF-MEK-ERK signaling pathway (MAPK pathway) frequently occurs in many cancers harboring RAS or RAF oncogenic mutations. Because of the paradoxical activation induced by a single use of BRAF or MEK inhibitors, dual-target RAF and MEK treatment is thought to be a promising strategy. In this work, we evaluated erianin is a novel inhibitor of CRAF and MEK1/2 kinases, thus suppressing constitutive activation of the MAPK signaling pathway induced by BRAF V600E or RAS mutations. KinaseProfiler enzyme profiling, surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), cellular thermal shift assay, computational docking, and molecular dynamics simulations were utilized to screen and identify erianin binding to CRAF and MEK1/2. Kinase assay, luminescent ADP detection assay, and enzyme kinetics assay were investigated to identify the efficiency of erianin in CRAF and MEK1/2 kinase activity. Notably, erianin suppressed BRAF V600E or RAS mutant melanoma and colorectal cancer cell by inhibiting MEK1/2 and CRAF but not BRAF kinase activity. Moreover, erianin attenuated melanoma and colorectal cancer in vivo. Overall, we provide a promising leading compound for BRAF V600E or RAS mutant melanoma and colorectal cancer through dual targeting of CRAF and MEK1/2.


Assuntos
Neoplasias Colorretais , Melanoma , Humanos , Transdução de Sinais , Quinases de Proteína Quinase Ativadas por Mitógeno
6.
J Cancer ; 13(8): 2607-2619, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35711839

RESUMO

Esophageal squamous cell carcinoma (ESCC) is a malignant cancer that is responsible for a high mortality rate; it accounts for approximately 90% of the 456,000 esophageal cancer (EC) cases diagnosed annually. Effective natural or synthesized compounds to prevent, treat, and/or inhibit ESCC relapse are desperately needed. The natural di-indole compound 3,3'-diindolylmethane (DIM) is abundant in cruciferous vegetables and shows potent anti-tumor effects in multiple cancers. The synthesized Eflornithine (DFMO) is clinically used to treat African sleeping sickness. We demonstrated that the combination of DIM+DFMO could significantly suppress the ESCC growth in the in vivo study of three patient-derived xenograft (PDX) cases. Then, the corresponding underlying anticancer mechanisms were investigated via the isobaric tags for relative and absolute quantification (iTRAQ) on the proteome level. We found that the DNA Replication and Cell Cycle were the top-2 most significantly downregulated signaling pathways following the DIM+DFMO treatment. Correspondingly and interestingly, these two pathways were the top-2 upregulated ones in clinic ESCC tumors. Moreover, the involved differentially expressed genes (DEGs) including MCM2, MCM3, MCM5, MCM6, MCM7, CDK1, and LIG1 were all inversely downregulated by DIM+DFMO treatment. In the limited clinical study in two ESCC cases, the administration of DIM (250mg) +DFMO (500 mg) once daily showed favorable results, including alleviated swallowing difficulties, decreased blood tumor markers (CA19-9, CA15-3 and AFP), and no severe toxicity in at least one month progression free survival period. We concluded that DIM+DFMO is a promising therapeutic combination for ESCC treatment via the suppression of DNA Replication and Cell Cycle activities. However, these therapeutic effects should be verified in large cohort clinical trials with sufficient cases.

7.
Bioengineered ; 13(5): 12516-12531, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35587604

RESUMO

Transcriptional factor 3 (TCF3, also termed E2A), first reported to exert crucial functions during lymphocyte development, has been revealed to participate in the pathogenesis of human cancers. The aim of this work was to investigate the function of TCF3 in cervical cancer (CC) and the molecular interactions. The bioinformatics prediction suggested that TCF3 was highly expressed in CC and linked to poor prognosis. Increased TCF3 expression was identified in CC cell lines, and its downregulation reduced proliferation and migration of CC cells in vitro as well as growth of xenograft tumors in vivo. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that the TCF-3-related genes and genes showed differential expression between CC and normal tissues were mainly enriched in the Wnt/ß-catenin pathway. TCF3 bound to sirtuin 1 (SIRT1) promoter for transcriptional activation, and SIRT1 promoted deacetylation and nuclear translocation of ß-catenin in CC. SIRT1 overexpression blocked the role of TCF3 silencing and restored cell proliferation in vitro and tumor growth in vivo. Treatment with XAV-939, a ß-catenin inhibitor, significantly suppressed the cell proliferation and tumor growth induced by SIRT1 overexpression. In conclusion, this study demonstrates that TCF3 augments progression of CC by activating SIRT1-mediated ß-catenin signaling.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Sirtuína 1/metabolismo , Neoplasias do Colo do Útero , beta Catenina , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Humanos , Sirtuína 1/genética , Fator 3 de Transcrição/metabolismo , Neoplasias do Colo do Útero/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , beta Catenina/metabolismo
8.
Carcinogenesis ; 43(2): 126-139, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-34919670

RESUMO

Helicobacter pylori infection and alcohol intake are independent risk factors in gastric carcinogenesis; however, until now, the combined effect of H. pylori infection and alcohol consumption and the specific mechanism is still problematic. Here, we developed a series of mouse models that progress from chronic gastritis to gastric cancer, induced by infecting H. pylori combined with chronic alcohol consumption and then determining the molecular mechanism of the progression by flow cytometry, western blotting, qPCR, Mito Traker assay in the gastric cancer and T-cell lines. Interleukin-10 (IL-10) knockout mice was used to determine whether IL-10 deficiency directly contributes to H. pylori and alcohol induced gastric tumorigenesis. Alcohol consumption, together with H. pylori infection, causes gastric cancer; IL-10 downregulation and mitochondrial metabolic dysfunction in CD8+ cells are also involved. IL-10 knockout accelerates tumor development in mice with either H. pylori infection or alcohol induced gastric cancer or both. IL-10 inhibits glucose uptake and glycolysis and promotes oxidative phosphorylation with lactate inhibition. Consequently, in the absence of IL-10 signaling, CD8+ cells accumulate damaged mitochondria in a mouse model of gastric cancer induced with the combination of alcohol plus H. pylori infection, and this results in mitochondrial dysfunction and production of IL-1ß. IL-1ß promotes H. pylori infection and reduces NKX6.3 gene expression, resulting in increased cancer cell survival and proliferation. Gastric cancer can be induced by the combination of H. pylori infection and chronic alcohol consumption through IL-10 inhibition induced CD8+ cells dysfunction and NKX6.3 suppression.


Assuntos
Alcoolismo , Gastrite , Infecções por Helicobacter , Neoplasias Gástricas , Alcoolismo/complicações , Animais , Carcinogênese/patologia , Transformação Celular Neoplásica/patologia , Mucosa Gástrica/patologia , Gastrite/metabolismo , Gastrite/patologia , Infecções por Helicobacter/complicações , Helicobacter pylori , Interleucina-10/genética , Camundongos , Neoplasias Gástricas/patologia
9.
J Fungi (Basel) ; 7(8)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34436131

RESUMO

A round-the-clock photocatalyst with energy-storage ability has piqued the interest of researchers for removing microbial contaminants from indoor environments. This work presents a moderate round-the-clock method for inhibiting the growth of fungus spores on bamboo materials using Ag-modified TiO2 thin films. Photoactivated antifungal coating with catalytic memory activity was assembled on a hydrophilic bamboo by first anchoring anatase TiO2 thin films (TB) via hydrogen bonding and then decorating them with Ag nanoparticles (ATB) via electrostatic interactions. Antifungal test results show that the Ag/TiO2 composite films grown on the bamboo surface produced a synergistic antifungal mechanism under both light and dark conditions. Interestingly, post-illumination catalytic memory was observed for ATB, as demonstrated by the inhibition of Aspergillus niger (A. niger) spores, in the dark after visible light was removed, which could be attributed to the transfer of photoexcited electrons from TiO2 to Ag, their trapping on Ag under visible-light illumination, and their release in the dark after visible light was removed. The mechanism study revealed that the immobilized Ag nanoparticles served the role of "killing two birds with one stone": increasing visible-light absorption through surface plasmon resonance, preventing photogenerated electron-hole recombination by trapping electrons, and contributing to the generation of ●O2-and ●OH. This discovery creates a pathway for the continuous removal of indoor air pollutants such as volatile organic compounds, bacteria, and fungus in the day and night time.

10.
J Cancer ; 12(13): 3930-3944, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093800

RESUMO

Esophageal Squamous Cell Carcinoma (ESCC) is the predominant type of Esophageal Cancer (EC), accounting for nearly 88% of EC incidents worldwide. Importantly, it is also a life-threatening cancer for patients diagnosed in advanced stages, with only a 20% 5-year survival rate due to a limited number of actionable targets and therapeutic options. Increasing evidence has shown that inter-tumor and intra-tumor heterogeneity are widely distributed across ESCC tumor tissues. In our work, multi-omics data from ESCC cell lines, tumor tissue, normal tissue and Patient-Derived Xenograft (PDX) tissues were analyzed to investigate the heterogeneity among ESCC samples at the DNA, RNA, and protein level. We identified enrichment of ECM-receptor interaction and Focal adhesion pathways from the subset of protein-coding genes with non-silent mutations in ESCC patients. We also found that TP53, TTN, KMT2D, CSMD3, DNAH5, MUC16 and DST are the most frequently mutated genes in ESCC patient samples. Out of the identified genes, TP53 is the most frequently mutated, with 84 distinct non-silent mutation variants. We observed that p.R248Q, p.R175G/H, and p.R273C/H are the most common TP53 mutation variants. The diversity of TP53 mutations reveal its importance in ESCC progression and may also provide promising targets for precision therapeutics. Additionally, we identified the Olfactory transduction as the top signaling pathway, enriched from genes uniquely expressed in The Cancer Genome Atlas (TCGA)-ESCC patient tumor tissues, which may provide implications for the exact roles of the corresponding genes in ESCC. Cyclic nucleotide-gated channel subunit beta 1(CNGB1), a gene belonging to the Olfactory transduction pathway, was found exclusively overexpressed in ESCC. Expression of CNGB1 could serve as a marker, indicating potential diagnostic or therapeutic value. Finally, we investigated heterogeneity in the context of the ESCC PDX model, which is an emerging tool used to predict drug response and recapitulate tumor behavior in vivo. We observed trans-species heterogeneity in as high as 75% of the identified proteins, indicating that the ambiguity of proteins should be addressed by specific strategies to avoid drawing false conclusions. The identification and characterization of gene mutation and expression heterogeneity across different ESCC datasets, including various novel TP53 mutations, ECM-receptor interaction, Focal adhesion, and Olfactory transduction pathways (CNGB1), provide researchers with evidence and implications for accurate research and precision therapeutic development.

11.
Cancer Res ; 80(19): 4158-4171, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32816906

RESUMO

The key functional molecules involved in inflammatory bowel disease (IBD) and IBD-induced colorectal tumorigenesis remain unclear. In this study, we found that the apoptosis repressor with caspase recruitment domain (ARC) protein plays critical roles in IBD. ARC-deficient mice exhibited substantially higher susceptibility to dextran sulfate sodium (DSS)-induced IBD compared with wild-type mice. The inflammatory burden induced in ARC-deficient conditions was inversely correlated with CCL5 and CXCL5 levels in immune cells, especially CD4-positive T cells. Pathologically, ARC expression in immune cells was significantly decreased in clinical biopsy specimens from patients with IBD compared with normal subjects. In addition, ARC levels inversely correlated with CCL5 and CXCL5 levels in human biopsy specimens. ARC interacted with TNF receptor associated factor (TRAF) 6, regulating ubiquitination of TRAF6, which was associated with NF-κB signaling. Importantly, we identified a novel ubiquitination site at lysine 461, which was critical in the function of ARC in IBD. ARC played a critical role in IBD and IBD-associated colon cancer in a bone marrow transplantation model and azoxymethane/DSS-induced colitis cancer mouse models. Overall, these findings reveal that ARC is critically involved in the maintenance of intestinal homeostasis and protection against IBD through its ubiquitination of TRAF6 and subsequent modulation of NF-κB activation in T cells. SIGNIFICANCE: This study uncovers a crucial role of ARC in the immune system and IBD, giving rise to a novel strategy for IBD and IBD-associated colon cancer therapy.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias Colorretais/etiologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Proteínas Musculares/metabolismo , Animais , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/genética , Azoximetano/toxicidade , Transplante de Medula Óssea , Linfócitos T CD4-Positivos/imunologia , Quimiocina CCL5/metabolismo , Quimiocina CXCL5/metabolismo , Colite/induzido quimicamente , Neoplasias Colorretais/induzido quimicamente , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células Jurkat , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Musculares/química , Proteínas Musculares/genética , Ubiquitinação
12.
Oncogene ; 39(21): 4170-4182, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32277233

RESUMO

Nonmelanoma skin cancer (NMSC) such as cutaneous squamous cell carcinoma (cSCC) is caused by solar ultraviolet (SUV) exposure and is the most common cancer in the United States. T-LAK cell-originated protein kinase (TOPK), a serine-threonine kinase is activated by SUV irradiation and involved in skin carcinogenesis. Strategies with research focusing on the TOPK signaling pathway and targeted therapy in skin carcinogenesis may helpful for the discovery of additional treatments against skin cancer. In this study, we found that TOPK can directly bind to and phosphorylate c-Jun (as one of the core member of AP-1) at Ser63 and Ser73 after SSL exposure in a JNKs-independent manner. TOPK knocking down, or HI-TOPK-032 (TOPK specific inhibitor) attenuated colony formation and cell proliferation of skin cancer cells. Phosphorylated levels of c-Jun were overexpressed in human AK and cSCC compared with normal skin tissues, and HI-TOPK-032 inhibited the phosphorylation of c-Jun in SCC cell line in a dose-dependent manner. Furthermore, HI-TOPK-032 decreased SSL-induced AP-1 transactivation activity. Moreover, acute SSL-induced inflammation was attenuated by the topical application of HI-TOPK-032 in SKH1 hairless mice. Importantly, HI-TOPK-032 suppressed chronic SSL-induced skin carcinogenesis and c-Jun phosphorylation levels in SKH1 hairless mice. Our results demonstrate that TOPK can phosphorylate and activate c-Jun at Ser63 and Ser73 in the process of skin carcinogenesis and HI-TOPK-032 could be used as a potential chemopreventive drug against cSCC development.


Assuntos
Carcinogênese , Indolizinas/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno , Proteínas de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Quinoxalinas/farmacologia , Neoplasias Cutâneas , Luz Solar/efeitos adversos , Raios Ultravioleta/efeitos adversos , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/efeitos da radiação , Humanos , Camundongos , Camundongos Pelados , Camundongos Knockout , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
13.
EBioMedicine ; 49: 145-156, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31707149

RESUMO

BACKGROUND: Barrett's esophagus (BE), a complication of gastroesophageal reflux disease (GERD), predisposes patients to esophageal adenocarcinoma (EAC). Reliable biomarkers for early detection and discovery of potential drug targets are urgently needed for improved BE and EAC patient outcomes. METHODS: Patient biopsy samples were evaluated for COX1/2, and thromboxane A2 synthase (TBXAS) expression. Circulating prostaglandins biosynthesis was determined using enzyme immunoassay kits. Anchorage-independent cell growth assay, crystal violet staining assay, and xenograft experiments were conducted to assess BE and EAC cell growth. A surgical mouse model of reflux (i.e., esophagoduodenostomy) was established and samples were analyzed using an enzyme immunoassay kit, immunohistochemistry, immunoblotting, or RT-PCR. Esophageal biopsy samples (pre- and post-intervention) were obtained from a randomized clinical trial in which participants were administered esomeprazole (40 mg) twice daily in combination with an acetylsalicylic acid (ASA) placebo or 81 or 325 mg ASA for 28 days. Esophageal biopsy specimens before and after the intervention period were analyzed. FINDINGS: COX2 and TBXAS are highly expressed in BE and EAC patients accompanied by a pronounced elevation of circulating TXA2 levels. ASA suppressed BE and EAC growth by targeting the TXA2 pathway. Additionally, biopsies from 49 patients (with similar baseline characteristics) showed that ASA substantially decreased serum TXA2 levels, resulting in reduced inflammation. INTERPRETATION: This study establishes the importance of the COX1/2-driven TXA2 pathway in BE and EAC pathophysiology and lays the groundwork for introducing a TXA2-targeting strategy for EAC prevention and early detection. FUNDING: Hormel Foundation, Exact Sciences, Pentax Medical, Intromedic and National Cancer.


Assuntos
Adenocarcinoma/tratamento farmacológico , Esôfago de Barrett/tratamento farmacológico , Carcinogênese/patologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Terapia de Alvo Molecular , Transdução de Sinais , Tromboxano A2/metabolismo , Adenocarcinoma/sangue , Animais , Aspirina/farmacologia , Esôfago de Barrett/sangue , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Neoplasias Esofágicas/sangue , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fator de Transcrição STAT3/metabolismo , Tromboxano A2/sangue
14.
Cancer Prev Res (Phila) ; 12(12): 837-848, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31554629

RESUMO

Lung cancer is the leading cause of cancer-related death worldwide. However, promising agents for lung cancer prevention are still very limited. Identification of preventive targets and novel effective preventive agents is urgently needed for clinical applications. In this study, we found that fluvastatin targeted 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), which a rate-limiting enzyme in the mevalonate pathway, and inhibited non-small cell lung cancer (NSCLC) tumorigenesis. Initially, we demonstrated that HMGCR is overexpressed in human lung adenocarcinoma tissues compared with normal tissues. Knockdown of HMGCR in NSCLC cells attenuated growth and induced apoptosis in vitro and in vivo Furthermore, we found that fluvastatin, an inhibitor of HMGCR, suppressed NSCLC cell growth and induced apoptosis. Intriguingly, fluvastastin functions by inhibiting the HMGCR-driven Braf/MEK/ERK1/2 and Akt signaling pathways. Notably, fluvastatin attenuated tumor growth in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis and in a patient-derived xenograft lung tumor model. Overall, our findings suggest that fluvastatin might be promising chemopreventive or potential therapeutic drug against NSCLC tumorigenesis, providing hope for rapid clinical translation.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/prevenção & controle , Fluvastatina/farmacologia , Hidroximetilglutaril-CoA Redutases/metabolismo , Neoplasias Pulmonares/prevenção & controle , Acil Coenzima A/metabolismo , Adulto , Idoso , Animais , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Carcinógenos/toxicidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Feminino , Fluvastatina/uso terapêutico , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Inibidores de Hidroximetilglutaril-CoA Redutases , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Ácido Mevalônico/metabolismo , Camundongos , Pessoa de Meia-Idade , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Nitrosaminas/toxicidade , RNA Interferente Pequeno/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
EBioMedicine ; 44: 361-374, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31085102

RESUMO

BACKGROUND: Our preclinical data showed that the leukotriene A4 hydrolase (LTA4H) pathway plays a role in colorectal cancer (CRC). High expression of LTA4H and leukotriene B4 receptor type 1 (BLT1) were also associated with CRC survival probability. Clinical samples were evaluated to determine whether LTA4H could serve as a therapeutic target and whether leukotriene B4 (LTB4) could be used as a biomarker for evaluating the efficacy of bestatin in CRC. METHODS: Patients with Stage I-III CRC did or did not receive bestatin prior to surgery. Evaluable pairwise CRC patient blood samples were collected to evaluate LTB4 concentration. Tissues were processed by immunohistochemistry to detect the LTA4H pathway and Ki-67 expression. We also determined whether LTA4H or BLT1 was associated with CRC survival probability and explored the mechanism of bestatin action in CRC. FINDINGS: Samples from 13 CRC patients showed a significant decrease in LTB4, the LTA4H signaling pathway, and Ki-67 in the bestatin-treated group compared with the untreated group. LTA4H and BLT1 are overexpressed in CRC and associated with CRC survival probability. Bestatin effectively inhibited LTB4 and tumorigenesis in the ApcMin/+ and CRC patient-derived xenograft mouse model. INTERPRETATION: These results demonstrate that LTB4 could serve as a biomarker for evaluating bestatin efficacy in CRC and the antitumor effects of bestatin through its targeting of LTA4H and support further studies focusing on LTA4H inhibition in CRC.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Leucina/análogos & derivados , Adulto , Idoso , Animais , Biomarcadores , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Epóxido Hidrolases/genética , Epóxido Hidrolases/metabolismo , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Leucina/farmacologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Modelos Biológicos , Estadiamento de Neoplasias , Prognóstico , Receptores do Leucotrieno B4/genética , Receptores do Leucotrieno B4/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
16.
EBioMedicine ; 28: 51-61, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29398601

RESUMO

The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer (NSCLC). Constitutively active EGFR mutations, including in-frame deletion in exon 19 and L858R point mutation in exon 21, contribute about 90% of all EGFR-activating mutations in NSCLC. Although oral EGFR-tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, show dramatic clinical efficacy with significantly prolonged progression-free survival in patients harboring these EGFR-activating mutations, most of these patients will eventually develop acquired resistance. Researchers have recently named genomic instability as one of the hallmarks of cancer. Genomic instability usually involves a transient phase of polyploidization, in particular tetraploidization. Tetraploid cells can undergo asymmetric cell division or chromosome loss, leading to tumor heterogeneity and multidrug resistance. Therefore, identification of signaling pathways involved in tetraploidization is crucial in overcoming drug resistance. In our present study, we found that gefitinib could activate YAP-MKK3/6-p38 MAPK-STAT3 signaling and induce tetraploidization in gefitinib-resistance cells. Using p38 MAPK inhibitors, SB203580 and losmapimod, we could eliminate gefitinib-induced tetraploidization and overcome gefitinib-resistance. In addition, shRNA approach to knockdown p38α MAPK could prevent tetraploidy formation and showed significant inhibition of cancer cell growth. Finally, in an in vivo study, losmapimod could successfully overcome gefitinib resistance using an in-house established patient-derived xenograft (PDX) mouse model. Overall, these findings suggest that losmapimod could be a potential clinical agent to overcome gefitinib resistance in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ciclopropanos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Piridinas/uso terapêutico , Quinazolinas/uso terapêutico , Tetraploidia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclopropanos/farmacologia , Ativação Enzimática/efeitos dos fármacos , Gefitinibe , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Camundongos , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , Quinazolinas/farmacologia , Fatores de Transcrição , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Sinalização YAP , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Oncotarget ; 8(43): 74673-74687, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-29088816

RESUMO

Although it has been known that the tumor microenvironment affects angiogenesis, the precise mechanism remains unclear. In this study, we simulated the microenvironment of human esophageal squamous cell carcinoma (ESCC) by tumor conditioned medium (TCM) to assess the influence on normal endothelial cells (NECs). We found that the TCM-induced NECs showed enhanced angiogenic properties, such as migration, invasion and tube formation. Moreover, the TCM-induced NECs expressed tumor endothelial cells (TECs) markers at higher levels, which indicated that TCM probably promoted tumor angiogenesis by coercing NECs to change toward TECs. The microarray gene expression analysis indicated that TCM induced great changes in the genome of NECs and altered many regulatory networks, especially c-MYC and JAK/STAT3 signaling pathway. More importantly, we investigated the anti-angiogenic effect of metformin, and found that metformin abrogated the ESCC microenvironment-induced transition of NECs toward TECs by inhibiting JAK/STAT3/c-MYC signaling pathway. Furthermore, we verified the anti-angiogenic activity of metformin in vivo by a human ESCC patient-derived xenograft (PDX) mouse model for the first time. Taken together, our research provides a novel mechanism for the anti-angiogenic effect of metformin, and sets an experimental basis for the development of new anti-angiogenic drugs by blocking the transition of NECs toward TECs, which possibly open new avenues for targeted treatment of cancer.

18.
Carcinogenesis ; 38(7): 728-737, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28575166

RESUMO

Leukotriene A4 hydrolase (LTA4H), a bifunctional zinc metallo-enzyme, is reportedly overexpressed in several human cancers. Our group has focused on LTA4H as a potential target for cancer prevention and/or therapy. In the present study, we report that LTA4H is a key regulator of cell cycle at the G0/G1 phase acting by negatively regulating p27 expression in skin cancer. We found that LTA4H is overexpressed in human skin cancer tissue. Knocking out LTA4H significantly reduced skin cancer development in the 7,12-dimethylbenz(a)anthracene (DMBA)-initiated/12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted two-stage skin cancer mouse model. LTA4H depletion dramatically decreased anchorage-dependent and -independent skin cancer cell growth by inducing cell cycle arrest at the G0/G1 phase. Moreover, our findings showed that depletion of LTA4H enhanced p27 protein stability, which was associated with decreased phosphorylation of CDK2 at Thr160 and inhibition of the CDK2/cyclin E complex, resulting in down-regulated p27 ubiquitination. These findings indicate that LTA4H is critical for skin carcinogenesis and is an important mediator of cell cycle and the data begin to clarify the mechanisms of LTA4H's role in cancer development.


Assuntos
Carcinogênese/genética , Ciclo Celular/genética , Epóxido Hidrolases/genética , Neoplasias Cutâneas/genética , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Quinase 2 Dependente de Ciclina/biossíntese , Quinase 2 Dependente de Ciclina/genética , Epóxido Hidrolases/biossíntese , Fase G1 , Humanos , Camundongos , Fosforilação , Antígeno Nuclear de Célula em Proliferação/biossíntese , Piridinas/toxicidade , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/patologia
19.
EBioMedicine ; 18: 73-82, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28412249

RESUMO

Approximately 90% of all cancer deaths arise from the metastatic dissemination of primary tumors. Metastasis is the most lethal attribute of colorectal cancer. New data regarding the molecules contributing to the metastatic phenotype, the pathways they control and the genes they regulate are very important for understanding the processes of metastasis prognosis and prevention in the clinic. The purpose of this study was to investigate the role of T-LAK cell-originated protein kinase (TOPK) in the promotion of colorectal cancer metastasis. TOPK is highly expressed in human metastatic colorectal cancer tissue compared with malignant adenocarcinoma. We identified p53-related protein kinase (PRPK) as a new substrate of TOPK. TOPK binds with and phosphorylates PRPK at Ser250 in vitro and ex vivo. This site plays a critical role in the function of PRPK. Cell lines stably expressing mutant PRPK (S250A), knockdown TOPK, knockdown PRPK or knockdown of both TOPK and PRPK significantly inhibited liver metastasis of human HCT116 colon cancer cells in a xenograft mouse model. Therefore, we conclude that TOPK directly promotes metastasis of colorectal cancer by modulating PRPK. Thus, these findings may assist in the prediction of prognosis or development of new therapeutic strategies against colon cancer.


Assuntos
Neoplasias Colorretais/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Adenocarcinoma/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Colorretais/metabolismo , Células HCT116 , Células HEK293 , Células HT29 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Camundongos , Camundongos Nus , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação , Fosforilação , Ligação Proteica , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais
20.
J Invest Dermatol ; 137(6): 1322-1332, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28131816

RESUMO

TRAF1 is a member of the TRAF protein family, which regulates the canonical and noncanonical NF-κB signaling cascades. Although aberrant TRAF1 expression in tumors has been reported, the role of TRAF1 remains elusive. Here, we report that TRAF1 is required for solar UV-induced skin carcinogenesis. Immunohistochemical analysis showed that TRAF1 expression is up-regulated in human actinic keratosis and squamous cell carcinoma. In vivo studies indicated that TRAF1 expression levels in mouse skin are induced by short-term solar UV irradiation, and a long-term skin carcinogenesis study showed that deletion of TRAF1 in mice results in a significant inhibition of skin tumor formation. Moreover, we show that TRAF1 is required for solar UV-induced extracellular signal-regulated kinase-5 (ERK5) phosphorylation and the expression of AP-1 family members (c-Fos/c-Jun). Mechanistic studies showed that TRAF1 expression enhances the ubiquitination of ERK5 on lysine 184, which is necessary for its kinase activity and AP-1 activation. Overall, our results suggest that TRAF1 mediates ERK5 activity by regulating the upstream effectors of ERK5 and also by modulating its ubiquitination status. Targeting TRAF1 function might lead to strategies for preventing and treating skin cancer.


Assuntos
Carcinogênese/efeitos da radiação , Regulação da Expressão Gênica , Queratinócitos/efeitos da radiação , Fator 1 Associado a Receptor de TNF/genética , Raios Ultravioleta/efeitos adversos , 9,10-Dimetil-1,2-benzantraceno/farmacologia , Análise de Variância , Animais , Carcinogênese/efeitos dos fármacos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Modelos Animais de Doenças , Células Epidérmicas , Epiderme/patologia , Cromatografia Gasosa-Espectrometria de Massas/métodos , Queratinócitos/citologia , Queratinócitos/patologia , Ceratose Actínica/etiologia , Ceratose Actínica/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Proteína Quinase 7 Ativada por Mitógeno/efeitos da radiação , Distribuição Aleatória , Transdução de Sinais , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/fisiopatologia , Regulação para Cima
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