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BACKGROUND: Although, immune checkpoint inhibitors (ICIs) have been widely applied in the therapy of malignant tumors, the efficacy and safety of ICIs in patients with tumors and pre-existing CAD, especially chronic coronary syndromes (CCS) or their risk factors (CRF), is not well identified. METHODS: This was a nationwide multicenter observational study that enrolled participants who diagnosed with solid tumors and received ICIs therapy. The main efficacy indicators were progression-free survival (PFS) and overall survival (OS), followed by objective response rate (ORR) and disease control rate (DCR). Safety was assessed by describing treatment-related adverse events (TRAEs) during ICIs therapy evaluated by the Common Terminology Criteria for Adverse Events 5.0 (CTCAE 5.0). RESULTS: In the current research, we retrospectively analyzed the data of 551 patients diagnosed with solid tumors and received ICIs therapy, and these patients were divided into CCS/CRF group and non-CCS/CRF group. Patients with CCS/CRF had more favorable PFS and OS than patients without CCS/CRF (P < 0.001) and the pre-existing CCS/CRF was a protective factor for survival. The ORR (51.8% vs. 39.1%) and DCR (95.8% vs. 89.2%) were higher in CCS/CRF group than in non-CCS/CRF group (P = 0.003, P = 0.006). In this study, there was no significant difference in treatment-related adverse events (TRAEs), including immune-related adverse events (irAEs), between the two groups. CONCLUSIONS: We concluded that ICIs appear to have better efficacy in malignant solid tumor patients with pre-existing CCS/CRF and are not accompanied by more serious irAEs.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Femenino , Masculino , Neoplasias/tratamiento farmacológico , Neoplasias/complicaciones , Neoplasias/inmunología , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Factores de Riesgo , Adulto , Anciano de 80 o más Años , Estudios de CohortesRESUMEN
BACKGROUND AND AIM: The objective of this study was to investigate the association between inflammatory burden index (IBI) and all-cause mortality in the general population aged over 45 years. METHODS AND RESULTS: The study included 8827 participants from the National Health and Examination Nutrition Survey (NHANES) who were aged over 45 years. The IBI was calculated using three markers: C-reaction protein × neutrophil/lymphocyte, and all the participants were classified into four groups (Quartile 1: IBI ≤0.178, N = 2206; Quartile 2: 0.178
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Proteína C-Reactiva , Enfermedades Cardiovasculares , Humanos , Anciano , Encuestas Nutricionales , Modelos de Riesgos Proporcionales , LinfocitosRESUMEN
Novel biomarkers are essential to improve the treatment efficacy and overall survival of stage II and III colorectal cancer (CRC), allowing for personalized treatment decisions. Here, the densities of CD8+ and FOXP3+ T cells in the tumor and invasive margin were processed by immunohistochemistry and digital pathology to form a scoring system named regulatory-Immunoscore (RIS). Cox proportional hazards regression models were used to determine the risk factors associated with time to recurrence. Harrell's concordance index and the time-dependent area under the curve were used to assess model performance. A total of 1213 stage I-III DNA mismatch repair-proficient colorectal cancer (pMMR CRC) patients were randomly assigned to a training set (n = 642) and a validation set (n = 571). From the Cox multivariable analysis, the association of RIS with survival was independent of patient age, sex and anatomy-based tumor risk parameters (P < .0001). For stage II patients, chemotherapy was significantly associated with better recurrence time in patients with low (95% confidence interval [CI]: 0.11-0.54, P = .001) and intermediate (95% CI = 0.25-0.57, P < .001) RIS values. In stage III patients treated with adjuvant chemotherapy, a treatment duration of 6 or more months was significantly associated with better recurrence time in patients with intermediate RIS values (95% CI = 0.38-0.90, P = .016) when compared with duration under 6 months. Therefore, these findings suggest that RIS is reliable for predicting recurrence risk and treatment responsiveness for patients with stage I-III pMMR CRC.
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Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Neoplasias del Colon/patología , Estadificación de Neoplasias , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Resultado del Tratamiento , Quimioterapia Adyuvante , PronósticoRESUMEN
BACKGROUND: Multitarget tyrosine kinase inhibitors (mTKIs) such as Regorafenib and Sorafenib have already been approved for the treatment of many solid tumours. However, the efficacy of mTKIs in colorectal cancer (CRC) is limited; the underlined mechanism remains largely elusive. Our study was aimed to find out the resistance mechanism of mTKIs in CRC. METHODS: RNA sequencing was used to identify the expression of Activin A receptor-like type 1 (ACVRL1) under the treatment of mTKIs. Gain/loss-of-function experiments were performed to assess the biological function of ACVRL1 in resistance to mTKIs. The underlying mechanisms of ACVRL1-mediated mTKI resistance were investigated by using liquid chromatography-mass spectrometry assays (LC-MS), co-immunoprecipitation assays (Co-IP), chromatin immunoprecipitation assays, ubiquitination assays, dual luciferase reporter assays, etc. RESULTS: RNA sequencing identified the activation of ACVRL1 under the treatment of mTKIs in CRC cells. ACVRL1 knockdown and overexpression significantly affects the sensitivity of CRC cells to mTKIs both in vitro and vivo. Mechanistically, we found the ß-catenin/TCF-1-KCNQ1OT1/miR-7-5p axis mediated the activation of ACVRL1. Furthermore, LC-MS assays indicated the interaction between ACVRL1 and glutathione peroxidase 2(GPX2) protein. IP assay defined ACVRL1 truncation (282-503aa) could be responsible for interacting with GPX2, and rescue experiments with ACVRL1 truncations confirmed the importance of this interaction in driving mTKI resistance. Co-IP assays confirmed that ACVRL1 associates with ubiquitin-specific peptidase 15(USP15) which directly deubiquinates GPX2 at the K187(K, lysine) site, leading to the accumulation of GPX2 protein. Rescue experiments performed with the lysine mutants in GPX2 CRISPR knockout cell model confirmed the importance of GPX2 K187 mutant. As a result, the increased ROS clearance and decreased cell apoptosis eventually lead to mTKI resistance in CRC. CONCLUSIONS: Our results demonstrate that the Wnt/ß-catenin/KCNQ1OT1/miR-7-5p/ACVRL1/GPX2 biological axis plays a vital role in CRC, targeting which may be an effective approach for overcoming mTKI resistance.
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Neoplasias Colorrectales , MicroARNs , Humanos , beta Catenina/genética , beta Catenina/metabolismo , beta Catenina/farmacología , Lisina/genética , Lisina/metabolismo , Lisina/farmacología , MicroARNs/metabolismo , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Glutatión Peroxidasa/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/metabolismo , Receptores de Activinas Tipo II/farmacología , Proteasas Ubiquitina-Específicas/genética , Proteasas Ubiquitina-Específicas/metabolismo , Proteasas Ubiquitina-Específicas/farmacologíaRESUMEN
To investigate whether the Warburg effect is a key modulator on the resistance mechanism of photodynamic therapy (PDT). Glycolysis was examined by the test of lactate product and glucose uptake at different post-PDT time points. Cell viability was detected by the CCK-8 assay and cell proliferation was detected by colony formation assay. The expression of glycolysis and related proteins were examined by western blotting. Target gene was silenced by RNAi. In the present study, we assessed the effect of PDT on cancer cell glycolysis. Our team has demonstrated that pyruvate kinase M2 (PKM2), a key speed-limiting enzyme of glycolysis, was significantly overexpressed in patients with esophageal cancer. Our results in the present study showed that PKM2 was downregulated, and lactate product and glucose uptake were inhibited in cells exposed to 5-aminolevulinic acid (5-ALA)-mediated PDT at 4 h after treatment. However, at 24 h after PDT, we observed a substantial increase in PKM2 expression, lactate product, and glucose uptake. Moreover, silencing of PKM2 gene abrogated the upregulatory effect of PDT on glycolysis at late post-PDT period. 2-Deoxy-D-glucose (2-DG) is a recognized chemical inhibitor of glycolysis. The combined treatment of 2-DG and PDT significantly inhibited tumor growth in vitro at 24 h. These results demonstrate that PDT drives the Warburg effect in a time-dependent manner, and PKM2 plays an important role in this progress, which indicated that PKM2 may be a potential molecular target to increase the sensitivity of esophageal cancer cells to PDT.
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Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/metabolismo , Glucólisis , Fotoquimioterapia , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Muerte Celular , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Desoxiglucosa/metabolismo , Regulación hacia Abajo , Neoplasias Esofágicas/patología , Técnicas de Silenciamiento del Gen , Glucosa/metabolismo , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Hormonas Tiroideas/genética , Hormonas Tiroideas/metabolismo , Proteínas de Unión a Hormona TiroideRESUMEN
Immunotherapy using an immune-checkpoint blockade has significantly improved its therapeutic effects. CM-272, which is a novel epigenetic inhibitor of G9a, induces immunogenic cell death (ICD) for recovering the sensitivity to anti-PD-1 antibodies; however, the efficacy of CM-272 is greatly limited by promoting the transcription activity of HIF-1α to form a hypoxic environment. Here, a Fe3+ -based nanoscale metal-organic framework (MIL-53) is used to load CM-272 (ultra-high loading rate of 56.4%) for realizing an MIL-53@CM-272 nanoplatform. After entering bladder cancer cells, Fe3+ not only promotes the decomposition of H2 O2 into O2 for O2 -compensated sonodynamic therapy but reduces the high level of glutathione in the tumor microenvironment (TME) for enhancing reactive oxygen species, including ferroptosis and apoptosis. MIL-53 carriers can be degraded in response to the TME, accelerating the release of CM-272, which helps achieve the maximum effectiveness in an O2 -sufficient TME by attenuating drug resistance. Furthermore, MIL-53@CM-272 enhances dendritic cell maturation and synergistically combines it with an anti-programmed cell death protein 1 antibody during the study of immune-related pathways in the transcriptomes of bladder cancer cells using RNA-seq. This study presents the first instance of amalgamating nanomedicine with CM-272, inducing apoptosis, ferroptosis, and ICD to achieve the "one arrow three eagle" effect.
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Águilas , Neoplasias de la Vejiga Urinaria , Animales , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Vejiga Urinaria , Inmunoterapia , Apoptosis , Microambiente TumoralRESUMEN
Although immunogenic cell death (ICD) inducers evidently enhance the effectiveness of immunotherapy, their potential is increasingly restricted by the development of apoptosis resistance in tumor cells, poor immunogenicity, and low T-cell immune responsiveness. In this study, for the first time, piezoelectrically catalyzed Mg2+-doped hydroxyapatite (Mg-HAP) nanoparticles, which are coated with a mesoporous silica layer and loaded with ONC201 as an agonist to specifically target the death receptor DR5 on tumor cells, ultimately developing an Mg-HAP@MS/ONC201 nanoparticle (MHMO NP) system, are engineered. Owing to its excellent piezoelectric properties, MHMO facilitates the release of a significant amount of reactive oxygen species and Ca2+ within tumor cells, effectively promoting the upregulation of DR5 expression and inducing tumor cell necroptosis to ultimately overcome apoptosis resistance. Concurrently, Mg2+ released in the tumor microenvironment promotes CD8+ T receptor activation in response to the antitumor immune reaction induced by ICD. Using RNA-seq analysis, it is elucidated that MHMO can activate the NF-κB pathway under piezoelectric catalysis, thus inducing M1-type macrophage polarization. In summary, a dual-targeting therapy system that targets both tumor cells and the tumor microenvironment under piezoelectric catalysis is designed. This system holds substantial potential for advancements in tumor immunotherapy.
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Antineoplásicos , Durapatita , Línea Celular Tumoral , Necroptosis , Apoptosis , Antineoplásicos/farmacología , Receptores de Muerte CelularRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0303858.].
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OBJECTIVE: The study aims to explore the driving forces behind physical activity engagement among patients with chronic obstructive pulmonary disease, focusing on motivation, opportunity, and capability. DESIGN: A phenomenological qualitative study applied the motivation, opportunity, and capability model, conducted in two respiratory units of a Chinese university hospital. METHODS: Participants, selected by age, gender, and illness duration, included inpatients during the interview sessions and those recently discharged within six months. One-on-one semi-structured interviews were recorded, transcribed, and analyzed by the Colaizzi seven-step method. RESULTS: Seventeen participants diagnosed with chronic obstructive pulmonary disease for over one year aged between 66 (range: 42-96) participated. Three major themes were identified: Inspiring participation motivation-transitioning from recognizing significance to habit formation; Offering participation opportunities-reiterating demand for personalized strategies and ideal environmental settings; Enhancing participation capability-addressing strategies for overcoming fears, setting goals, ensuring safety, and adjusting activity levels. CONCLUSIONS: This research underscores the vital role of inspiring participation motivation, offering opportunities, and enhancing the capability for participation in effective engagement. Advocating increased attention from healthcare departments, fostering interdisciplinary collaboration, improving activity guidance and counseling effectiveness, and considering individual preferences can significantly benefit those patients with chronic obstructive pulmonary disease who hesitate or are unable to participate in physical activities, thereby increasing the dose of non-leisure time physical activity.
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Ejercicio Físico , Motivación , Enfermedad Pulmonar Obstructiva Crónica , Investigación Cualitativa , Humanos , Enfermedad Pulmonar Obstructiva Crónica/psicología , Enfermedad Pulmonar Obstructiva Crónica/terapia , Persona de Mediana Edad , Masculino , Femenino , Anciano , Adulto , Anciano de 80 o más Años , Ejercicio Físico/psicologíaRESUMEN
BACKGROUND: Although numerous studies have indicated that activated pyroptosis can enhance the efficacy of antitumour therapy in several tumours, the precise mechanism of pyroptosis in colorectal cancer (CRC) remains unclear. METHODS: Pyroptosis in CRC cells treated with antitumour agents was assessed using various techniques, including Western blotting, lactate dehydrogenase release assay and microscopy analysis. To uncover the epigenetic mechanisms that regulate NLRP3, chromatin changes and NLRP3 promoter histone modifications were assessed using Assay for Transposase-Accessible Chromatin using sequencing and RNA sequencing. Chromatin immunoprecipitationâquantitative polymerase chain reaction was used to investigate the NLRP3 transcriptional regulatory mechanism. Additionally, xenograft and patient-derived xenograft models were constructed to validate the effects of the drug combinations. RESULTS: As the core molecule of the inflammasome, NLRP3 expression was silenced in CRC, thereby limiting gasdermin D (GSDMD)-mediated pyroptosis. Supplementation with NLRP3 can rescue pyroptosis induced by antitumour therapy. Overexpression of HDAC2 in CRC silences NLRP3 via epigenetic regulation. Mechanistically, HDAC2 suppressed chromatin accessibility by eliminating H3K27 acetylation. HDAC2 knockout promotes H3K27ac-mediated recruitment of the BRD4-p-P65 complex to enhance NLRP3 transcription. Inhibiting HDAC2 by Santacruzamate A in combination with classic antitumour agents (5-fluorouracil or regorafenib) in CRC xenograft-bearing animals markedly activated pyroptosis and achieved a significant therapeutic effect. Clinically, HDAC2 is inversely correlated with H3K27ac/p-P65/NLRP3 and is a prognostic factor for CRC patients. CONCLUSION: Collectively, our data revealed a crucial role for HDAC2 in inhibiting NLRP3/GSDMD-mediated pyroptosis in CRC cells and highlighted HDAC2 as a potential therapeutic target for antitumour therapy. HIGHLIGHTS: Silencing of NLRP3 limits the GSDMD-dependent pyroptosis in colorectal cancer. HDAC2-mediated histone deacetylation leads to epigenetic silencing of NLRP3. HDAC2 suppresses the NLRP3 transcription by inhibiting the formation of H3K27ac/BRD4/p-P65 complex. Targeting HDAC2 activates pyroptosis and enhances therapeutic effect.
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Neoplasias Colorrectales , Gasderminas , Histona Desacetilasa 2 , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Animales , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Gasderminas/metabolismo , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteínas de Unión a Fosfato , Piroptosis/efectos de los fármacos , Piroptosis/genéticaRESUMEN
Tumor cell migration, specifically epithelial-mesenchymal transition (EMT), serves as a key contributor to treatment failure in colon cancer patients. However, the limited comprehension of its genetic and biological aspects presents challenges for its investigation. EDAR-associated death domain (EDARADD), an important TNFR superfamily member, is elevated in colon cancer. However, it remains unclear about the exact role of EDARADD in the progression of colon cancer metastasis. In this study, we initially demonstrated that both protein and mRNA levels of EDDARADD are elevated in colon cancer tissues and cells, associated with reduced overall survival. Furthermore, functional experiments demonstrated that EDARADD promotes colon cancer cell proliferation and participates in EMT both in vitro and vivo. Mechanistically, Co-IP verified EDARADD could stabilize Snail1 by interacting with E3 ubiquitin ligase Trim21 to inhibit ubiquitination of Snail1. Interestingly, RNA-seq and ubiquitination assay revealed EDARADD's dual downregulation of Trim21 expression at the translational level via Cul1-mediated ubiquitin degradation, and at the transcriptional level through PPARa regulation. Moreover, EDARADD activates NF-κB signaling and experiences feedback transcriptional regulation by p65. In conclusion, this study highlights the signal pathway of EDARADD-PPARa-Trim21-Snail1-EMT and a feedback regulation of NF-κB signaling on EDARADD, which indicated EDARADD as an emerging therapeutic target for colon cancer.
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Neoplasias del Colon , Ubiquitina-Proteína Ligasas , Humanos , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Línea Celular Tumoral , Ubiquitinación , Neoplasias del Colon/genética , Transición Epitelial-Mesenquimal/genética , Proteína de Dominio de Muerte Asociada a Edar/genética , Proteína de Dominio de Muerte Asociada a Edar/metabolismoRESUMEN
The DNA damage response (DDR) plays crucial roles in cancer prevention and therapy. Poly(ADP-ribose) polymerase 1 (PARP1) mediates multiple signal transduction in the DDR as a master regulator. Uncovering the regulatory factors of PARP1 contributes to a more comprehensive view of tumorigenesis and treatment strategies. Here, we reveal that MARVELD1 acts as a mediator of DDR to perform early events and maintain genome stability. Mechanistically, PARP1 PARylates MARVELD1 at D102, D118 and D130, and in turn, MARVELD1 stabilizes PARP1 by enhancing NAA50-mediated acetylation, thus forming a positive feedback loop. MARVELD1 knockout mice and their embryo fibroblasts exhibit genomic instability and shorter half-life of PARP1. Moreover, MARVELD1 partnering with PARP1 facilitates resistance to genotoxic drugs and disrupts PARP inhibitor (PARPi) effect in PDX model of colorectal cancer (CRC). Overall, our results underline the link between MARVELD1 and PARP1 in therapeutic resistance based on DDR and provide new insights for clinical tumor therapy of PARPi.
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Daño del ADN , Inestabilidad Genómica , Animales , Ratones , Carcinogénesis , Reparación del ADN , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Procesamiento Proteico-PostraduccionalRESUMEN
Homeobox B9 (HOXB9) is involved in the occurrence and development of malignant tumors. However, the functions and underlying molecular mechanisms of HOXB9 in pancreatic cancer have yet to be identified. In this study, we find that both HOXB9 mRNA and protein levels are down-regulated in pancreatic cancer tissues and cell lines. Kaplan-Meier survival plots of 150 pancreatic cancer cases show that higher expression of HOXB9 in pancreatic cancer patients is associated with higher survival rates. We also find that over-expression of HOXB9 inhibits pancreatic cancer cell proliferation both in cell lines and the nude mouse xenograft as well as PDX models. Applying cell cycle PCR array analysis, Flow CytoMetry, ChIP-qPCR, and luciferase experiments, we observe that HOXB9 blocks cell cycle progression in the G0/G1 phase via up-regulating RBL2 and inhibiting c-Myc, and we further find that DNMT1 inhibits the expression of HOXB9 in pancreatic cancer by promoting the methylation of its promoter. Our findings highlight a novel mechanism of the DNMT1/HOXB9/RBL2/c-Myc pathway in regulating the cell cycle and proliferation of pancreatic cancer cells and provide a research basis for the prognosis and therapeutic application of HOXB9 in pancreatic cancer.
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Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas , Animales , Ciclo Celular/genética , División Celular , Línea Celular Tumoral , Proliferación Celular , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Ratones , Neoplasias Pancreáticas/genética , Proteína p130 Similar a la del Retinoblastoma/genética , Neoplasias PancreáticasRESUMEN
Esophageal cancer, especially esophageal squamous cell carcinoma (ESCC) threatens so many lives in China every year. Traditional treatment of ESCC has usually been disappointing. The development of novel therapy is worth investigation. We have previously demonstrated that dihydroartemisinin (DHA) has anticancer effect on esophageal cancer. However, the mechanism has not been completely known. In this present study, we explored the effect of DHA on cancer cell glycolysis, also known as Warburg effect. Pyruvate kinase M2 (PKM2) is a key regulatory factor of glycolysis, and our results showed that it is significantly overexpressed in patients with ESCC and ESCC cell lines. In DHA treatment cells, PKM2 was down-regulated and lactate product and glucose uptake were inhibited. Overexpression of PKM2 by lentiviral transfection abrogated the inhibition effect of DHA. These results suggested that DHA might repress esophageal cancer glycolysis partly by down-regulating PKM2 expression. We believe that DHA might be a prospective agent against esophageal cancer.