RESUMEN
Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.
Asunto(s)
Antineoplásicos , Sistemas CRISPR-Cas , Resistencia a Antineoplásicos , Irinotecán , Oxaliplatino , Proteínas Serina-Treonina Quinasas , Resistencia a Antineoplásicos/genética , Humanos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Oxaliplatino/farmacología , Irinotecán/farmacología , Sistemas CRISPR-Cas/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Animales , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Ratones , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
BACKGROUND: Bladder cancer (BC) is one of the most common malignancies of the genitourinary system. Phosphofructokinase 1 (PFK-1) is one of member of PFK, which plays an important role in reprogramming cancer metabolism, such as lactylation modification. Zinc finger E-box-binding homeobox 1 (ZEB1) has been demonstrated to be a oncogene in many cancers. Therefore, this study was performed to explore the effects of PFK-1 on the lactylation of ZEB1 in BC development. METHODS: Cell viability was measured using the CCK-8 kit. The glucose assay kit and lactate assay kit were used to detect glucose utilization and lactate production. The DNA was purified and quantified by qRT-PCR. RESULTS: In the present study, we found that ZEB1 expression levels were significantly elevated in bladder cancer cells. Impaired PFK-1 expression inhibits proliferation, migration, and invasion of BC cells and suppresses tumour growth in vivo. We subsequently found that knockdown of PFK-1 decreases glycolysis, including reduced glucose consumption, lactate production and total extracellular acidification rate (ECAR). Mechanistically, PFK-1 inhibits histone lactylation of bladder cancer cells, and thus inhibits the transcription activity of ZEB1. CONCLUSION: Our results suggest that PFK-1 can inhibit the malignant phenotype of bladder cancer cells by mediating the lactylation of ZEB1. These findings suggested PFK-1 to be a new potential target for bladder cancer therapy.
Asunto(s)
Neoplasias de la Vejiga Urinaria , Humanos , Línea Celular Tumoral , Movimiento Celular , Neoplasias de la Vejiga Urinaria/patología , Fosfofructoquinasa-1/genética , Fosfofructoquinasa-1/metabolismo , Lactatos , Glucosa , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismoRESUMEN
INTRODUCTION: Cancer and neurodegeneration are two major leading causes of morbidity and death worldwide. Neurodegeneration results in excessive neuronal cell death, and cancer emerges from increased proliferation and resistance to cell death. Although most epidemiological studies support an inverse association between the risk for the development of neurodegenerative diseases and cancer, increasing evidence points to a positive correlation between specific types of cancer, like prostate adenocarcinoma (PRAD), and neurodegenerative diseases, like Parkinson's disease (PD). METHODS: PD and PRAD differential genes were screened through the GEO database, and the differential genes were analyzed using David, String, GEPIA, Kaplan-Meier plotter, TIMER2.0, proteinatlas, cBioPortal, and CTD databases to elucidate the biological function and molecular mechanism of PD and PRAD-related genes. RESULTS: Studies have shown that the hub gene and differentially expressed genes (DEGs) in PD were differentially expressed in PRAD, including CDC20, HSPA4L, ROBO1, DMKN, IFI27L2, LUZP2, PTN, PTGDS. In PRAD, the high expression of HSPA4L, ROBO1, DMKN, IFI27L2, PTN, and PTGDS genes was associated with longer survival, while the patients with low expression of CDC20 and LUZP2 genes had longer survival. The mRNA of CDC20 and LUZP2 were highly expressed, while the mRNAs of HSPA4L, ROBO1, DMKN, IFI27L2, and PTGDS were low expressed. Gene methylation did not affect the survival of patients. The high expression of miR-142, miR-186, miR-30a, miR-497, miR-590, miR-28, and miR-576 in microRNA (miRNA) might potentially be used as biomarkers for the progression of PD and PRAD and for the early diagnosis of PD and PRAD in the populations. The genes in this study were highly associated with B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Somatic mutation mainly focused on missense mutation. Therapeutic drugs included acetaminophen and valproic acid (VPA). CONCLUSION: Bioinformatics was used to identify potential targets and novel molecular mechanisms that may serve as clinical markers for the diagnosis and treatment of PD and PRAD.
Asunto(s)
Adenocarcinoma , MicroARNs , Enfermedad de Parkinson , Masculino , Humanos , Proteínas del Tejido Nervioso , Enfermedad de Parkinson/genética , Próstata/patología , Pronóstico , Receptores Inmunológicos , MicroARNs/genética , Biomarcadores , Adenocarcinoma/genética , Adenocarcinoma/patología , Factores de Riesgo , Proteínas de Unión al ADNRESUMEN
Background: Transurethral split of the prostate (TUSP) is effective in treating benign prostatic hyperplasia (BPH). However, there is still a lack of research focusing on the optimal target population for TUSP. This study aimed to compare the efficacy of TUSP in patients with different prostate volumes or ages. Methods: The study was a multicenter retrospective study. The outcomes of TUSP in BPH patients with different prostate volumes or different ages were compared. A total of 439 patients were included in the study. Patients were divided into two groups according to prostate volume, with a cut-off value of 50 mL. Similarly, the cut-off value for the age groups was 70 years. Baseline patient characteristics and perioperative outcomes were recorded. Follow-up was performed at 1, 6, and 12 months after surgery. Results: The mean age of the patients was 73.4 years, and the mean prostate volume was 51.2 mL. At 12-month follow-up after TUSP treatment, the patients' International Prostate Symptom Scores (IPSS), quality of life (QoL) scores, and postvoid residual (PVR) volumes decreased significantly, while peak urinary flow rate (Qmax) increased significantly. Intraoperative hemoglobin (Hb) reduction was significantly lower in the small volume group than in the large volume group. The incidence of postoperative urinary urgency and transient incontinence was lower in the small volume group. IPSS score, PVR, and Qmax in the small volume group showed more remarkable changes at several time points compared to the preoperative period. Postoperative pain scores were higher in the small volume group than in the large volume group. There were no differences between the two groups in terms of long-term complications. The younger group showed greater variation in PVR and Qmax at some time points but less variation in QoL than the older group. Conclusions: TUSP is overall safe and effective in treating BPH. This study showed differences in the outcomes of TUSP in treating different prostate volumes or ages of BPH patients. The optimal surgical approach for BPH patients might be selected clinically based on a combination of prostate volume or patient age.