RESUMO
Small cell lung cancer (SCLC), recognized as the most aggressive subtype of lung cancer, presents an extremely poor prognosis. Currently, patients with small cell lung cancer face a significant dearth of effective alternative treatment options once they experience recurrence and progression after first-line therapy. Despite the promising efficacy of immunotherapy, particularly immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) and various other tumours, its impact on significantly enhancing the prognosis of SCLC patients remains elusive. DLL3 has emerged as a compelling target for targeted therapy in SCLC due to its high expression on the membranes of SCLC and other neuroendocrine carcinoma cells, with minimal to no expression in normal cells. Our previous work led to the development of a novel multiple chain chimeric antigen receptor (CAR) leveraging the TREM1 receptor and DAP12, which efficiently activated T cells and conferred potent cell cytotoxicity. In this study, we have developed a DLL3-TREM1/DAP12 CAR-T (DLL3-DT CAR-T) therapy, demonstrating comparable anti-tumour efficacy against SCLC cells in vitro. In murine xenograft and patient-derived xenograft models, DLL3-DT CAR-T cells exhibited a more robust tumour eradication efficiency than second-generation DLL3-BBZ CAR-T cells. Furthermore, we observed elevated memory phenotypes, induced durable responses, and activation under antigen-presenting cells in DLL3-DT CAR-T cells. Collectively, these findings suggest that DLL3-DT CAR-T cells may offer a novel and potentially effective therapeutic strategy for treating DLL3-expressing SCLC and other solid tumours.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Imunoterapia Adotiva , Neoplasias Pulmonares , Proteínas de Membrana , Receptores de Antígenos Quiméricos , Carcinoma de Pequenas Células do Pulmão , Receptor Gatilho 1 Expresso em Células Mieloides , Ensaios Antitumorais Modelo de Xenoenxerto , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/terapia , Humanos , Animais , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Imunoterapia Adotiva/métodos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Linhagem Celular Tumoral , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Camundongos SCID , FemininoRESUMO
Currently, conventional immunotherapies for the treatment of non-small cell lung cancer (NSCLC) have low response rates and benefit only a minority of patients, particularly those with advanced disease, so novel therapeutic strategies are urgent deeded. Therapeutic cancer vaccines, a form of active immunotherapy, harness potential to activate the adaptive immune system against tumor cells via antigen cross-presentation. Cancer vaccines can establish enduring immune memory and guard against recurrences. Vaccine-induced tumor cell death prompts antigen epitope spreading, activating functional T cells and thereby sustaining a cancer-immunity cycle. The success of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rendered cancer vaccines a promising avenue, especially when combined with immunotherapy or chemoradiotherapy for NSCLC. This review delves into the intricate antitumor immune mechanisms underlying therapeutic cancer vaccines, enumerates the tumor antigen spectrum of NSCLC, discusses different cancer vaccines progress and summarizes relevant clinical trials. Additionally, we analyze the combination strategies, current limitations, and future prospects of cancer vaccines in NSCLC treatment, aiming to offer fresh insights for their clinical application in managing NSCLC. Overall, cancer vaccines offer promising potential for NSCLC treatment, particularly combining with chemoradiotherapy or immunotherapy could further improve survival in advanced patients. Exploring inhaled vaccines or prophylactic vaccines represents a crucial research avenue.
RESUMO
BACKGROUND: Neoadjuvant chemo-immunotherapy combination has shown remarkable advances in the management of esophageal squamous cell carcinoma (ESCC). However, the identification of a reliable biomarker for predicting the response to this chemo-immunotherapy regimen remains elusive. While computed tomography (CT) is widely utilized for response evaluation, its inherent limitations in terms of accuracy are well recognized. Therefore, in this study, we present a novel technique to predict the response of ESCC patients before receiving chemo-immunotherapy by testing volatile organic compounds (VOCs) in exhaled breath. METHODS: This study employed a prospective-specimen-collection, retrospective-blinded-evaluation design. Patients' baseline breath samples were collected and analyzed using high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS). Subsequently, patients were categorized as responders or non-responders based on the evaluation of therapeutic response using pathology (for patients who underwent surgery) or CT images (for patients who did not receive surgery). RESULTS: A total of 133 patients were included in this study, with 91 responders who achieved either a complete response (CR) or a partial response (PR), and 42 non-responders who had stable disease (SD) or progressive disease (PD). Among 83 participants who underwent both evaluations with CT and pathology, the paired t-test revealed significant differences between the two methods (p < 0.05). For the breath test prediction model using breath test data from all participants, the validation set demonstrated mean area under the curve (AUC) of 0.86 ± 0.06. For 83 patients with pathological reports, the breath test achieved mean AUC of 0.845 ± 0.123. CONCLUSIONS: Since CT has inherent weakness in hollow organ assessment and no other ideal biomarker has been found, our study provided a noninvasive, feasible, and inexpensive tool that could precisely predict ESCC patients' response to neoadjuvant chemo-immunotherapy combination using breath test based on HPPI-TOFMS.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/terapia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/tratamento farmacológico , Estudos Retrospectivos , Estudos Prospectivos , Terapia Neoadjuvante , Testes Respiratórios/métodos , BiomarcadoresRESUMO
Lung adenocarcinomas manifesting as subsolid nodules (SSN-LUADs) possess distinct dormant behaviour. This study was designed to compare the immune landscapes of normal lungs (nLungs), SSN-LUADs and LUADs manifesting as solid nodules (SN-LUADs) so as to better understand the status of anti-tumour immunity in SSN-LUADs. Mass cytometry by time-of-flight analysis was performed on 299, 570 single cells from nLung, SSN-LUAD and SN-LUAD tissues. The immune cells were identified by phenotype, and the percentages of different immune cell subclusters were compared between SSN-LUADs, SN-LUADs and nLungs. Elevated percentage of CD8+ T cells were identified in SSN-LUADs compared with in nLungs and SN-LUADs. Elevated CD56bright NK cells and decreased CD56dim NK cells were identified in both SSN-LUADs and SN-LUADs compared with in nLungs. The immune landscape of SSN-LUAD fits the theory of equilibrium phase of immunoediting, thus functional adaptive anti-tumour immunity but impaired innate anti-tumour immunity potentially contributes to the maintaining of its dormant behaviour.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Linfócitos T CD8-Positivos/patologia , Tomografia Computadorizada por Raios X , Adenocarcinoma de Pulmão/patologiaRESUMO
The impact of host condition on prognosis of non-small cell lung cancer (NSCLC) and the interaction between host and NSCLC remain unclear. This study investigated the association between systemic inflammation and prognosis and characteristics of radically resected NSCLC. This study consisted of a cohort study and an exploratory study of institutional prospective databases. All participants underwent video-assisted thoracoscopic lobectomy as the primary treatment. Systemic inflammation was assessed before surgery using the advanced lung cancer inflammation index and the systemic inflammation response index. Next-generation sequencing and multiplex immunofluorescence analysis were conducted to delineate tumor characteristics. In the cohort study including 1507 participants, high inflammation was associated with poor disease-free survival and overall survival before and after propensity score matching and in multivariable analysis. Systemic inflammation showed good prognostic value for stage IA-IB NSCLC, and the prognostic value diminished with upstaging of NSCLC. In the exploratory study including 217 adenocarcinomas, tumor microenvironment of high inflammation group showed a greater abundance of PDL1+ tumor cells and immune cells, which were independent from driver gene mutations and clinicopathological characteristics. Spatial analysis demonstrated a higher frequency of immune-suppressed cellular neighborhood, increased avoidance between immune cells and PDL1- tumor cells and compromised immune killing and presentation in tumor microenvironment of high inflammation group. Systemic inflammation showed limited association with genomic mutations. Systemic inflammation may influence the prognosis of NSCLC at both the systematic level and the local immune response. The correlation between high inflammation and immunosuppressive microenvironment indicates a novel thread for anticancer treatment.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Estudos de Coortes , Prognóstico , Inflamação , Estudos Retrospectivos , Microambiente TumoralRESUMO
BACKGROUND: Emerging evidence indicates that circular RNAs (circRNAs) play vital roles in tumor progression, including lung adenocarcinomas (LUAD). However, the mechanisms by which circRNAs promote the progression of LUAD still require further investigation. METHODS: Quantitative real-time PCR was performed to detect the expression of circP4HB in LUAD tissues and cells. Then, Kaplan-Meier analysis was used to determine the prognostic value of circP4HB expression. We employed RNA pull-down, RNA immunoprecipitation, mass spectrometry, cells fraction, glucose consumption, lactate production, pyruvate kinase M2 (PKM2) activity, and macrophage polarization assays to uncover the underlying mechanisms of circP4HB in LUAD. RESULTS: We found that circP4HB is upregulated in LUAD tissues and correlated with advanced TNM stages and lymph node metastasis. LUAD patients with high circP4HB expression had poor prognoses. Functionally, circP4HB promoted LUAD progression in vivo and in vitro. Upregulated circP4HB increased glucose consumption, lactate production and accelerated aerobic glycolysis in LUAD cells. Mechanically, circP4HB mainly accumulated in the cytoplasm of LUAD cells and bound with PKM2 and subsequently upregulating PKM2 enzymatic activity by increasing its tetramer formation. Additionally, circP4HB promoted M2 macrophage phenotype shift via targeting PKM2. Finally, rescue assays further confirmed that circP4HB could promote LUAD cell progression through its interaction with PKM2. CONCLUSION: These results demonstrate that circP4HB could promote LUAD progression, indicating circP4HB might be a potential therapeutic target of LUAD.
Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , MicroRNAs , RNA Circular , Humanos , Adenocarcinoma/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Glucose , Glicólise/genética , Lactatos , Neoplasias Pulmonares/metabolismo , MicroRNAs/genética , Pró-Colágeno-Prolina Dioxigenase/genética , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Isomerases de Dissulfetos de Proteínas/genética , Isomerases de Dissulfetos de Proteínas/metabolismo , RNA Circular/genética , Proteínas de Ligação a Hormônio da TireoideRESUMO
Compared to normal cells, cancer cells exhibit specific metabolic characteristics that facilitate the growth and metastasis of cancer. It is now widely appreciated that long non-coding RNAs (lncRNAs) exert extensive regulatory effects on a spectrum of biological processes through diverse mechanisms. In this review, we focus on the rapidly advancing field of lncRNAs and summarize the relationship between the dysregulation of lncRNAs and cancer metabolism, with a particular emphasis on the specific roles of lncRNAs in glycolysis, mitochondrial function, glutamine, and lipid metabolism. These investigations reveal that lncRNAs are a key factor in the complexity of malignant cancer metabolism. Only through understanding the relevance between lncRNAs and cancer metabolic reprogramming can we open a new chapter in the history of carcinogenesis, one that promises to alter the methods of cancer diagnosis and treatment.
Assuntos
Glutamina/metabolismo , Glicólise , Metabolismo dos Lipídeos , Mitocôndrias/metabolismo , Neoplasias/patologia , RNA Longo não Codificante/genética , Animais , Humanos , Mitocôndrias/genética , Neoplasias/genética , Neoplasias/metabolismo , RNA Longo não Codificante/metabolismoRESUMO
This work investigated the distribution and chemical fingerprints of 24 metals in particulate matter (PM) deposited in nonoccupational human lungs. Metals in the pulmonary PM can be grouped by the mean concentration as > 5 × 103 µg/g (Al/Fe/Ca/Mg/Zn), 1-5 × 103 µg/g (Ti/Ba/Pb/Mn), 0.2-1 × 103 µg/g (Cu/Cr/As/V) and < 100 µg/g (Ni/Sn/Cd/Sb). Three parameters (LFL, LR, EFP) were defined to predict different metal leaching behaviors. The leaching factor (LFL) of metals was 10-60 for Pb/Sb/Cd/Co/Cu and decreased to 1-2 for Ni/Cr/Mg/Al/Fe. Metals showed a divergent extent of lung retention (LR), including high retention (LR>10, Al/Cd/Cr/Ba/Ni/Ti/Sn/V/Sb), moderate retention (2 Assuntos
Metais Pesados
, Material Particulado
, Monitoramento Ambiental
, Humanos
, Pulmão/química
, Metais/análise
, Metais Pesados/análise
, Material Particulado/análise
RESUMO
Recently, long non-coding RNAs (lncRNAs) have been shown to have important regulatory roles in human cancer biology. In our study, we found that lncRNA CCAT1, whose expression is significantly increased and is correlated with outcomes in Esophageal Squamous Cell Carcinoma (ESCC). Consecutive experiments confirmed that H3K27-acetylation could activate expression of colon cancer associated transcript-1 (CCAT1). Further experiments revealed that CCAT1 knockdown significantly repressed the proliferation and migration both in vitro and in vivo. RNA-seq analysis revealed that CCAT1 knockdown preferentially affected genes that are linked to cell proliferation, cell migration and cell adhesion. Mechanistic investigations found that CCAT1 could serve as a scaffold for two distinct epigenetic modification complexes (5Î domain of CCAT1 binding Polycomb Repressive Complex 2 (PRC2) while 3Î domain of CCAT1 binding SUV39H1) and modulate the histone methylation of promoter of SPRY4 (sprouty RTK signaling antagonist 4) in nucleus. In cytoplasm, CCAT1 regulates HOXB13 as a molecular decoy for miR-7, a microRNA that targets both CCAT1 and HOXB13, thus facilitating cell growth and migration. Together, our data demonstrated the important roles of CCAT1 in ESCC oncogenesis and might serve as targets for ESCC diagnosis and therapy.
Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas do Tecido Nervoso/genética , RNA Longo não Codificante/metabolismo , Acetilação , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Inativação Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Metiltransferases/metabolismo , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Prognóstico , RNA Longo não Codificante/fisiologia , Proteínas Repressoras/metabolismoRESUMO
Esophageal cancer is one of the leading causes of cancer-related mortality, and most esophageal squamous cell carcinoma (ESCC) cases are located in Asian area. Recent studies about long noncoding RNAs (lncRNA) have offered a new perspective for cancer research and provided new approaches to understand the complex regulation network in cancer. Our group has reported that the novel lncRNA colon cancer-associated transcript 2 (CCAT2) has important biological function and could be a potential biomarkers in lung cancer. Here, we performed in silico analysis and characterized the expression profile of CCAT2 in a cohort of esophageal squamous cell carcinoma (ESCC) patients and cell lines. In silico analysis showed that no CpG island is found in the chromosome region of CCAT2, indicating that the expression of CCAT2 is possibly not regulated by DNA methylation. Compared with paired adjacent normal esophageal tissues, CCAT2 was significantly overexpressed in ESCC tissues with an average fold of 7.18. In ESCC cell lines, CCAT2 was mostly upregulated in KYSE410 cell (24.7-fold upregulation) when normalized to normal esophageal epithelium cell line (HEEC) and most CCAT2 transcripts were located in nucleus (> 95 %). Statistical analysis showed that CCAT2 expression level was significantly associated with smoking status (P = 0.036). Receiver operative curve and the area under curve were calculated to assess the diagnostic potential of CCAT2. Measured by area under curve (AUC), CCAT2 showed higher diagnostic performance than conventional serum biomarkers, like AFP, CA153, and NSE. In this study, we firstly characterized the expression profile of CCAT2 in ESCC and evaluated its potential diagnostic value as a biomarker.
Assuntos
Biomarcadores Tumorais/biossíntese , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Prognóstico , RNA Longo não Codificante/biossíntese , Fumar/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/patologia , Simulação por Computador , Ilhas de CpG/genética , Metilação de DNA/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/genética , Fumar/patologiaRESUMO
Due to the application of low-dose computed tomography screening, more and more early-stage lung cancers have been diagnosed. Thus, it is essential to characterize the gene expression profile of early-stage lung cancer to develop potential biomarkers for early diagnosis and therapeutic targets. Here, we analyzed microarray data of 181 early-stage lung cancer patients. By comparing gene expression between different tumor and lymph node metastasis stages, we identified various differentially expressed protein-coding genes and long noncoding RNA (lncRNA) in the comparisons of T2 vs. T2 and N1- vs. N0-stage lung cancer. Functional analyses revealed that these differentially expressed genes were enriched in various tumorigenesis or metastasis-related pathways. Survival analysis indicated that two protein-coding genes, C7 and SCN7A, were significantly associated survival of lung cancer. Notably, a novel lncRNA, LINC00313, was highly expressed in both T2- and N1-stage lung cancers. On the other hand, LINC00313 was also upregulated in lung cancer and metastasized lung cancer tissues, compared with adjacent lung tissues and primary lung cancer tissues. Additionally, higher expression level of LINC00313 indicated poor prognosis of lung cancer (hazard ratio = 0.658). Overall, we characterized the expression profiles of protein-coding genes and lncRNA in early-stage lung cancer and found that LINC00313 could be a biomarker for lung cancer.
Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/biossíntese , RNA Longo não Codificante/biossíntese , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , RNA Longo não Codificante/genéticaRESUMO
Esophageal squamous cell carcinoma (ESCC) is one of the prevalent and deadly cancers worldwide, especially in Eastern Asia. The prognosis of ESCC remains poor; thus, it is still necessary to further dissect the underlying mechanisms and explore therapeutic targets of ESCC. Recent studies show that long noncoding RNAs (lncRNAs) have critical roles in diverse biological processes, including tumorigenesis. Some lncRNAs, such as HOTAIR and POU3F3, were reported to play important roles in ESCC. Here, we characterized the expression profile of taurine-upregulated gene 1 (TUG1), a lncRNA recruiting and binding to polycomb repressive complex 2 (PRC2), in ESCC. In a cohort of 62 patients, TUG1 was significantly overexpressed in ESCC tissues compared with paired adjacent normal tissues, and high expression level of TUG1 was associated with family history and upper segment of esophageal cancer (p < 0.05). Further, in vitro silencing TUG1 via siRNA inhibited the proliferation and migration of ESCC cells and blocked the progression of cell cycle. Therefore, our study indicates that TUG1 promotes proliferation and migration of ESCC cells and is a potential oncogene of ESCC.
Assuntos
Carcinoma de Células Escamosas/genética , Movimento Celular/genética , Neoplasias Esofágicas/genética , RNA Longo não Codificante , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complexo Repressor Polycomb 2/genética , Prognóstico , RNA Interferente Pequeno/genética , Regulação para CimaRESUMO
The prognosis of non-small cell lung cancer (NSCLC) is still poor, and it is necessary to identify effectively diagnostic and prognostic biomarkers for NSCLC. Recent evidence demonstrates that long non-coding RNA (lncRNA) is actively transcribed from human genome. Some lncRNAs show a time- or tissue-specific expression manner and play important roles in diverse biological processes. Additionally, various cancer-associated lncRNAs have been identified, such as metastasis-associated lung adenocarcinoma transcript 1 for lung cancer. Here, we characterized the expression profile of a novel lncRNA, colon cancer-associated transcript 2 (CCAT2), in lung cancer and found that CCAT2 was significantly over-expressed in NSCLC tissues compared with paired adjacent normal tissues, with an average up-regulation fold of 7.5. Intriguingly, over-expression of CCAT2 was significantly associated with lung adenocarcinoma (p=0.033) but not squamous cell cancer. Silencing CCAT2 by siRNA led to inhibition of proliferation and invasion in NSCLC cell lines in vitro. Additionally, CCAT2 combined with CEA could predict lymph node metastasis. Our findings indicate that CCAT2 is a lung adenocarcinoma-specific lncRNA and promotes invasion of NSCLC and highlight its potential as a biomarker for lymph node metastasis.
Assuntos
Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/fisiologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Feminino , Humanos , Neoplasias Pulmonares/genética , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade NeoplásicaRESUMO
MicroRNA-145 (MiR-145) is an important regulator of tumorigenesis. Our previous work indicated that miR-145 reduced the proliferation and invasion as well as the tumorosphere growth capacity in lung adenocarcinoma cells. However, the underlying molecular mechanisms remain elusive. Here, we reported that the expression level of miR-145 was downregulated in lung adenocarcinoma tissues and negatively correlated with the expression level of Oct4. MiR-145 inhibited the proliferation of lung cancer-initiating cells (LCICs), partially by regulating Oct4 expression. Furthermore, we found that miR-145 exerted repressive effect on cancer stem cell properties and inhibited epithelial-mesenchymal transition (EMT) in vitro, also partially by regulating Oct4. Finally, we confirmed the repressive effect of miR-145 on cancer stem cell properties and EMT in vivo. Taken together, these evidences suggest that miR-145 serves as a tumor suppressor which downregulates LCICs' cancer stem cell properties and EMT process by targeting Oct4, leading to the inhibition of tumor growth and metastasis.
Assuntos
Adenocarcinoma/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Células-Tronco Neoplásicas/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Imuno-Histoquímica , Camundongos Nus , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Carga Tumoral/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Epidural analgesia is generally accepted as the most effective form of pain relief during labor. Remifentanil patient-controlled IV analgesia (PCIA), which is less invasive than epidural analgesia, may be an attractive alternative. In this meta-analysis, we compared the efficacy and safety of the 2 analgesic techniques for labor pain. METHODS: Databases of PubMed, EMBASE, and Cochrane Library were searched independently by 2 reviewers to retrieve eligible randomized controlled clinical trials. The primary end points were pain scores at 1 and 2 hours, and the secondary end points were nausea, vomiting, pruritus, and umbilical artery pH values. Mean difference (MD) or risk ratio with 95% confidence intervals (CIs) were calculated for each end point. GRADE profiler was applied to assess the quality of evidence. RESULTS: Five eligible trials were retrieved and analyzed. We found that parturients with remifentanil PCIA had higher visual analog scale (10-cm scale) pain scores than those who received epidural analgesia at 1 hour (MD = 1.9 cm; 95% CI, 0.5-3.3; I = 94%) and 2 hours (MD = 3.0 cm; 95% CI, 0.7-5.2; I = 89%) after initiation of analgesia. There was no statistical difference between epidural analgesia and remifentanil PCIA in the incidence of nausea, vomiting, pruritus, or umbilical artery pH values. However, the CIs are quite wide and contain clinically significant differences. According to GRADE profiler, most end points had moderate quality except that pain scores at 1 hour were of low quality. CONCLUSIONS: This meta-analysis suggests that remifentanil PCIA is not superior to epidural analgesia in analgesic efficacy during labor. Given the wide CIs of the pooled results for secondary maternal and neonatal outcomes, definite conclusions cannot be drawn for those outcomes. Further studies are still warranted to validate these conclusions.
Assuntos
Analgesia Epidural/métodos , Analgesia Controlada pelo Paciente/métodos , Anestésicos Intravenosos/administração & dosagem , Dor do Parto/tratamento farmacológico , Piperidinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Feminino , Humanos , Dor do Parto/diagnóstico , Gravidez , RemifentanilRESUMO
BACKGROUND: Cell-free DNA (cfDNA) has shown promise in detecting various cancers, but the diagnostic performance of cfDNA end motifs for multiple cancer types requires verification. This study aimed to assess the utility of cfDNA end motifs for multi-cancer detection. METHODS: This study included 206 participants: 106 individuals with cancer, representing 20 cancer types, and 100 healthy individuals. The participants were divided into training and testing cohorts. All plasma cfDNA samples were profiled by whole-genome sequencing. A random forest model was constructed using cfDNA 4 bp-end-motif profiles to predict cancer in the training cohort, and its performance was evaluated in the testing cohort. Additionally, a separate random forest model was developed to predict immunotherapy responses. RESULTS: In the training cohort, the model based on 4 bp-end-motif profiles achieved an AUC of 0.962 (95% CI 0.936-0.987). The AUC in the testing cohort was 0.983 (95% CI 0.960-1.000). The model also maintained excellent predictive ability in different tumor sub-cohorts, including lung cancer (AUC 0.918, 95% CI 0.862-0.974), gastrointestinal cancer (AUC 0.966, 95% CI 0.938-0.993), and other cancer cohort (AUC 0.859, 95% CI 0.776-0.942). Moreover, the model utilizing 4 bp-end-motif profiles exhibited sensitivity in identifying responders to immunotherapy (AUC 0.784, 95% CI 0.609-0.960). CONCLUSION: The model based on 4 bp-end-motif profiles demonstrates superior sensitivity in multi-cancer detection. Detection of 4 bp-end-motif profiles may serve as potential predictive biomarkers for cancer immunotherapy.
Assuntos
Ácidos Nucleicos Livres , Neoplasias Pulmonares , Humanos , Biomarcadores , Prognóstico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Ácidos Nucleicos Livres/genética , ImunoterapiaRESUMO
Most recurrences of lung cancer (LC) occur within 3 years after surgery, but the underlying mechanism remains unclear. Here, we collect LC tissues with shorter (<3 years, recurrence group) and longer (>3 years, non-recurrence group) recurrence-free survival. By using 16S sequencing, we find that intratumor microbiome diversity is lower in the recurrence group and butyrate-producing bacteria are enriched in the recurrence group. The intratumor microbiome signature and circulating microbiome DNA can accurately predict LC recurrence. We prove that intratumor injection of butyrate-producing bacteria Roseburia can promote subcutaneous tumor growth. Mechanistically, bacteria-derived butyrate promotes LC metastasis by increasing expression of H19 in tumor cells through inhibiting HDAC2 and increasing H3K27 acetylation at the H19 promoter and inducing M2 macrophage polarization. Depletion of macrophages partially abolishes the metastasis-promoting effect of butyrate. Our results provide evidence for the cross-talk between the intratumor microbiome and LC metastasis and suggest the potential prognostic and therapeutic value of the intratumor microbiome.
Assuntos
Neoplasias Pulmonares , Microbiota , Humanos , Neoplasias Pulmonares/patologia , Butiratos/metabolismo , Recidiva Local de Neoplasia/metabolismo , MacrófagosRESUMO
Lung cancer mortality is exacerbated by late-stage diagnosis. Emerging evidence indicates the potential clinical significance of distinct microbial signatures as diagnostic and prognostic biomarkers across various cancers. However, circulating microbiome DNA (cmDNA) profiles are underexplored in lung cancer (LC). Here, whole-genome sequencing is performed on plasma of LC patients and healthy controls (HCs). Differentially enriched microbial species are identified between LC and HC. A diagnostic model is developed, which has a high sensitivity of 87.7% and achieves an AUC of 93.2% in the independent validation dataset. Crucially, this model demonstrates the capability to detect early-stage LC, achieving a sensitivity of 86.5% for stage I and 87.1% for tumors <1 cm. In addition, we construct a cmDNA model for recurrence, which precisely predicts LC recurrence after surgery. Overall, this study highlights the significant alterations of cmDNA profiles in LC, indicating its potential as biomarkers for early diagnosis and recurrence.
Assuntos
Ácidos Nucleicos Livres , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Biomarcadores Tumorais/genética , Detecção Precoce de Câncer , Recidiva Local de NeoplasiaRESUMO
Metabolic reprogramming has been observed in cancer metastasis, whereas metabolic changes required for malignant cells during lymph node metastasis of esophageal squamous cell carcinoma (ESCC) are still poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) of paired ESCC tumor tissues and lymph nodes to uncover the reprogramming of tumor microenvironment (TME) and metabolic pathways. By integrating analyses of scRNA-seq data with metabolomics of ESCC tumor tissues and plasma samples, we found nicotinate and nicotinamide metabolism pathway was dysregulated in ESCC patients with lymph node metastasis (LN+), exhibiting as significantly increased 1-methylnicotinamide (MNA) in both tumors and plasma. Further data indicated high expression of N-methyltransferase (NNMT), which converts active methyl groups from the universal methyl donor, S-adenosylmethionine (SAM), to stable MNA, contributed to the increased MNA in LN+ ESCC. NNMT promotes epithelial-mesenchymal transition (EMT) and metastasis of ESCC in vitro and in vivo by inhibiting E-cadherin expression. Mechanically, high NNMT expression consumed too much active methyl group and decreased H3K4me3 modification at E-cadherin promoter and inhibited m6A modification of E-cadherin mRNA, therefore inhibiting E-cadherin expression at both transcriptional and post-transcriptional level. Finally, a detection method of lymph node metastasis was build based on the dysregulated metabolites, which showed good performance among ESCC patients. For lymph node metastasis of ESCC, this work supports NNMT is a master regulator of the cross-talk between cellular metabolism and epigenetic modifications, which may be a therapeutic target.
RESUMO
Recent studies have demonstrated the importance of non-protein coding part of human genome in carcinogenesis and metastasis. Among numerous kinds of non-protein coding RNAs, long noncoding RNAs (lncRNAs) play a key regulatory role in cancer biology. LncRNAs are dysregulated in different kinds of cancer and the expression levels of certain lncRNAs are associated with recurrence, metastasis, and prognosis of cancer. It is also proved that overexpression of certain lncRNAs, behaving like oncogenes, can promote matrix invasion of cancer cells and tumor growth. In this review, we focus our attention on lncRNAs those have been validated in human cancer tissues to suggest reasonable strategies for future research. We introduce an update view of lncRNA, extract cancer-related lncRNAs from literature, and describe the known functions and possible underlying molecular mechanisms of some well investigated lncRNAs (MALAT1, HOX antisense intergenic RNA, and highly upregulated in hepatocellular cancer), as well as their current and potential future application in cancer diagnosis (PCA3) and treatment (H19).