RESUMO
Overconsumption of fructose is closely related to cancer. Ketohexokinase (KHK) catalyzes the conversion from fructose to fructose-1-phosphate (F1P), which is the first and committed step of fructose metabolism. Recently, aberrant KHK activation has been identified in multiple malignancies. However, the roles of KHK in gastric cancer (GC) cells are largely unclear. Herein, we reveal that the expression of ketohexokinase-A (KHK-A), one alternatively spliced KHK isoform that possesses low affinity for fructose, was markedly increased in GC cells. Depletion of endogenous KHK-A expression using lentiviruses encoding short hairpin RNAs (shRNAs) or pharmaceutical disruption of KHK-A activity using KHK-IN-1 hydrochloride in GC NCI-N87 and HGC-27 cells inhibited the proliferation in vitro and in vivo. Additionally, the mitochondrial respiration in the GC cells with KHK-A deficiency compared with the control cells was significantly impaired. One commercially-available antibody array was used to explore the effects of KHK-A knockdown on signaling pathways, showing that ß-catenin was remarkably reduced in the KHK-A deficient GC cells compared with the control ones. Pharmaceutical reduction in ß-catenin levels slowed down the proliferation of GC cells. These data uncover that KHK-A promotes the proliferation in GC cells, indicating that this enzyme might be a promising therapeutical target for GC treatment.
Assuntos
Proliferação de Células , Frutoquinases , Neoplasias Gástricas , beta Catenina , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Humanos , beta Catenina/metabolismo , beta Catenina/genética , Animais , Linhagem Celular Tumoral , Frutoquinases/metabolismo , Frutoquinases/genética , Camundongos , Camundongos Nus , Regulação Neoplásica da Expressão Gênica , Camundongos Endogâmicos BALB CRESUMO
BACKGROUND: The expression of Egl-9 family hypoxia-inducible factor 3 (EGLN3) is notably decreased in various malignancies, including gastric cancer (GC). While the predominant focus has been on the hydroxylase activity of EGLN3 for its antitumour effects, recent findings have suggested nonenzymatic roles for EGLN3. METHODS: This study assessed the clinical significance of EGLN3 expression in GC and explored the connection between EGLN3 DNA promoter methylation and transcriptional silencing. To investigate the effect of EGLN3 on GC cells, a gain-of-function strategy was adopted. RNA sequencing was conducted to identify the key effector molecules and signalling pathways associated with EGLN3. RESULTS: EGLN3 expression was significantly reduced in GC tissues, correlating with poorer patient prognosis. EGLN3 hypermethylation disrupts transcriptional equilibrium, contributing to deeper tumour invasion and lymph node metastasis, thus exacerbating GC progression. Conversely, restoration of EGLN3 expression in GC cells substantially inhibited cell proliferation and metastasis. EGLN3 was also found to impede the malignant progression of GC cells by downregulating Jumonji C domain-containing protein 8-mediated activation of the NF-κB pathway, independent of its hydroxylase activity. CONCLUSIONS: EGLN3 has the potential to hinder the spread of GC cells through a nonenzymatic mechanism, thereby shedding light on the complex nature of GC progression.
Assuntos
NF-kappa B , Neoplasias Gástricas , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Neoplasias Gástricas/patologia , Transdução de Sinais/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Oxigenases de Função Mista/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismoRESUMO
BACKGROUND: Accurate preoperative prediction of lymph node (LN) involvement is essential for the management of early gastric cancer (EGC). Our objective was to formulate a potent nomogram for predicting LN involvement in EGC by leveraging an innovative predictor of tumor budding. METHODS: We assembled a cohort of EGC patients who underwent radical surgery at two tertiary cancer centers. Tumor budding was stratified by using an optimal cutoff value and integrated with other clinicopathological variables to ascertain the risk factors associated with LN involvement. A nomogram was developed and its predictive performance was assessed by using receiver operating characteristic (ROC) curves and calibration plots. In addition, we conducted decision curve analysis to evaluate its clinical utility. Finally, an external validation was conducted by using an independent cohort. RESULTS: Finally, 307 eligible patients (215 in the primary cohort and 92 in the validation cohort) were included. Tumor budding, categorized by a count of two, exhibited a robust association with LN involvement (OR 14.12, p = 0.012). Other significant risk factors include lymphovascular invasion, depth of tumor invasion, ulceration, and tumor differentiation. Notably, the nomogram demonstrated exceptional discriminative power (area under the ROC curve, 0.872 in the primary cohort and 0.885 in the validation cohort) and precise predictive capabilities. Furthermore, the nomogram showed notable clinical applicability through decision curve analysis, particularly in endoscopic curability C-2, by mitigating the risk of overtreatment. CONCLUSIONS: Tumor budding is a robust predictor of LN involvement in EGC. The incorporation of tumor budding into a nomogram is an effective strategy, thereby informing and enhancing clinical decision-making.
Assuntos
Linfonodos , Metástase Linfática , Nomogramas , Neoplasias Gástricas , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , China , Seguimentos , Gastrectomia , Linfonodos/patologia , Linfonodos/cirurgia , Invasividade Neoplásica , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Curva ROC , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Reprodutibilidade dos TestesRESUMO
BACKGROUND AND AIMS: Lymph node metastasis significantly affects the prognosis of early gastric cancer patients. EUS plays a crucial role in the preoperative assessment of early gastric cancer. This study evaluated the efficacy of EUS in identifying lymph node metastasis in early gastric cancer patients and developed a risk score model to aid in choosing the best treatment options. METHODS: We retrospectively analyzed the effectiveness of EUS for detecting lymph node metastasis in early gastric cancer patients. A risk score model for predicting lymph node metastasis preoperatively was created using independent risk factors identified through binary logistic regression analysis and subsequently validated. Receiver operating characteristic curves were generated for both the development and validation cohorts. RESULTS: The overall accuracy of EUS in identifying lymph node metastasis was 85.3%, although its sensitivity (29.2%) and positive predictive value (38.7%) were relatively low. Patients were categorized based on preoperative risk factors for lymph node metastasis, including tumor size of ≥20 mm, lymph nodes of ≥10 mm, body mass index of ≥24 kg/m2, and lymph node metastasis on CT scans. A 7-point risk score model was developed to assess the likelihood of lymph node metastasis. The areas under the receiver operating characteristic curve for the development and validation sets were 0.842 and 0.837, respectively, with sensitivities of 64% and 79%, respectively. CONCLUSIONS: We developed a practical risk score model based on preoperative factors to help EUS predict lymph node metastasis in early gastric cancer patients, guiding the selection of optimal treatment approaches for these patients.
RESUMO
Aberrantly activated mTOR signaling pathway is commonly found in malignancies including gastric cancer (GC). DEPTOR, as a naturally occurred inhibitor of mTOR, functions in the pro- or anti-tumor manner depending on distinct tumor contexts. However, the roles of DEPTOR in GC remain largely unknown. In this study, DEPTOR expression was identified to be significantly decreased in GC tissues compared with matched normal gastric tissues, and reduced DEPTOR level was indicative of poor prognosis in patients. Restored DEPTOR expression inhibited the propagation in AGS and NCI-N87 cells, whose DEPTOR levels are low, via deactivating mTOR signaling pathway. Likewise, cabergoline (CAB) attenuated the proliferation in AGS and NCI-N87 cells via partially rescuing DEPTOR protein level. Targeted metabolomics analysis showed that several key metabolites, such as l-serine, significantly changed in AGS cells with DEPTOR restoration. These results revealed the anti-proliferation function of DEPTOR in GC cells, suggesting that restored DEPTOR expression using CAB may be a potential therapeutic approach for patients with GC.
Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Prognóstico , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular TumoralRESUMO
The aberrant expression of microRNAs (miRNAs) is involved in the initiation and progression of human cancers. In our study, we found that miR-539 was down-regulated in breast cancer tissues and cell lines. Decreased expression of miR-539 was significantly associated with lymph node metastasis in patients with breast cancer. Overexpression of miR-539 inhibited the proliferation and promoted apoptosis of breast cancer cells. Moreover, highly expressed miR-539 significantly suppressed the epithelial-mesenchymal transition (EMT) and sensitized cells to cisplatin treatment. Mechanistically, miR-539 was found to target the specificity protein 1 (SP1) and down-regulated the expression of SP1 in breast cancer cells. Knockdown of miR-539 consistently increased the expression of SP1. The expression of miR-539 in breast cancer tissues was negatively correlated with the expression of SP1. Restoration of SP1 significantly attenuated the inhibitory effect of miR-539 on the proliferation of breast cancer cells. Taken together, our results indicate that miR-539 has a tumor suppressive role in breast cancer via targeting SP1, suggesting miR-539 as a promising target for the diagnosis of breast cancer.
Assuntos
Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Fator de Transcrição Sp1/metabolismo , Apoptose , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Cisplatino/farmacologia , Transição Epitelial-Mesenquimal , Feminino , Humanos , Metástase Linfática , Células MCF-7 , Invasividade Neoplásica , Metástase Neoplásica , FenótipoRESUMO
Isoliquiritigenin (ISL), a natural flavonoid derived from the root of liquorice, has been reported to possess anti-inflammatory and antioxidant activities. Previous studies have found that ISL plays a crucial role in anti-fibrosis of adipose tissue and renal tissue; however, its effect on pulmonary fibrogenesis has not been demonstrated. In this study, we aimed to explore the roles and the underlying mechanisms of ISL in TGF-ß1-induced fibrogenesis using human lung fibroblast-derived MRC-5 cells. Cell proliferation and migration were determined by MTT and wound healing assay, respectively. The expression levels of alpha-smooth muscle actin (α-SMA), collagen type I alpha 1 (COLIA1) and fibronectin (FN), microtubule-associated protein light chain 3 (LC3) and related signaling molecules were detected by quantitative real-time PCR, western blot and immunofluorescence assay, correspondingly. EGFP-LC3 transfection was used for autophagy analysis. The results showed that ISL inhibited the TGF-ß1-induced proliferation and migration, and down-regulated the expressions of α-SMA, COLIA1 and FN. ISL treatment led to up-regulation of LC3 in TGF-ß1-treated MRC-5 cells, accompanied by significant decrease in the phosphorylation levels of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In addition, the inhibitory effects of ISL on TGF-ß1-induced fibrogenic features in MRC-5 cells were enhanced by pretreatment with autophagy activator Rapmycin and PI3K/AKT inhibitor LY294002 and reversed by autophagy inhibitor 3-methyladenine and PI3K/AKT activator IGF-1. Taken together, our results demonstrated that ISL could attenuate the fibrogenesis of TGF-ß1-treated MRC-5 cells by activating autophagy via suppressing the PI3K/AKT/mTOR pathway. Therefore, ISL holds a great potential to be developed as a novel therapeutic agent for the treatment of pulmonary fibrosis.
Assuntos
Autofagia/efeitos dos fármacos , Chalconas/farmacologia , Fibroblastos/metabolismo , Pulmão/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Linhagem Celular , Cadeia alfa 1 do Colágeno Tipo I , Fibroblastos/patologia , Humanos , Pulmão/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
The SOX17 (SRY-related HMG-box) transcription factor is involved in a variety of biological processes and is related to the tumorigenesis and progression of multiple tumors. However, the clinical application of SOX17 for breast cancer prognosis is currently limited. The aim of this study was to investigate the clinicopathologic and prognostic significance of SOX17 expression in human breast cancer. qPCR and western blot assays were performed to measure the expression of SOX17 in breast cancer cell lines and 30 matched pairs of breast cancer and corresponding noncancerous tissues. A SOX17 overexpression cell model was used to examine changes in cell growth in vitro. Immunohistochemical analyses were performed to retrospectively examine the prognostic impact of SOX17 expression in 187 additional breast cancer patients. Our results showed that SOX17 expression was decreased at both the messenger RNA (mRNA) and protein levels in the breast cancer cell lines and tissues, and that SOX17 overexpression could strongly suppress cell growth in vitro. Furthermore, the lack of SOX17 protein expression was strongly correlated with higher tumor grade (P = 0.002), lymph node metastasis (P < 0.001), and tumor node metastasis (TNM) stage (P = 0.001) and had poorer disease-free survival (DFS) and overall survival (OS) compared to normal SOX17 expression (P = 0.002 and 0.001, respectively). Univariate and multivariate analyses indicated that lower SOX17 expression was an independent prognostic factor for DFS (P = 0.007; HR = 2.854; 95 % CI 1.326-6.147) and OS (P = 0.005; HR = 5.035; 95 % CI 1.648-15.385) for breast cancer. Our findings indicate that SOX17 expression is a useful prognostic biomarker for breast cancer.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Mama/metabolismo , Fatores de Transcrição SOXF/metabolismo , Adulto , Idoso , Apoptose , Biomarcadores Tumorais/genética , Western Blotting , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Estudos de Casos e Controles , Proliferação de Células , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição SOXF/genética , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
BACKGROUND: Cases of primary gastric adenocarcinoma with metastasis to the breast are extremely rare. Till now, only 38 cases have been reported in PubMed since 1908. CASE PRESENTATION: We herein reported a race case of gastric adenocarcinoma with metastasis to the right breast. Breast biopsy showed invasive signet-ring cell breast carcinoma in the right breast. She was given a TEC regimen (docetaxel 75 mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 600 mg/m(2) every 3 weeks) for one cycle but showed no objective response. Upper gastrointestinal endoscopy demonstrated an ulcerative mass in the gastric body. Biopsy demonstrated low-grade gastric adenocarcinoma with signet-ring features. In immunohistochemistry, mammary malignant cells were positive for cytokeratin 7, cytokeratin 20, villin, and ErbB2/HER2, but negative for gross cystic disease fluid protein-15, estrogen receptor, and progesterone receptor. The diagnosis of metastatic poorly differentiated signet-ring cell adenocarcinoma of the right breast identical to gastric primary was confirmed finally. CONCLUSIONS: Gastric cancer with metastasis to the breast can be diagnosed by clinical history, histological findings, and immunohistochemical markers.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/secundário , Carcinoma de Células em Anel de Sinete/patologia , Neoplasias Gástricas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Carcinoma de Células em Anel de Sinete/tratamento farmacológico , Carcinoma de Células em Anel de Sinete/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismoRESUMO
Purpose: The functions of C-type lectin domain family 4 member D (CLEC4D), one member of the C-type lectin/C-type lectin-like domain superfamily, in immunity have been well described, but its roles in cancer biology remain largely unknown. Patients and Methods: This study aims to explore the role of CLEC4D in gastric cancer (GC). Bioinformatics preliminarily analyzed the expression of CLEC4D in gastric cancer. Immunohistochemical staining was used to detect the expression level and clinical pathological characteristics of CLEC4D in gastric cancer. The biological function of CLEC4D in gastric cancer cell lines was verified through in vitro and in vivo experiments. Results: In this study, CLEC4D expression was found to be markedly increased in gastric cancer (GC) tissues compared with matched normal gastric tissues, and high CLEC4D expression independently predicted unfavorable overall survival in patients with GC. Knockdown of CLEC4D markedly inhibited GC cell proliferation and migration. Mechanistically, CLEC4D knockdown deactivated the Akt and NF-κB signaling pathways in GC cells. Conclusion: Together, these results demonstrate that aberrantly increased CLEC4D expression promotes cancer phenotypes via the Akt and NF-κB signaling pathways in GC cells.
RESUMO
The contributions of aberrantly expressed metabolic enzymes to gastric cancer (GC) initiation and progression have been widely appreciated in recent years. Acetyl-CoA acetyltransferase 2 (ACAT2) is one member of the acetyl- CoA thiolase family. Previous studies demonstrated that ACAT2 either promotes or suppresses tumor progression in different conditions. However, the function and mechanisms of ACAT2 in GC remain unknown. We found that the expression of this enzyme was significantly increased in GC tissues compared with normal counterparts, which prompted us to further investigate the roles of this protein in GC biology. In vitro functional studies showed that ACAT2 knockdown markedly halted the proliferation and the motility of GC cells; these functions favoring malignant phenotypes of GC cells were further validated in animal experiments. Mechanistically, ACAT2 depletion significantly reduced the transcription of SETD7, which is a histone methyltransferase and plays critical roles in GC cells. We found that the pro-tumoral functions of ACAT2 were largely dependent on SETD7. Moreover, SETD7 decreased the ubiquitination level of Yes-associated protein 1 (YAP1), thereby protecting YAP1 from proteasome degradation. Increased YAP1 protein expression remarkably activated the YAP1/TAZ-TEAD1 signaling pathway, which further boosted the malignant phenotypes in GC cells. In conclusion, these findings highlight the pro-tumoral functions and molecular underpinnings of ACAT2 in GC cells, and suggest that ACAT2 could be a promising target in GC treatment.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proliferação de Células , Camundongos Nus , Neoplasias Gástricas , Fatores de Transcrição , Ubiquitinação , Regulação para Cima , Proteínas de Sinalização YAP , Humanos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Proteínas de Sinalização YAP/metabolismo , Animais , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Linhagem Celular Tumoral , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Camundongos , Regulação Neoplásica da Expressão Gênica , Movimento Celular , Masculino , Metástase Neoplásica , Feminino , Camundongos Endogâmicos BALB CRESUMO
Automatic breast ultrasound image segmentation plays an important role in medical image processing. However, current methods for breast ultrasound segmentation suffer from high computational complexity and large model parameters, particularly when dealing with complex images. In this paper, we take the Unext network as a basis and utilize its encoder-decoder features. And taking inspiration from the mechanisms of cellular apoptosis and division, we design apoptosis and division algorithms to improve model performance. We propose a novel segmentation model which integrates the division and apoptosis algorithms and introduces spatial and channel convolution blocks into the model. Our proposed model not only improves the segmentation performance of breast ultrasound tumors, but also reduces the model parameters and computational resource consumption time. The model was evaluated on the breast ultrasound image dataset and our collected dataset. The experiments show that the SC-Unext model achieved Dice scores of 75.29% and accuracy of 97.09% on the BUSI dataset, and on the collected dataset, it reached Dice scores of 90.62% and accuracy of 98.37%. Meanwhile, we conducted a comparison of the model's inference speed on CPUs to verify its efficiency in resource-constrained environments. The results indicated that the SC-Unext model achieved an inference speed of 92.72 ms per instance on devices equipped only with CPUs. The model's number of parameters and computational resource consumption are 1.46M and 2.13 GFlops, respectively, which are lower compared to other network models. Due to its lightweight nature, the model holds significant value for various practical applications in the medical field.
Assuntos
Algoritmos , Neoplasias da Mama , Ultrassonografia Mamária , Humanos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Feminino , Ultrassonografia Mamária/métodos , Interpretação de Imagem Assistida por Computador/métodos , Processamento de Imagem Assistida por Computador/métodos , Mama/diagnóstico por imagem , Mama/patologia , ApoptoseRESUMO
Protein lysine methyltransferase SET and MYND domain-containing 3 (SMYD3) is aberrantly expressed in various cancer settings. The mechanisms that SMYD3 activates the expression of critical pro-tumoral genes in an H3K4me3-dependent manner have been well described in previous reports. Besides H3K4me3, H4K20me3 is another catalytic product of SMYD3, however it is a transcriptionally repressive hallmark. Since it is not clear that how SMYD3-elicited transcriptionally repressive program functions in cancer, we used gastric cancer (GC) as a model to investigate the roles of SMYD3-H4K20me3. Herein, online bioinformatics tools, quantitative PCR, western blotting and immunohistochemistry assays demonstrated that SMYD3 expression was markedly increased in GC tissues from our institutional and The Cancer Genome Atlas (TCGA) cohort. Additionally, aberrantly increased SMYD3 expression was closely associated with aggressive clinical characteristics and poor prognosis. Depletion of endogenous SMYD3 expression using shRNAs significantly attenuates the proliferation in GC cells and Akt signaling pathway in vitro and in vivo. Mechanistically, chromatin immunoprecipitation (ChIP) assay showed that SMYD3 epigenetically repressed the expression of epithelial membrane protein 1 (EMP1) in an H4K20me3-dependent manner. Gain-of-function and rescue experiments validated that EMP1 inhibited the propagation of GC cells and reduced p-Akt (S473) level. Based on these data, pharmaceutical inhibition of SMYD3 activity using the small inhibitor BCI-121 deactivated Akt signaling pathway in GC cells and further impaired the cellular viability in vitro and in vivo. Together, these results demonstrate that SMYD3 promotes the proliferation in GC cells and may be a valid target for therapeutic intervention of patients with GC.
Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Proteínas Proto-Oncogênicas c-akt , Proliferação de Células/genética , Histona-Lisina N-Metiltransferase/genéticaRESUMO
BACKGROUND: Neoadjuvant chemotherapy has become the standard treatment for locally advanced gastric cancer. The tumor regression grade system is an effective and widely used tool for the evaluation of treatment response to neoadjuvant chemotherapy. However, whether tumor regression grade could be predicted using clinical characteristics is uncertain. METHODS: A total of 287 locally advanced gastric cancer patients from 2014 to 2021 were retrospectively included. According to the College of American Pathologists' tumor regression grade system, patients were classified into response group (tumor regression grade 0-1) and non-response group (tumor regression grade 2-3). Associations between clinical characteristics and neoadjuvant chemotherapy response were performed by the logistic regression model. The Kaplan-Meier method was used to estimate the survival. A prediction scoring system was constructed based on the ß coefficients of multivariate analysis. The receiver operating characteristic curve and decision curve analysis were used to evaluate the performance of the predictive scoring system. RESULTS: Survival analysis showed that patients with tumor regression grades 0 to 1 had significantly better disease-free survival and overall survival than the tumor regression grades 2 to 3. Tumor differentiation, ycT stage, immunotherapy, and lymph node regression were independent predictors of pathological response to neoadjuvant chemotherapy. We further developed a scoring system to predict the tumor regression grade. The receiver operating characteristic and decision curve analysis showed good predictive performance of the scoring system. CONCLUSION: Lymph node regression could be used as a predictor for pathological response. We developed a scoring system to predict the treatment response of patients with gastric cancer receiving neoadjuvant chemotherapy. The scoring system based on the predictors could provide guidance for making clinical decisions.
Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/tratamento farmacológico , Terapia Neoadjuvante/métodos , Estudos Retrospectivos , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Intervalo Livre de DoençaRESUMO
BACKGROUND: Zinc finger and scan domain containing 18 (ZSCAN18) belongs to the zinc finger transcription factor superfamily, which consists of hundreds of members that play critical roles in all steps of tumorigenesis. METHODS: This study aims to investigate the roles of ZSCAN18 in gastric cancer (GC). The expression level in GC and the clinicopathologic features of ZSCAN18 were detected by immunohistochemistry staining. Methylation of ZSCAN18 promoter in GC tissues and cell lines was analyzed via MassARRAY; the same method was used to detect GC cell lines demethylated by 5-aza-2'-deoxycytidine treatment. The biological function of ZSCAN18 in GC cells was verified by in vitro and in vivo experiments. The downstream molecular mechanism of ZSCAN18 was explored using RNA next-generation sequencing, immunofluorescence and chromatin immunoprecipitation. RESULTS: Our work revealed ZSCAN18 expression was markedly reduced in GC tissues compared with adjacent normal tissues as a result of hypermethylation in GC. Likewise, ZSCAN18 expression was significantly reduced in a panel of GC cell lines as a result of the densely methylated ZSCAN18 promoter. Functionally, ZSCAN18 overexpression inhibited the biological progression of GC cells, which was characterized by weaken proliferation, enhanced autophagy and suppressed tumor growth. ZSCAN18 acted as a transcription factor and played an important role in binding to the promoter of tumor protein 53-induced nuclear protein 2 (TP53INP2), and we also confirmed the anti-tumor effect of TP53INP2 in GC. Furthermore, the knockdown of TP53INP2 alleviated the inhibiting effects of ZSCAN18 in GC cells by in vitro and in vivo experiments. CONCLUSIONS: Collectively, this study unveiled that ZSCAN18 played an anticancer role in GC by promoting autophagy and transcriptional regulation of TP53INP2 and provided a promising target for the diagnosis and treatment of GC.
Assuntos
Autofagia , Proteínas de Ligação a DNA , Proteínas Nucleares , Neoplasias Gástricas , Humanos , Autofagia/genética , Linhagem Celular Tumoral , Proliferação de Células , Decitabina/farmacologia , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/genética , Neoplasias Gástricas/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Ligação a DNA/genética , Regiões Promotoras GenéticasRESUMO
BACKGROUND: Downregulation of certain tumor-suppressor genes (TSGs) by aberrant methylation of CpG islands in the promoter region contributes a great deal to the oncogenesis and progression of several cancers, including gastric cancer (GC). Protocadherin 10 (PCDH10) is a newly identified TSG in various cancers and is downregulated in GC; however, the specific mechanisms of PCDH10 in GC remain elusive. Here, we elucidated a novel epigenetic regulatory signaling pathway involving the E3 ubiquitin ligase RNF180 and DNA methyltransferase 1 (DNMT1), responsible for modulating PCDH10 expression by affecting its promoter methylation. RESULTS: We revealed that PCDH10 was downregulated in GC cells and tissues, and low PCDH10 expression was correlated with lymph node metastasis and poor prognosis in patients with GC. Additionally, PCDH10 overexpression suppressed GC cell proliferation and metastasis. Mechanistically, DNMT1-mediated promoter hypermethylation resulted in decreased expression of PCDH10 in GC tissues and cells. Further analysis revealed that RNF180 can bind directly to DNMT1 and was involved in DNMT1 degradation via ubiquitination. Additionally, a positive correlation was found between RNF180 and PCDH10 expression and an inverse association between DNMT1 and PCDH10 expression showed considerable prognostic significance. CONCLUSION: Our data showed that RNF180 overexpression upregulated PCDH10 expression via ubiquitin-dependent degradation of DNMT1, thus suppressing GC cell proliferation, indicating that the RNF180/DNMT1/PCDH10 axis could be a potential therapeutic target for GC treatment.
Assuntos
DNA (Citosina-5-)-Metiltransferase 1 , Protocaderinas , Neoplasias Gástricas , Ubiquitina-Proteína Ligases , Humanos , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Protocaderinas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , DNA (Citosina-5-)-Metiltransferase 1/metabolismoRESUMO
BACKGROUND: Regional lymph node metastasis (LNM) is a competent and the most intensive predictor for the prognostic evaluation of patients after curative surgery. This study is based on the databases of two large medical centers in North and South China. It aims to establish a prognostic model based on extragastric LNM (ELNM) and lymph node ratio (LNR) in node-positive gastric cancer (GC). METHODS: Clinical data of 874 GC patients with pathologically confirmed LNM in a large medical center in southern China, were included as the training cohort. In addition, the clinical data of 674 patients with pathologically confirmed LNM from a large medical center in northern China were used as the validation cohort. RESULTS: In the training cohort, a modified N staging system (mNstage) based on ELNM and LNR was established; it has a significantly higher prognostic accuracy than the pN, LNR and ELNM staging system (Akaike Information Criterion, pN stage vs. LNR stage vs. ELNM stage vs. mN stage=5498.479 vs. 5537.815 vs. 5569.844 vs. 5492.123; Bayesian Information Criterion, pN stage vs. LNR stage vs. ELNM stage vs. mN stage=5512.799 vs. 5547.361 vs. 5574.617 vs. 5506.896; likelihood-ratio χ2 , pN stage vs. LNR stage vs. ELNM stage vs. mN stage=177.7 vs. 149.8 vs. 115.79 vs. 183.5). In the external validation, mNstage also has higher prognostic accuracy than the pN, LNR and ELNM staging system. Cox multivariate regression analysis showed that age, mNstage, pT stage, and perineural invasion were independent factors. A nomogram model was established according to the four factors (age, mNstage, pT stage, and perineural invasion). The nomogram model was greater than the traditional tumor-node-metastasis (TNM) staging in the training cohort [1-year area under the curve (AUC), American Joint Commission for Cancer (AJCC) 8th TNM vs. nomogram=0.692 vs. 0.746, 3-year AUC: AJCC 8th TNM vs. nomogram=0.684 vs. 0.758, 5-year AUC: AJCC 8th TNM vs. nomogram=0.725 vs. 0.762]. In the external validation, the nomogram also showed better prognostic value and greater prediction accuracy than the traditional TNM staging. CONCLUSION: The prognostic model based on ELNM and LNR has good prognostic prediction in patients with node-positive GC.
Assuntos
Linfonodos , Neoplasias Gástricas , Humanos , Prognóstico , Linfonodos/cirurgia , Linfonodos/patologia , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Estudos Retrospectivos , Metástase Linfática/patologia , Teorema de Bayes , Razão entre Linfonodos , Estadiamento de NeoplasiasRESUMO
Whereas cysteine dioxygenase 1 (CDO1) expression is lost due to its hypermethylated promoter across a range of cancer types including gastric cancer (GC), its functions and molecular underpinnings remain largely unknown. Here we demonstrate that reduced CDO1 expression is indicative of unfavorable prognosis in patients with GC. CDO1 overexpression in GC cells markedly inhibits cellular proliferation in vitro and in vivo. Mechanistically, CDO1 exerts this cytostatic effect via increasing oxidative stress and thus activating integrated stress response (ISR) in GC cells. High throughput screening (HTS) of antioxidants library identifies that Engeletin, a flavanonol glycoside, blunts oxidative stress and the ISR to relieve the inhibitory effect of CDO1 on the proliferation in GC cells. Additionally, genetic disruption or pharmaceutical inhibition of the ISR boosts the growth in the GC cells with CDO1 expression. Our data uncover the molecular mechanisms underlying the cytostatic function of CDO1 in the proliferation of GC cells.
RESUMO
BACKGROUND: Treatment options for early gastric cancer have evolved toward achieving accurate evaluation of lymph node metastasis. This study aimed to investigate risk factors of lymph node metastasis in patients with early gastric cancer and establish a risk score model to guide the selection of optimal treatment. METHODS: The clinicopathological characteristics of 351 patients with early gastric cancer from January 2016 to December 2018 were reviewed retrospectively. On the basis of the independent risk factors determined by multivariate binary logistic regression analysis, we established a risk score model for predicting lymph node metastasis and then verified it. The receiver operating characteristic curves were plotted using the test and validation sets. The area under the receiver operating characteristic curve was used to assess the discriminant ability of the model. RESULTS: Lymph node metastasis was observed in 10.5% (37/351) of early gastric cancer cases. Patients with early gastric cancer were grouped based on the independent risk factors for lymph node metastasis (tumor size, depth, histological type, and lymphovascular involvement) determined by multivariate analysis. A 7-point risk score model was established to predict the risk of lymph node metastasis. The area under the receiver operating characteristic curve in the development and validation sets were 0.839 (95% confidence interval, 0.769%-0.910%) and 0.820 (95% confidence interval, 0.711%-0.930%), respectively. CONCLUSION: A feasible risk score model for lymph node metastasis was established to guide the optimal treatment of patients with early gastric cancer early gastric cancer.
Assuntos
Neoplasias Gástricas , Gastrectomia , Humanos , Linfonodos/patologia , Metástase Linfática/patologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Neoplasias Gástricas/cirurgiaRESUMO
Cancer metastasis is a major cause of death among women afflicted with breast cancer (BC) and understanding the molecular processes involved is a major focus in BC research. Circular RNAs (circRNAs) have emerged as genomic regulatory molecules in carcinogenesis and metastasis; however, their role in BC is unclear. We characterized a novel circRNA, hsa_circ_0000515, in context of BC. We collected 340 cancerous tissues surgically resected from BC patients and found hsa_circ_0000515 was upregulated in BC tissues and associated with poor prognosis of BC. Silencing of hsa_circ_0000515 impaired cell cycle progression, cell proliferation, and invasion, attenuated inflammatory response, and reduced the proangiogenetic potential of BC cells. RNA pull-down and dual-luciferase reporter gene assays showed that hsa_circ_0000515 binds miR-296-5p, preventing it from repressing CXCL10 expression. We also observed that miR-296-5p inhibition or CXCL10 overexpression promoted cell cycle progression, restored proliferative, invasive and proangiogenetic abilities, and increased inflammatory response in MCF-7 cells in the absence of hsa_circ_0000515. In vivo analyses showed that partial loss of hsa_circ_0000515 reduced the tumor growth of MCF-7 cells in nude mice. The key findings from this study revealed that targeting hsa_circ_0000515 might be an effective strategy to combat BC.