RESUMEN
The serine protease CORIN catalyzes pro-atrial natriuretic peptide (pro-ANP) into an active ANP and maintains homeostasis of the internal environment. However, it is unclear whether CORIN participates in the regulation of tumor progression. We analyzed the expression profile of CORIN in gastric cancer tissues (GCs) and adjacent nontumoral tissues (NTs). We investigated the prognostic value of CORIN in GC patients. We characterized the in vitro and in vivo activity of CORIN in cultured GC cells with gain-of-function and loss-of-function experiments. The underlying mechanism was explored by using bioinformatics, a signaling antibody array, and confirmative western blot analyses, as well as rescue experiments with highly selective small-molecule inhibitors targeting the ERK1/2 MAPK signaling pathway. CORIN was upregulated in GCs than in NTs. Overexpression of CORIN was correlated with unfavorable prognoses in patients with GC. Ectopic expression of CORIN was promoted, whereas silencing of CORIN suppressed proliferation, colony formation, migration and invasion of GC cells, and tumor growth in vivo. Overexpression of CORIN-induced epithelial-mesenchymal transition (EMT) and activation of the ERK1/2 MAPK signaling pathway, while silencing of CORIN yielded opposite results. The in vitro tumor-promoting potency of CORIN could be antagonized by selective inhibitors targeting the ERK1/2 MAPK pathway. In conclusion, CORIN is a potential prognostic marker and therapeutic target for GC patients, which may promote tumor progression by mediating the ERK1/2 MAPK signaling pathway and EMT in GC cells.
Asunto(s)
Proliferación Celular , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Sistema de Señalización de MAP Quinasas , Serina Endopeptidasas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Serina Endopeptidasas/metabolismo , Serina Endopeptidasas/genética , Animales , Ratones , Femenino , Masculino , Pronóstico , Línea Celular Tumoral , Movimiento Celular , Persona de Mediana Edad , Ratones Desnudos , Ratones Endogámicos BALB C , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genéticaRESUMEN
This work examined the physical and chemical properties and biocompatibility in vivo and in vitro of a unique triple composite scaffold incorporating silk fibroin, chitosan, and extracellular matrix. The materials were blended, cross-linked, and freeze-dried to create a composite scaffold of silk fibroin/chitosan/colon extracellular matrix (SF/CTS/CEM) with varying CEM contents. The SF/CTS/CEM (1:1:1) scaffold demonstrated the preferable shape, outstanding porosity, favorable connectivity, good moisture absorption, and acceptable and controlled swelling and degradation properties. Additionally, HCT-116 cells cultivated with SF/CTS/CEM (1:1:1) showed excellent proliferation capacity, cell malignancy, and delayed apoptosis, according to the in vitro cytocompatibility examination. We also examined the PI3K/PDK1/Akt/FoxO signaling pathway and discovered that cell culture using a SF/CTS/CEM (1:1:1) scaffold may prevent cell death by phosphorylating Akt and suppressing FoxO expression. Our findings demonstrate the potential of the SF/CTS/CEM (1:1:1) scaffold as an experimental model for colonic cancer cell culture and for replicating the three-dimensional in vivo cell growth environment.
RESUMEN
Resistance to oxaliplatin (OXA) is a major cause of recurrence in gastric cancer (GC) patients. Autophagy is an important factor ensuring the survival of cancer cells under chemotherapeutic stress. We aimed to investigate the role of OXA-related genes in autophagy and chemoresistance of gastric cancer cells. We established OXA-resistant gastric cancer cells and used RNA-seq to profile gene expression within OXA-resistant GC and corresponding parental cells. Immunohistochemistry and RT-qPCR was performed to detect gene expression in tissues of two cohorts of GC patients who received OXA-based chemotherapy. The chemoresistant effects of the gene were assessed by cell viability, apoptosis, and autophagy assays. The effects of the gene on autophagy were assessed with mRFP-GFP-LC3 and Western blotting (WB). Gene set enrichment analysis (GSEA) and WB were performed to detect the activity of PI3K/AKT/mTOR signaling under the regulation of the gene. The OXA-resistant property of GC cells is related to their enhanced autophagic activity. Based on RNA-seq profiling, ANXA1 was selected as a candidate, as it was upregulated significantly in OXA-resistant cells. Furthermore, we found that higher ANXA1 expression before chemotherapy was associated with subsequent development of resistance to oxaliplatin, and overexpression of ANXA1 promoted the resistance of gastric cancer cells to oxaliplatin. So, it may serve as a key regulator in GC chemo-resistance knockdown of ANXA1, via inhibiting autophagy, enhancing the sensitivity of OXA-resistant GC cells to OXA in vitro and in vivo. Mechanically, we identified that PI3K/AKT/mTOR signaling pathway was activated in the ANXA1 stable knockdown AGS/OXA cells, which leads to the suppression of autophagy. ANXA1 functions as a chemoresistant gene in GC cells by targeting the PI3K/AKT/mTOR signaling pathway and might be a prognostic predictor for GC patients who receive OXA-based chemotherapy.
Asunto(s)
Anexina A1 , Neoplasias Gástricas , Humanos , Anexina A1/metabolismo , Autofagia/genética , Línea Celular Tumoral , Proliferación Celular , Resistencia a Antineoplásicos/genética , Oxaliplatino/farmacología , Oxaliplatino/uso terapéutico , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
B cells constitute a major component of infiltrating immune cells in colorectal cancer (CRC). However, the characteristics of B cells and their clinical significance remain unclear. In this study, using single-cell RNA sequencing and multicolour immunofluorescence staining experiments, we identified five distinct subtypes of B cells with their marker genes, distribution patterns and functional properties in the CRC tumour microenvironment. Meanwhile, we found a higher proportion of IgG plasma cells in tumour sites than that in adjacent normal mucosal tissues. In addition, the CXCL13-producing CD8+ T cells in the tumour tissues could promote the formation of tertiary lymphoid structure (TLS) B cells, and the CCL28-CCR10 axis is pivotal for IgG plasma cell migration from the periphery of TLSs to the tumour stroma. Finally, we identified four distinct colon immune classes (CICs: A-D) and found that CD20+ B cells within TLSs were enriched in one immune-inflamed or hot tumour group (CIC D). This B cell-rich group, which was characterized by strong antigen presentation, IgG plasma cells accumulation, microsatellite instability-high (MSI-H) and high tumour mutation burden (TMB-H), as well as immunosuppressive property in particular, might become a potential predictive biomarker for future immunotherapy. Additionally, in an immunotherapy cohort, patients with the enrichment of B cells and TLSs were demonstrated to obtain significant therapeutic advantages. Together, our findings provide the detailed landscape of infiltrating B cells and their potential clinical significance in CRC.
Asunto(s)
Neoplasias Colorrectales , Estructuras Linfoides Terciarias , Humanos , Linfocitos T CD8-positivos , Pronóstico , Linfocitos B , Inmunoglobulina G , Microambiente TumoralRESUMEN
Background: There are few models to predict the survival of patients of different ethnicities initially diagnosed with metastatic gastric cancer (mGC). Therefore, the aim of this study was to construct a nomogram to predict the cancer-specific survival (CSS) of these patients. Methods: Data for 994 patients initially diagnosed with mGC between 2000 and 2013 were extracted from the Surveillance, Epidemiology, and End Results database. Patients were randomly classified into a training (n = 696) or internal validation (n = 298) cohort, and a cohort of 133 patients from Fudan cohort was used for external validation. A nomogram to predict the CSS of mGC patients was derived and validated using a concordance index (C-index), calibration curves, and decision-curve analysis (DCA). Results: Multivariate Cox regression indicated that five factors were independent predictors of CSS: differentiation grade, T stage, N stage, metastatic site at diagnosis, and with or without chemotherapy. Thus, these factors were integrated into the nomogram model. The C-index value of the nomogram model was 0.63 (95% CI: 0.60-0.65), and those of the internal and external validation cohorts were 0.60 (95%: CI 0.55-0.64) and 0.63 (95%: CI 0.57-0.69), respectively. The calibration curves showed good consistency between the actual and predicted survival rates in both the internal and external validation cohorts. The DCA also showed the clinical utility of the nomogram model. Conclusions: We established a practical nomogram to predict the CSS of patients initially diagnosed with mGC. The nomogram can be used for individualized prediction of survival and to guide clinicians in making treatment decisions.
RESUMEN
Selenium-binding protein 1 (SELENBP1) is frequently dysregulated in various malignancies including colorectal cancer (CRC); however, its roles in progression of CRCs and the underlying mechanism remain to be elucidated. In this study, we compared the expression of SELENBP1 between CRCs and colorectal normal tissues (NTs), as well as between primary and metastatic CRCs; we determined the association between SELENBP1 expression and CRC patient prognoses; we conducted both in vitro and in vivo experiments to explore the functional roles of SELENBP1 in CRC progression; and we characterized the potential underlying mechanisms associated with SELENBP1 activities. We found that the expression of SELENBP1 was significantly and consistently decreased in CRCs than that in adjacent NTs, while significantly and frequently decreased in metastatic than primary CRCs. High expression of SELENBP1 was an independent predictor of favorable prognoses in CRC patients. Overexpression of SELENBP1 suppressed, while silencing of SELENBP1 promoted cell proliferation, migration and invasion, and in vivo tumorigenesis of CRC. Mechanically, SELENBP1 may suppress CRC progression by inhibiting the epithelial-mesenchymal transition.
RESUMEN
BACKGROUND: Selenium binding protein 1 (SELENBP1) is frequently downregulated in malignancies such as colorectal cancer (CRC), however, whether it is involved in tumor angiogenesis is still unknown. METHODS: We analyzed the expression and localization of SELENBP1 in vessels from CRC and neighboring tissues. We investigated the in vitro and in vivo activity of SELENBP1 in angiogenesis and explored the underlying mechanism. RESULTS: SELENBP1 was localized to endothelial cells in addition to glandular cells, while its vascular expression was decreased in tumor vessels compared to that in vessels from neighboring non-tumor tissues. Gain-of-function and loss-of-function experiments demonstrated that SELENBP1 inhibited angiogenesis in vitro, and blocked communications between HUVECs and CRC cells. Overexpression of SELENBP1 in CRC cells inhibited tumor growth and angiogenesis, and enhanced bevacizumab-sensitivity in a mouse subcutaneous xenograft model. Mechanic analyses revealed that SELENBP1 may suppress tumor angiogenesis by binding with Delta-like ligand 4 (DLL4) and antagonizing the DLL4/Notch1 signaling pathway. The inhibitory effects of SELENBP1 on in vitro angiogenesis could largely be rescued by DLL4. CONCLUSION: These results revealed a novel role of SELENBP1 as a potential tumor suppressor that antagonizes tumor angiogenesis in CRC by intervening the DLL4/Notch1 signaling pathway.
RESUMEN
Background: Rectal cancer is usually treated by surgery, but recurrence or metastasis seriously affect the quality of life and survival of patients. Identifying the risk factors for postoperative recurrence or metastasis of rectal cancer has important guiding value for the treatment of rectal cancer. However, the research on risk factors of postoperative recurrence or metastasis of rectal cancer has not been unified. Methods: The data of all patients undergoing rectal cancer surgery in The Fifth People's Hospital of Shanghai, Fudan University, from 2016 to 2020 were collected and analyzed. A total of 185 patients were included for statistical analysis and were divided into a recurrence or metastasis group and a non-recurrence or metastasis group. Patients were followed up according to National Comprehensive Cancer Network (NCCN) guidelines by enhanced CT or MRI, and colonoscopy. The cut-off of the research was recurrence, metastasis, or death. Logistic regression analysis and Cox regression analysis were used to analyze the risk factors related to postoperative recurrence or metastasis of rectal cancer, and the survival curve was drawn. Results: Multiple logistic regression analysis showed involvement of the mesorectal fascia (MRF) [OR (odds ratio) =2.9, 95% confidence interval (CI): 1.16-7.29, P=0.023], nerve and vascular invasion (OR =1.7, 95% CI: 1.08-2.59, P=0.022), intraoperative blood transfusion (OR =3.7, 95% CI: 1.45-9.40, P=0.006), and Dukes staging (OR =2.3, 95% CI: 1.26-4.35, P=0.007) were independent risk factors for postoperative recurrence or metastasis of rectal cancer. Involvement of mesenteric fascia infiltration (OR =11.5, 95% CI: 1.49-88.79, P=0.019) and Dukes stage (OR =3.0, 95% CI: 1.46-6.26, P=0.003) were independent risk factors for liver metastasis, while nerve and vascular invasion (OR =2.4, 95% CI: 1.19-5.00, P=0.015) was an independent risk factor for pulmonary metastasis. Conclusions: Postoperative recurrence or metastasis of rectal cancer is related to many factors. These findings have clinical guiding value and significance for the follow up and prognosis of patients with rectal cancer after surgery. Large-scale prospective clinical studies are needed.
RESUMEN
BACKGROUND: Colorectal cancer (CRC) is the third most common cancer, according to recently published literature. While the incidence and the mortality of CRC has decreased due to effective cancer screening measures, there has been an increase in the number of young patients diagnosed with colon cancer due to unclear reasons. As a target molecule of the Wnt signaling pathway, Ascl2 is an important marker of CRC stem cells and plays an important role in maintaining the nature of colon cancer stem/precursor cells. However, the role of Ascl2 in autophagy in CRC cells is rarely elucidated. METHODS: In this study, we found that Ascl2 was increased in CRC compared with adjacent tissue. Downregulation of Ascl2 in CRC cells could suppress proliferation and invasion, and induce apoptosis, of CRC cells. Moreover, we found that autophagy-relative protein LC3 increased after Ascl2 knockdown. Furthermore, we treated CRC cells with autophagy inhibitors 3-MA (3-Methyladenine) and CQ (Chloroquine). RESULTS: The results showed that autophagy inhibitors could prevent apoptosis, which was induced by Ascl2 knockdown. Finally, we confirmed that the downregulation of Ascl2 in CRC cells could alleviate the pathological process in vivo by xenograft experiment. CONCLUSIONS: Our findings indicated that si-Ascl2 (small/short interfering) exerted a tumor suppression function in CRC by inducing autophagic cell death, and suggest that Ascl2 targeted therapy represents a novel strategy for CRC treatment.
RESUMEN
Little is known about the functional roles of gamma-aminobutyric acid type A receptor subunit delta (GABRD) in colorectal cancer (CRC). The expression of GABRD between CRCs and adjacent normal tissues (NTs), metastasis and primary tumors was compared using public transcriptomic datasets. A tissue microarray and immunohistochemical staining (IHC) were used to determine the clinical and prognostic significance of the GABRD in CRC. We used gain-of-function and loss-of-function experiments to investigate the in vitro roles of GABRD in cultured CRC cells. We characterized the potential mechanism of GABRD's activities in CRC using a Gene Set Enrichment Analysis (GSEA) with The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) dataset. We found that the GABRD expression was significantly increased in CRCs compared to that in NTs, but was similar between metastasis and primary tumors. Overexpression of GABRD was significantly associated with later pTNM stages and unfavorable patient survival. Overexpression of GABRD accelerated while knock-down of GABRD inhibited cell growth and migration. Mechanistically, the function of GABRD might be ascribed to its influence on major oncogenic events such as epithelial-mesenchymal transition (EMT), angiogenesis, and hedgehog signaling. Collectively, GABRD could be a novel prognostic predictor for CRC that deserves further investigation.
RESUMEN
Homeostasis of membrane phospholipids plays an important role in cell oncogenesis and cancer progression. The flippase ATPase class I type 8b member 1 (ATP8B1), one of the P4-ATPases, translocates specific phospholipids from the exoplasmic to the cytoplasmic leaflet of membranes. ATP8B1 is critical for maintaining the epithelium membrane stability and polarity. However, the prognostic values of ATP8B1 in colorectal cancer (CRC) patients remain unclear. We analyzed transcriptomics, genomics, and clinical data of CRC samples from The Cancer Genome Atlas (TCGA). ATP8B1 was the only potential biomarker of phospholipid transporters in CRC. Its prognostic value was also validated with the data from the Gene Expression Omnibus (GEO). Compared to the normal group, the expression of ATP8B1 was downregulated in the tumor group and the CRC cell lines, which declined with disease progression. The lower expression level of ATP8B1 was also significantly associated with worse survival outcomes in both the discovery samples (359 patients) and the validation samples (566 patients). In multivariate analyses, low ATP8B1 levels predicted unfavorable OS (adjusted HR 1.512, 95% CI: 1.069-2.137; P = 0.019) and were associated with poor progress-free interval (PFI) (adjusted HR: 1.62, 95% CI: 1.207-2.174; P = 0.001). The pathway analysis results showed that the underexpression of ATP8B1 was negatively associated with phospholipid transport, phospholipid metabolic process, and cell-cell adherent junction and positively associated with the epithelial-mesenchymal transition in CRC. Our analysis suggests that ATP8B1 is a potential cancer suppressor in CRC patients and may offer new strategies for CRC therapy.
Asunto(s)
Adenosina Trifosfatasas/genética , Neoplasias Colorrectales , Genes Supresores de Tumor , Fosfolípidos/metabolismo , Anciano , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Femenino , Homeostasis/genética , Humanos , Masculino , Persona de Mediana Edad , Transcriptoma/genéticaRESUMEN
Purpose: Hepatocellular carcinoma (HCC) is an aggressive and prevalent tumor threatening human health. A previous study suggested low PRELP (proline/arginine-rich end leucine-rich repeat protein) expression was associated with poor patient survival in pancreatic ductal adenocarcinoma (PDAC). However, the role of PRELP in HCC has not yet been illuminated. Methods: PRELP expression analyses were carried out using transcriptomic datasets from the Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB). The correlations between PRELP expression and clinicopathological features, and prognostic analyses were performed with a tissue microarray (TMA) and immunohistochemistry (IHC). The endogenous expression and in vitro roles of PRELP were investigated in cultured HCC cell lines. The potential mechanisms were characterized by a Gene Set Enrichment Analysis (GSEA) and gene-gene correlation analyses. Results: We found that PRELP mRNA expression was dramatically decreased in HCCs in comparison with that in adjacent normal tissues (NTs) or hepatic cirrhosis. IHC staining showed that PRELP was down-regulated in HCCs, which mainly located in cytoplasm, and was also found in nuclei. The correlation analyses revealed that PRELP expression was relevant to later p-stages (p= 0.028) and tumor size (p= 0.001). The overall survival (OS) and relapse free survival (RFS) time was shorter in HCC patients with lower PRELP expression levels than that with higher PRELP expression levels. Overexpression of PRELP inhibited, while knockdown of PRELP promoted proliferation and migration of HCC cells. For potential mechanisms, PRELP may inhibit progression of HCCs by interacting with integrin family members and the extracellular microenvironment. Conclusion: Our findings demonstrated that overexpression of PRELP correlates with better patient survival and inhibits both cell proliferation and migration in HCC. Therefore, PRELP can serve as a potential prognostic biomarker and therapeutic target which deserves further investigation.
RESUMEN
BACKGROUND Three-dimensional (3D) cell-culture scaffolds are ideal in vitro models to bridge the gap between two-dimensional cell culture in vitro and in vivo cancer models. Construction of 3D scaffolds using two kinds of biomaterials has been reported, but there are still many defects. To improve the performance of the scaffolds for 3D cell culture of colonic carcinoma (CC) cells in vitro, we attempted to construct triple composite scaffolds using silk fibroin (SF), chitosan (Cs), and alginate (Alg). MATERIAL AND METHODS We explored the suitability of triple composite scaffolds of SF/Cs/Alg at ratios of 1: 1: 0.5, 1: 1: 1, and 1: 1: 2 for 3D culture of CC cells, and used the dual composite scaffold of SF/Cs (1: 1) as a control group. We analyzed the physicochemical characteristics of these scaffolds and studied cell adhesion, cell proliferation, migration, colony-forming ability, microstructure and ultrastructure, and spheroid-forming capacity of the commercially available CC cell line HCT-116 on the prepared scaffolds. RESULTS Our results show that SF/Cs/Alg (1: 1: 1) scaffolds demonstrated the best profile, the highest uniform porosity and connectivity, and excellent hydroscopicity, and also exhibited appropriate and controlled swelling and degradation characteristics. The adhesion, proliferation, colony-forming, and wound-healing assays, green fluorescent protein-labeled HCT116 cell imaging, 4',6-diamidino-2-phenylindole and DY-554-phalloidin staining, scanning electron microscopy, and haematoxylin and eosin staining revealed that the triple composite scaffolds of SF/CS/Alg (1: 1: 1) supported cell adhesion, proliferation, migration, colony-forming ability, and spheroid formation far better than the dual composite scaffold of SF/CS (1: 1). CONCLUSIONS This study successfully demonstrated the potential of SF/Cs/Alg (1: 1: 1) scaffold as an alternative for the 3D in vitro culture of CC cells.
Asunto(s)
Alginatos/química , Quitosano/química , Fibroínas/química , Andamios del Tejido , Adhesión Celular , Técnicas de Cultivo de Célula/métodos , Movimiento Celular , Proliferación Celular , Neoplasias del Colon/patología , Células HCT116 , HumanosRESUMEN
TAFA chemokine like family member 5 (TAFA5), a TAFA family member that encodes small secreted proteins in the central nervous system, has been demonstrated to have increased expression in human malignancies. However, the expression and function of TAFA5 in gastric cancer (GC) remains unclear. In the present study, public datasets and human GC samples were used to determine the TAFA5 expression levels. The results revealed that TAFA5 was upregulated in GC when compared with adjacent normal tissues. Overexpression of TAFA5 in GC was associated with poor differentiation, and worse tumor, nodal and metastasis stages. In addition, high TAFA5 expression was correlated with unfavorable patient prognoses. In vitro experiments indicated that downregulation of TAFA5 inhibited the proliferation and migration of GC cell lines. Finally, the results from gene set enrichment analysis using data from The Cancer Genome Atlas revealed that TAFA5 expression was significantly correlated with genes associated with epithelialmesenchymal transition, which was further confirmed by western blot analysis. In conclusion, the results of the present study suggested that TAFA5 had significant effects on GC progression, suggesting that it may serve as a potential therapeutic target for GC therapy.
Asunto(s)
Movimiento Celular , Proliferación Celular , Citocinas/biosíntesis , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/biosíntesis , Neoplasias Gástricas/metabolismo , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Citocinas/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologíaRESUMEN
Carboxypeptidase X, M14 family member 2 (CPXM2), has been associated with several human disorders such as developmental diseases. However, whether CPXM2 is involved in oncogenesis or tumor progression remains unclear. In the present study, we used clinical samples from gastric cancer (GC) patients to investigate potential roles of CPXM2 in GC. We also analyzed datasets from the Oncomine database, The Cancer Genome Atlas (TCGA), and the KaplanMeier Plotter to validate these results. We found that CPXM2 was overexpressed in GC and that the overexpression was associated with an unfavorable prognosis, regardless of the Lauren classification and tumor node metastasis staging. In addition, knockdown of CPXM2 in cultured GC cells significantly impeded cell proliferation and migration, as indicated by the cholecystokinin octapeptide, colony formation assay, scratch wound healing assay, and Transwell® migration assay. Furthermore, gene set enrichment analysis using RNAseq data from TCGA indicated that high CPXM2 expression in GC patients was positively correlated with the HALLMARK_APICAL_JUNCTION and HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION gene sets. Finally, western blotting results revealed that several key molecules involved in the epithelial mesenchymal transition were regulated by CPXM2. Taken together, these results imply an active role for CPXM2 in promoting tumor aggressiveness via epithelial to mesenchymal transition (EMT) modulation in GCs.
Asunto(s)
Carboxipeptidasas/biosíntesis , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/patología , Anciano , Carboxipeptidasas/genética , Carboxipeptidasas/metabolismo , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Transición Epitelial-Mesenquimal , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Neoplasias Gástricas/genética , Regulación hacia ArribaRESUMEN
BACKGROUND: Nucleoporin NUP153 (NUP153) is well known to be involved in the regulating of nuclear transport. Although NUP153 is associated with several cancers, its role in colorectal cancer (CRC) and the underlying mechanism are still unknown. OBJECTIVE: The aim of this study was to access the effect of NUP153 on the prognosis of patients with CRC, and cancer cell proliferation. METHODS: The expression levels of NUP153 in CRC tissues and matched normal colon tissues were examined by real-time quantitative PCR and immunohistochemistry. Then the association between NUP153 levels with clinical variables as well as survival time was investigated. Moreover, overexpression of NUP153 in HCT116 cells was established to study its influence on cell proliferation in vitro, and a xenograft model was performed to explore this effect in vivo. RESULTS: We found that NUP153 was highly expressed in adjacent normal tissues than in cancer tissues, and elevated NUP153 expression was negatively associated with pathological grade (P= 0.015), T stage (P= 0.048) and distant metastasis (P= 0.006). Kaplan-Meier analysis revealed that patients with higher NUP153 expression had a longer overall survival (OS) (P= 0.01) and recurrence free disease (RFS) (P= 0.001). Logistic regression analysis further identified NUP153 as an independent prognostic safe factor for OS and recurrence. Moreover, NUP153 overexpression suppressed CRC cells proliferation and inhibited tumor growth in a xenograft model. Its mechanistic investigations showed that NUP153 overexpression inhibited ß-catenin transcriptional activity and down-regulated the mRNA expression levels of Wnt downstream proteins-Axin2, cyclinD1, c-myc and lef-1. CONCLUSIONS: NUP153 might be a promising prognostic factor, a potential tumor suppressor and therapeutic target in human CRC through an interaction with the Wnt/ß-catenin signaling pathway.
Asunto(s)
Biomarcadores de Tumor , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Expresión Génica , Proteínas de Complejo Poro Nuclear/genética , Vía de Señalización Wnt , Anciano , Anciano de 80 o más Años , Animales , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Reporteros , Humanos , Masculino , Ratones , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , PronósticoRESUMEN
Objectives: The aims of this study were to compare the expression of fibronectin type III domain containing 1 (FNDC1) in gastric cancer (GC) and normal gastric tissue, to explore the prognostic significance of FNDC1 expression in patients with gastric adenocarcinoma, and to analyze FNDC1-related signaling pathways. Methods: The expression level of FNDC1 was initially predicted using the Oncomine and Cancer Genome Atlas databases. A Kaplan-Meier plotter database was mined to examine the clinical prognostic significance of FNDC1 mRNA in patients with GC. Subsequently, immunohistochemistry was used to measure FNDC1 protein expression levels in tissue from 90 cases of GC and paired adjacent normal tissue. Kaplan-Meier univariate and Cox multivariate survival analyses were used to determine the prognostic role of FNDC1 expression. Results: Bioinformatic data indicated that FNDC1 mRNA expression levels were significantly highly expressed in GC compared with normal gastric tissue (all P < 0.05), and patients with GC with high FNDC1 mRNA expression levels had remarkably lower overall survival (all P < 0.01). Immunohistochemical results revealed that expression levels of FNDC1 protein were significantly increased in GC compared with normal gastric tissue (P < 0.001). Additionally, Kaplan-Meier univariate and Cox multivariate survival analyses indicated that increased expression of FNDC1 was an independent predictor of poor prognosis in patients with GC (all P < 0.05). Conclusions: FNDC1 was highly expressed in GC, and high expression of FNDC1 was an independent predictor of poor prognosis in patients with GC. FNDC1 co-expressed genes were largely enriched in extracellular matrix-receptor interactions, which are closely related to tumor metastasis.
RESUMEN
BACKGROUND Age is a prognostic factor for multiple malignancies. In this study, we aimed to assess the effect of age on the cancer-specific survival (CSS) of patients with gastric signet-ring cell carcinoma (SRC). MATERIAL AND METHODS Information on patients with gastric SRC was extracted from the Surveillance, Epidemiology, and End Results database. Chi-squared tests were used to demonstrate distribution differences, and Kaplan-Meier analysis and Cox regression models were used to analyze the impact of age on CSS. RESULTS A total of 4596 patients were enrolled and divided into 3 subgroups according to age (<45, 45-74, and >74 years old). Higher percentages of T4, N2, and M1 disease were observed in the <45-year-old group (all P<0.001). Kaplan-Meier plots showed that the youngest group had the most favorable 5-year CSS rate (36.3%), which remained true after stratification according to tumor stage. Multivariate Cox regression models demonstrated a poorer survival outcome for >74-year-old than for <45-year-old patients (hazard ratio 1.841, 95% confidence interval 1.636-2.071; P<0.001). CONCLUSIONS Young age is associated with improved survival, even though younger patients generally present with a more advanced-stage disease.
Asunto(s)
Carcinoma de Células en Anillo de Sello/mortalidad , Neoplasias Gástricas/mortalidad , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Carcinoma de Células en Anillo de Sello/patología , Bases de Datos Factuales , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Modelos de Riesgos Proporcionales , Programa de VERF , Neoplasias Gástricas/patología , Tasa de SupervivenciaRESUMEN
BACKGROUND G-protein receptor 125 (GPR125), as a transmembrane signal transducer, is involved in regulating cancer development. Although GPR125 is related with several cancers, its role in colorectal cancer (CRC) and the underlying mechanism are still unknown. Here, we investigated the clinical significance of GPR125 in CRC. MATERIAL AND METHODS We assessed the expression level of GPR125 in CRC tissues by analyzing 3 datasets in the Gene Expression Omnibus (GEO) database and in human samples. The correlation between GPR125 expression and clinicopathological features was further analyzed. Survival analysis was performed to assess the association between GPR125 expression and recurrence-free survival (RFS). Cox logistic regression analysis was used to analyze the role of GPR125 expression in overall survival (OS). Moreover, we activated the Wnt pathway in HCT116 cells to investigate their potential mechanism. RESULTS Analysis of the GEO database showed that the expression of GPR125 was down-regulated in CRC tissues, consistent with our human samples experiments, and patients with higher GPR125 expression had a longer RFS. Also, we found that high GPR125 expression was associated with better tumor outcomes in clinical stage, metastasis, and KRAS status. Cox logistic regression analysis demonstrated that GPR125 was an independent prognostic factor for favorable outcome. Mechanistically, GPR125 overexpression inhibited the ß-catenin transcriptional activity, and down-regulated the expression levels of the Wnt downstream proteins-Axin2, c-Myc, cylinD1, and lef-1. CONCLUSIONS GPR125 may be a potential prognosis-related anti-oncogene and its effects on inactivating Wnt/ß-catenin signaling pathway might be a key link to inhibiting CRC formation.
Asunto(s)
Neoplasias Colorrectales/metabolismo , Receptores Acoplados a Proteínas G/biosíntesis , Vía de Señalización Wnt/fisiología , Proteína Wnt1/antagonistas & inhibidores , beta Catenina/antagonistas & inhibidores , Adulto , Anciano , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Análisis de Supervivencia , Proteína Wnt1/genética , Proteína Wnt1/metabolismo , beta Catenina/metabolismoRESUMEN
BACKGROUND: Laparoscopic total gastrectomy (LTG) is frequently performed for treating patients with gastric cancer; however, the absence of anastomotic techniques with greater superiority has impaired its popularization. We have compared two types of anastomotic techniques with regard to technical perspectives and clinical outcomes. METHODS: We reviewed 43 patients with gastric cancer who underwent LTG. Two types of anastomotic techniques have been applied after LTG-the trans-orally inserted anvil (OrVil™) and the reverse puncture device (RPD). Data on the type of anastomosis, blood loss, operation time, anastomosis time, location of tumors, distance between the top border of tumors and top resection margin, diameter of tumor, length of postoperative hospital stay, early and late postoperative complications, and total cost of surgical consumables were obtained by reviewing patient medical records and analyzed thereafter. RESULTS: We included 32 men and 11 women (mean age 61 years). The loss to follow-up rate was 13.2%. The median survival time for the OrVil™ and RPD groups was 23 and 22 months, respectively. The total rate of complications was 9.3%. The difference in the anastomosis times between the groups was statistically significant. OrVil™ required more time than RPD and cost more than RPD. CONCLUSIONS: Both the OrVil™ and RPD techniques showed good safety and applicability in LTG. RPD showed an advantage with regard to lesser operative complexity and lower cost.