β-Galactosidase is a target enzyme for detecting peritoneal metastasis of gastric cancer.
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ABSTRACT:
SUBMITTER: Kubo H
PROVIDER: S-EPMC8139979 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Peritoneal metastasis is a common form of metastasis among advanced gastric cancer patients. In this study, we reported the identification of LIM domain kinase 1 (LIMK1) as a promoter of gastric cancer peritoneal metastasis, and its potential to be a therapeutic target of dabrafenib (DAB). Using transcriptomic sequencing of paired gastric cancer peritoneal metastasis, primary tumors, and normal gastric tissues, we first unveiled that LIMK1 is selectively up-regulated in metastatic tumors. Increased LIMK1 in gastric cancer peritoneal metastasis was validated by immunohistochemistry analysis of an independent patient cohort. In vitro functional studies demonstrated that LIMK1 knockout or knockdown significantly inhibited cell migration and invasion of gastric cancer cells. LIMK1 knockout also abrogated peritoneal and liver metastases of gastric cancer cells in nude mice in vivo. Dabrafenib, a small molecule targeting LIMK1, was found to decrease cell migration and invasion of gastric cancer cells in vitro and abolish peritoneal and liver metastasis formation in vivo. Mechanistically, either LIMK1 knockout or Dabrafenib inhibited LIMK1 expression and phosphorylation of its downstream target cofilin. Taken together, our results demonstrated that LIMK1 functions as a metastasis promoter in gastric cancer by inhibiting LIMK1-p-cofilin and that Dabrafenib has the potential to serve as a novel treatment for gastric cancer peritoneal metastasis.
| S-EPMC8116207 | biostudies-literature
Project description:BackgroundPeritoneal metastasis is one of the main causes of death in patients with gastric cancer (GC). Galectin-1 regulates various undesirable biological behaviors in GC and may be key in GC peritoneal metastasis.MethodsIn this study, we elucidated the regulatory role of galectin-1 in GC cell peritoneal metastasis. GC and peritoneal tissues underwent hematoxylin-eosin (HE), immunohistochemical (IHC), and Masson trichrome staining to analyze the difference in galectin-1 expression and peritoneal collagen deposition in different GC clinical stages. The regulatory role of galectin-1 in GC cell adhesion to mesenchymal cells and in collagen expression was determined using HMrSV5 human peritoneal mesothelial cells (HPMCs). Collagen and corresponding mRNA expression were detected with western blotting and reverse transcription PCR, respectively. The promoting effect of galectin-1 on GC peritoneal metastasis was verified in vivo. Collagen deposition and collagen I, collagen III, and fibronectin 1 (FN1) expression in the peritoneum of the animal models were detected by Masson trichrome and IHC staining.ResultsGalectin-1 and collagen deposition in the peritoneal tissues was correlated with GC clinical staging and were positively correlated. Galectin-1 enhanced the ability of GC cells to adhere to the HMrSV5 cells by promoting collagen I, collagen III, and FN1 expression. The in vivo experiments confirmed that galectin-1 promoted GC peritoneal metastasis by promoting peritoneal collagen deposition.ConclusionGalectin-1-induced peritoneal fibrosis may create a favorable environment for GC cell peritoneal metastasis.
| S-EPMC10276408 | biostudies-literature
Project description:PurposeTo develop a bounding box (BBOX)-based radiomics model for the preoperative diagnosis of occult peritoneal metastasis (OPM) in advanced gastric cancer (AGC) patients.Materials and methods599 AGC patients from 3 centers were retrospectively enrolled and were divided into training, validation, and testing cohorts. The minimum circumscribed rectangle of the ROIs for the largest tumor area (R_BBOX), the nonoverlapping area between the tumor and R_BBOX (peritumoral area; PERI) and the smallest rectangle that could completely contain the tumor determined by a radiologist (M_BBOX) were used as inputs to extract radiomic features. Multivariate logistic regression was used to construct a radiomics model to estimate the preoperative probability of OPM in AGC patients.ResultsThe M_BBOX model was not significantly different from R_BBOX in the validation cohort [AUC: M_BBOX model 0.871 (95% CI, 0.814-0.940) vs. R_BBOX model 0.873 (95% CI, 0.820-0.940); p = 0.937]. M_BBOX was selected as the final radiomics model because of its extremely low annotation cost and superior OPM discrimination performance (sensitivity of 85.7% and specificity of 82.8%) over the clinical model, and this radiomics model showed comparable diagnostic efficacy in the testing cohort.ConclusionsThe BBOX-based radiomics could serve as a simpler reliable and powerful tool for the preoperative diagnosis of OPM in AGC patients. And M_BBOX-based radiomics is simpler and less time consuming.
| S-EPMC8678129 | biostudies-literature
Project description:Being the major reason of recurrence and death after surgery, peritoneal metastasis of gastric cancer dooms the prognosis of advanced gastric cancer patients. Regenerating islet-derived family, member 4 (REG4) is believed to promote peritoneal metastasis, however, its mechanism is still a moot point at present. In the present study, we show that high expression of REG4 correlates with advanced stage and poor survival prognosis for gastric cancer patients. REG4 overexpression significantly enhances peritoneal metastasis by increasing adhesion ability. Moreover, SP1 is proved to be a transcription factor of REG4 and induce REG4 expression upon TGF-alpha stimulation. Also, G protein-coupled receptor 37 (GPR37) is identified to be in the same complex of REG4, which mediates REG4's signal transduction and promotes peritoneal metastasis of gastric cancer cell. Interestingly, we also discover a positive feedback loop triggered by REG4, amplifying itself through EGFR transactivation, consisting of GPR37, ADAM17, TGF-alpha, EGFR, SP1 and REG4. In conclusion, REG4 promotes peritoneal metastasis of gastric cancer through GPR37 and triggers a positive feedback loop.
| S-EPMC5053694 | biostudies-other
Project description:Gastric cancer is a lethal malignancy due to the combination of late-stage presentation, propensity for early metastasis, and lack of effective systemic therapies. Given the high rates of gastric peritoneal metastasis, both macro- and microscopic, regional therapy represents both an attractive and rational treatment option for patients given its success in other peritoneal surface malignancies. Bidirectional chemotherapy (intraperitoneal and intravenous) for treatment of metastatic gastric cancer has not been evaluated prospectively in a contemporary North American cohort. Here we present the rationale and design of a phase II clinical trial of intraperitoneal paclitaxel in combination with intravenous paclitaxel and oral capecitabine. We hypothesize that the combination of systemic and regional chemotherapy may result in improved progression free survival (PFS) for patients with gastric adenocarcinoma and peritoneal-only metastasis. In addition to studying clinical outcomes associated with this treatment regimen, both basic and translational science efforts are planned to better understand this complex malignancy.
| S-EPMC7052767 | biostudies-literature
Project description:Gastric cancer incidence and mortality are among the highest in China, with majority of the mortality related to peritoneal metastasis of gastric cancer. Treatment is limited to radical resection, which is impeded by incidence of metastasis at time of initial diagnosis, thus making it imperative to identify diagnostic and prognostic biomarkers. Legumain, a lysosomal cysteine endopeptidase of the asparaginyl endopeptidase family, has been shown to be overexpressed in patients with metastatic gastric cancer disease and its expression was positively correlated to both disease progression and outcome. However, the mechanism of legumain expression is currently unknown. Legumain overexpression was found to occur at the level of post transcriptional gene regulation. In situ prediction algorithms identified legumain as a putative target of miR-3978. MiR-3978 was significantly decreased in peritoneal metastatic tissue specimens and in MKN45 cells that mimic peritoneal metastasis features. Reporter assays using LGMN (encoding legumain) 3' untranslated region (UTR) showed that miR-3978 interacted with the wild-type but not miR-3978-seed mutant. Ectopic expression of miR-3978 mimic in the MKN45 cell line significantly decreased proliferation and suppressed in vitro migration and invasion. The miR-3978 mimic inhibited gastric carcinoma and metastatic progression in a mice model by regulating legumain protein expression. Inverse correlation of LGMN mRNA and miR-3978 levels in 20 gastric patients at different stages of metastatic disease confirmed the same. Cumulatively, our results indicate that loss of miR-3978 leads to increased expression of legumain, which indicates that miR-3978might be a biomarker for peritoneal metastasis in patients with gastric cancer.
| S-EPMC5347764 | biostudies-literature
Project description:Gastric cancer peritoneal metastases (GCPM) is a leading cause of GC-related death. Early detection of GCPM is critical for improving the prognosis of advanced GC. Differentially expressed genes (DEGs) were identified in the GSE62254 database to distinguish between GCPM and non-GCPM. The gastric cancer peritoneal metastases signature (GCPMs) was developed using DEGs. We analysed the effectiveness of GCPMs as indicators for prognosis, chemotherapy, and immune therapy response in GC patients. Subsequently, we analysed the correlation between GCPMs and immune microenvironment as well as immune escape in GC patients. Random forest model and immunohistochemistry was utilized to identify the crucial genes that can aid in the diagnosis of GCPM. We identified five DEGs and utilized their expression to construct GCPMs. Patients with high GCPMs had a higher likelihood of a poor prognosis, while those with low GCPMs appeared to potentially benefit more from chemotherapy. GCPMs were a dependable marker for predicting the response to immunotherapy. Additionally, GCPMs was found to be significantly linked to stromal score and cancer-associated fibroblasts. SYNPO2 has been identified as the gene with the highest significance in the diagnosis of GCPM. Immunohistochemistry suggests that SYNPO2-positive expression in tumour cells, fibroblasts, inflammatory cell may be associated with promoting peritoneal metastasis in GC. GCPMs have shown to be a promising biomarker for predicting the prognosis and response of GC patients to chemotherapy and immunotherapy. The use of GCPMs for individual tumour evaluation may pave the way for personalized treatment for GC patients in the future.
| S-EPMC10660625 | biostudies-literature
Project description:The prognosis of gastric cancer (GC) patients with peritoneal dissemination remains poor, and a better understanding of the underlying mechanisms is critical for the development of new treatments that will improve survival in these patients. This study aimed to clarify the clinical and biological role of two key metastasis-associated long non-coding RNAs (lncRNAs) in GC. We analyzed the expression levels of two lncRNAs-Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) and HOX-Antisense Intergenic RNA (HOTAIR)-by real-time reverse transcription PCR in 300 gastric tissues (150 GC and 150 adjacent normal mucosa), and in seven GC cell lines. Functional characterization for the role of HOTAIR in GC was performed by small interfering RNA (siRNA) knockdown, followed by series of in-vitro and in-vivo experiments. Expression of both lncRNAs was significantly higher in cancerous tissues than in corresponding normal mucosa, and higher expression of these lncRNAs significantly correlated with peritoneal metastasis in GC patients. In addition, elevated HOTAIR expression emerged both as an independent prognostic and risk factor for peritoneal dissemination. SiRNA knockdown of HOTAIR in GC cells significantly inhibited cell proliferation, migration and invasion, but concurrently enhanced the anoikis rate in transfected cells. In an in vivo assay, HOTAIR siRNA-transfected MKN45 cells injected into nude mice inhibited the growth of xenograft tumors and peritoneal metastasis compared with controls. Our data provide novel evidence for the biological and clinical significance of HOTAIR expression as a potential biomarker for identifying patients with peritoneal metastasis, and as a novel therapeutic target in patients with gastric neoplasia.
| S-EPMC4247518 | biostudies-literature
Project description:In China, majority of the mortality in gastric cancer are associated with peritoneal metastasis. Since most gastric tumors are metastatic at initial diagnosis, the treatment of gastric cancer is limited to radical resection. Therefore, it is imperative to identify diagnostic and prognostic biomarkers. From 2014 to 2015, 20 patients were enrolled in the study. To search translationally upregulated genes in the context of epithelial to mesenchymal transition (EMT), polysome profiling was performed. The MTT, migration, and invasion assay were conducted to determine cell proliferation, migration, and invasion ability respectively. Experiments of gain and loss of function were performed using the overexpression plasmid, siRNA, and shRNA. Xenograft assay was established using nude mice to explore the role of targets translationally upregulated gene in vivo. Polysome profiling defined the landscape of translationally regulated gene products with differential expression between non-metastatic and metastatic cohorts. Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) was found to be the most translationally upregulated gene product in either experimental groups. STEAP1 was found to be required for cell proliferation, in vitro migration and invasion, and in vivo tumorigenesis. RNAi-mediated silencing of STEAP1 potentiated chemosensitivity of the MKN45 cells to docetaxel treatment, highlighting the importance of STEAP1 as a novel biomarker in gastric cancer patients with peritoneal metastasis. STEAP1 is thus induced translationally and its expression promotes proliferation, migration, invasiveness, and tumorigenicity of gastric cancer. STEAP1 can be a potent candidate for designing of targeted therapy.
| S-EPMC6110897 | biostudies-literature
Project description:ObjectiveThe aim is to explore the prediction effect of 5 machine learning algorithms on peritoneal metastasis of gastric cancer.Methods1080 patients with postoperative gastric cancer were divided into a training group and test group according to the ratio of 7:3. The model of peritoneal metastasis was established by using 5 machine learning (gbm(Light Gradient Boosting Machine), GradientBoosting, forest, Logistic and DecisionTree). Python pair was used to analyze the machine learning algorithm. Gbm algorithm is used to show the weight proportion of each variable to the result.ResultCorrelation analysis showed that tumor size and depth of invasion were positively correlated with the recurrence of patients after gastric cancer surgery. The results of the gbm algorithm showed that the top 5 important factors were albumin, platelet count, depth of infiltration, preoperative hemoglobin and weight, respectively. In training group: Among the 5 algorithm models, the accuracy of GradientBoosting and gbm was the highest (0.909); the AUC values of the 5 algorithms are gbm (0.938), GradientBoosting (0.861), forest (0.796), Logistic(0.741) and DecisionTree(0.712) from high to low. In the test group: among the 5 algorithm models, the accuracy of forest, DecisionTree and gbm was the highest (0.907); AUC values ranged from high to low to gbm (0.745), GradientBoosting (0.725), forest (0.696), Logistic (0.680) and DecisionTree (0.657).ConclusionMachine learning can predict the peritoneal metastasis in patients with gastric cancer.
| S-EPMC7791448 | biostudies-literature