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BACKGROUND: Colorectal cancer (CRC) is characterized by its high malignancy and challenging prognosis. A significant aspect of cancer is metabolic reprogramming, where lactate serves as a crucial metabolite that contributes to the development of cancer and the tumor microenvironment (TME). Current studies have indicated that lactate plays a significant role in the progression of CRC. However, the relationship between lactate and the tumor microenvironment remains understudied, underscoring the potential of lactate as a novel biomarker. METHODS: We sourced transcriptomic data for colorectal cancer (CRC) patients from The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), and the Gene Expression Omnibus (GEO) portals, along with the corresponding clinical information. Utilizing univariate Cox regression in conjunction with LASSO regression analysis, we identified genes involved in lactate metabolism that are associated with CRC prognosis. Subsequently, we developed models based on multi-factor Cox regression. To evaluate the correlation between tumor mutational burden (TMB), tumor microenvironment (TME), and lactate scores with patient survival, we conducted gene set enrichment analysis (GSEA) and immunogenic signature analyses. RESULTS: 3 lactate metabolism-related genes (LMRGs) (SLC16A8, GATA1, and PYGL) were used to construct models that categorized patients into 2 subgroups based on their lactate scores. The function of the differential genes between the 2 subgroups was mainly enriched in cell cycle and mRNA division, and the prognosis of patients in the high score subgroup was poor. Furthermore, a significant positive correlation was observed between TMB and LMRGs scores in the high-scoring group (P = 0.003, r2 = 0.12). Lastly, LMRGs also reflected the characteristics of TME, with differences in immune cells and immune checkpoints between the 2 subgroups. CONCLUSIONS: LMRGs may serve as a promising biomarker for predicting prognostic survival in CRC patients and to assess the TME.
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Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais , Ácido Láctico , Microambiente Tumoral , Humanos , Microambiente Tumoral/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Ácido Láctico/metabolismo , Ácido Láctico/sangue , Prognóstico , Biomarcadores Tumorais/genética , Feminino , Masculino , Regulação Neoplásica da Expressão Gênica , Transcriptoma , Pessoa de Meia-Idade , IdosoRESUMO
Background: The interaction between cancer cells and the tumor microenvironment is of critical importance in liver cancer. Jiedu Granule formula (JDF) has been shown to minimize the risk of recurrence and metastasis following liver cancer resection. Investigating the mechanism underlying the therapeutic effects of JDF can extend its field of application and develop novel treatment approaches. Methods: We established a rat liver orthotopic transplantation tumor model, and recorded the prognostic effects of JDF adjuvant therapy on the recurrence and metastasis of liver cancer. Liver and lung tissues were collected for immunofluorescence staining and H&E staining, respectively. In addition, THP-1 cells were incubated with PMA and IL-4 to induce them to differentiate into M2 macrophages. CSF-1 expression was knocked down using lentivirus to determine the function of CSF-1. Liver cancer cells were cultured with a conditioned medium (CM) or co-cultured with macrophages. Cell viability was determined using the MTT assay. The levels of CSF-1, CSF-1R, E-cadherin, N-cadherin, PI3K, AKT, and cleaved caspase-3 were detected using ELISA, Western blotting and qPCR. The ability of cells to migrate was assessed using cell scratch and transwell assays. Apoptosis was evaluated using flow cytometry. Results: The JDF treatment decreased the risk of liver cancer metastasis after surgery and the infiltration of CD206/CD68 cells in liver cancer tissue. In cell experiments, JDF showed effects in suppressing M2 macrophages activity and downregulating the expression of CSF-1 and CSF-1R. The concentration of CSF-1 in the supernatant was also lower in the JDF-treated group. Futhermore, M2-CM was found to promote cancer cell migration and epithelial-mesenchymal transition (EMT); however, these effects were weakened after administering JDF. Knocking down endogenous CSF-1 in M2 macrophages resulted in a comparable suppression of cancer cell migration and EMT. Additionally, JDF treatment inhibited activation of the PI3K/AKT pathway, thus promoting the apoptosis of M2 macrophages. Conclusions: Treatment with JDF reduced the EMT and migratory capacity of liver cancer cells, which might be attributed to the inhibition of M2 macrophage infiltration and interruption of the CSF-1/PI3K/AKT signaling pathway. This mechanism may hold significant implications for mitigating the risk of metastatic spread in the aftermath of hepatic surgery.
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BACKGROUND: Fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) and diffusion-weighted magnetic resonance imaging (DWI or DW-MRI) are tools for the diagnosis of pancreatic cancer. However, comparison of their diagnostic performance remains unknown. PURPOSE: To indirectly compare the diagnostic value of DWI and FDG-PET/CT in the detection of pancreatic cancer. MATERIAL AND METHODS: A literature search of PubMed, Embase, and Cochrane Library electronic databases for articles published through May 2018 yielded 875 articles. For the meta-analysis, we included 26 studies evaluating the efficacy of DWI and FDG-PET/CT for determining pancreatic cancer with a total of 1377 patients. QUADAS (Quality Assessment of Diagnostic Accuracy Studies) was used to assess the study quality. Sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the receiver operating characteristic curves (AUC) with their 95% confidence intervals were calculated for each individual study. RESULTS: There were no significant differences between DWI and FDG-PET/CT for sensitivity, specificity, PLR, NLR, or DOR, while DWI AUC was higher than that of FDG-PET/CT for the detection of pancreatic cancer. CONCLUSION: The diagnostic value of both DWI and FDG-PET/CT were comparable and, hence, both techniques seem to be equally useful tools for the diagnosis of pancreatic cancer.
Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Fluordesoxiglucose F18 , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Radiofarmacêuticos , Diagnóstico Diferencial , Humanos , Pâncreas/diagnóstico por imagem , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Saikosaponin-d (SSd) is one of the major triterpenoid saponins derived from Bupleurum falcatum L., which has been reported to possess antifibrotic activity. At present, there is little information regarding the potential target of SSd in hepatic stellate cells (HSCs), which serve an important role in excessive extracellular matrix (ECM) deposition during the pathogenesis of hepatic fibrosis. Our recent study indicated that SSd may be considered a novel type of phytoestrogen with estrogenlike actions. Therefore, the present study aimed to investigate the effects of SSd on the proliferation and activation of HSCs, and the underlying mechanisms associated with estrogen receptors. In the present study, a rat HSC line (HSCT6) was used and cultured with dimethyl sulfoxide, SSd, or estradiol (E2; positive control), in the presence or absence of three estrogen receptor (ER) antagonists [ICI182780, methylpiperidinopyrazole (MPP) or (R,R)-tetrahydrochrysene (THC)], for 24 h as pretreatment. Oxidative stress was induced by exposure to hydrogen peroxide for 4 h. Cell proliferation was assessed by MTT growth assay. Malondialdehyde (MDA), CuZn-superoxide dismutase (CuZn-SOD), tissue inhibitor of metalloproteinases-1 (TIMP-1), matrix metalloproteinase-1 (MMP-1), transforming growth factor-ß1 (TGF-ß1), hydroxyproline (Hyp) and collagen-1 (COL1) levels in cell culture supernatants were determined by ELISA. Reactive oxygen species (ROS) was detected by ï¬ow cytometry. Total and phosphorylated mitogen-activated protein kinases (MAPKs) and α-smooth muscle actin (α-SMA) were examined by western blot analysis. TGF-ß1 mRNA expression was determined by RT-quantitative (q)PCR. SSd and E2 were able to significantly suppress oxidative stressinduced proliferation and activation of HSCT6 cells. Furthermore, SSd and E2 were able to reduce ECM deposition, as demonstrated by the decrease in transforming growth factorß1, hydroxyproline, collagen1 and tissue inhibitor of metalloproteinases1, and by the increase in matrix metalloproteinase1. These results suggested that the possible molecular mechanism could involve downregulation of the reactive oxygen species/mitogenactivated protein kinases signaling pathway. Finally, the effects of SSd and E2 could be blocked by coincubation with ICI182780 or THC, but not MPP, thus indicating that ERß may be the potential target of SSd in HSCT6 cells. In conclusion, these findings suggested that SSd may suppress oxidative stressinduced activation of HSCs, which relied on modulation of ERß.