An independent predictor of poor prognosis in locally advanced rectal cancer: rs867228 in formyl peptide receptor 1 (FPR1).
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ABSTRACT:
SUBMITTER: Chiang SF
PROVIDER: S-EPMC8128175 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThere are only limited studies on the long non-coding RNAs (lncRNAs) associated with neoadjuvant chemoradiotherapy (NCRT) response and prognosis of locally advanced rectal cancer (LARC) patients. This study identified lncRNAs associated with NCRT response and prognosis in CRC patients and explored their potential predictive mechanisms.MethodsThe study subjected the LncRNA expression profiles from our previous gene chip data to LASSO and identified a four-lncRNA signature that predicted NCRT response and prognosis. A Cox regression model was subsequently performed to identify the prognostic risk factors. The function of LINC00909, the lncRNA with the most powerful predictive ability, was finally identified in vivo and in vitro using CRC cell lines.ResultsA comparison of the relative lncRNA expression of NCRT-responsive and non-responsive patients revealed four hub lncRNAs: DBET, LINC00909, FLJ33534, and HSD52 with AUC = 0.68, 0.73, 0.73, and 0.70, respectively (all p < 0.05). COX regression analysis further demonstrated that DBET, LINC00909 and FLJ33534 were associated with the DFS in CRC patients. The expression of the four lncRNAs was also significant in LARC patients who had not undergone NCRT (all p < 0.05). A risk score model was subsequently constructed based on the results of the multivariate COX analysis and used to predict NCRT response and prognosis in the CRC and LARC patients. The expression and prognosis of DBET, LINC00909 and FLJ33534 in the CRC tissues were further validated in the R2 platform and Oncomine database. Notably, overexpression of the LINC00909 increased the cell line resistance to the 5-FU and radiotherapy in vivo and in vitro.ConclusionDBET, LINC00909, and FLJ33534 are potential novel biomarkers for predicting NCRT response and prognosis in CRC patients. In particular, LINC00909 is an effective oncogene in CRC that could be used as a novel therapeutic target to enhance NCRT response.
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Project description:Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) expressed on a variety of cell types. Because FPRs play an important role in the regulation of inflammatory reactions implicated in disease pathogenesis, FPR antagonists may represent novel therapeutics for modulating innate immunity. Previously, 4H-chromones were reported to be potent and competitive FPR1 antagonists. In the present studies, 96 additional chromone analogs, including related synthetic and natural isoflavones were evaluated for FPR1 antagonist activity. We identified a number of novel competitive FPR1 antagonists that inhibited fMLF-induced intracellular Ca2+ mobilization in FPR1-HL60 cells and effectively competed with WKYMVm-FITC for binding to FPR1 in FPR1-HL60 and FPR1-RBL cells. Compound 10 (6-hexyl-2-methyl-3-(1-methyl-1H-benzimidazol-2-yl)-4-oxo-4H-chromen-7-yl acetate) was found to be the most potent FPR1-specific antagonist, with binding affinity Ki?100 nM. These chromones inhibited Ca2+ flux and chemotaxis in human neutrophils with nanomolar-micromolar IC50 values. In addition, the most potent novel FPR1 antagonists inhibited fMLF-induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in FPR1-RBL cells. These antagonists were specific for FPR1 and did not inhibit WKYMVM/WKYMVm-induced intracellular Ca2+ mobilization in FPR2-HL60 cells, FPR3-HL60 cells, RBL cells transfected with murine Fpr1, or interleukin 8-induced Ca2+ flux in human neutrophils and RBL cells transfected with CXC chemokine receptor 1 (CXCR1). Moreover, pharmacophore modeling showed that the active chromones had a significantly higher degree of similarity with the pharmacophore template as compared to inactive analogs. Thus, the chromone/isoflavone scaffold represents a relevant backbone for development of novel FPR1 antagonists.
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Project description:Approximately 30% of locally advanced rectal cancer patients might not benefit from chemoradiotherapy; however, the response to neoadjuvant chemoradiotherapy in these cases is difficult to predict. Pim-3 is a member of the provirus integration site for a moloney murine leukemia virus family of proteins that contributes to cell proliferation, survival, and chemotherapy resistance. Therefore, the relationship between Pim-3 expression and response to neoadjuvant chemoradiotherapy in rectal cancer patients is important to evaluate. 175 rectal cancer patients who underwent neoadjuvant treatment enrolled in this study. The relationship between Pim-3 expression on immunohistochemical analysis of rectal cancer tissue, which was obtained before treatment, the response to chemoradiotherapy and survival was investigated. The patients with no Pim-3 expression were more likely to achieve a pathologic complete response to chemoradiotherapy than patients with Pim-3 expression (P?=?0.001). Cox multivariate analysis showed that the significant prognostic factors were Pim-3 expression (P?=?0.003) and the number of neoadjuvant chemotherapy cycles (P?=?0.005) for overall survival. Neoadjuvant chemotherapy cycles (P?=?0.007), adjuvant chemotherapy cycles (P?=?0.004) and pathology types (P?=?0.049) were significant prognostic factors for disease-free survival. Pim-3 is a potential predictive biomarker for the response of rectal cancer to chemoradiotherapy.
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Project description:BackgroundHuman cell division cycle associated 8 (CDCA8) a key regulator of mitosis, has been described as a potential prognostic biomarker for a variety of cancers, such as breast, colon and lung cancers. We aimed to evaluate the potential role of CDCA8 expression in the prognosis of liver cancer by analysing data from The Cancer Genome Atlas (TCGA).MethodsThe Wilcoxon rank-sum test was used to compare the difference in CDCA8 expression between liver cancer tissues and matched normal tissues. Then, we applied logistic regression and the Wilcoxon rank-sum test to identify the association between CDCA8 expression and clinicopathologic characteristics. Cox regression and the Kaplan-Meier method were used to examine the clinicopathologic features correlated with overall survival (OS) in patients from the TCGA. Gene set enrichment analysis (GSEA) was performed to explore possible mechanisms of CDCA8 according to the TCGA dataset.ResultsCDCA8 expression was higher in liver cancer tissues than in matched normal tissues. Logistic regression and the Wilcoxon rank-sum test revealed that the increased level of CDCA8 expression in liver cancer tissues was notably related to T stage (OR = 1.64 for T1/2 vs. T3/4), clinical stage (OR = 1.66 for I/II vs. III/IV), histologic grade (OR = 6.71 for G1 vs. G4) and histological type (OR = 0.24 for cholangiocarcinoma [CHOL] vs. hepatocellular carcinoma [LIHC]) (all P-values < 0.05). Kaplan-Meier survival analysis indicated that high CDCA8 expression was related to a poor prognosis in liver cancer (P = 2.456 × 10-6). Univariate analysis showed that high CDCA8 expression was associated with poor OS in liver cancer patients, with a hazard ratio (HR) of 1.85 (95% confidence interval [CI]: 1.47-2.32; P = 1.16 × 10-7). Multivariate analysis showed that CDCA8 expression was independently correlated with OS (HR = 1.74; CI: 1.25-12.64; P = 1.27 × 10-5). GSEA revealed that the apoptosis, cell cycle, ErbB, MAPK, mTOR, Notch, p53 and TGF-β signaling pathways were differentially enriched in the CDCA8 high expression phenotype.ConclusionsHigh CDCA8 expression is a potential molecular predictor of a poor prognosis in liver cancer.
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Project description:Locally advanced rectal cancer characterized by multiplex kinase activity profiling
2010-08-05 | E-TABM-913 | biostudies-arrayexpress
Project description:Tumor deposit (TD) was associated with poor survival in colorectal cancer. However, its prognostic and staging value in locally advanced rectal cancer (LARC) patients following neoadjuvant chemoradiotherapy (neo-CRT) is controversial. Four hundred and ninety-five LARC patients following neo-CRT and surgery were retrospectively analyzed. Univariate and multivariate analyses were performed using Kaplan-Meier method and Cox proportional hazards regression in all lymph node (LN) -negative and LN-positive patients. Next, we used three methods to classify the counts of LNs and TDs (oN, only LN counts; n1N, counts according to the N1c standards; n2N, total counts of LNs and TDs) to evaluate the impact of TD on N staging. TD-positive patients were associated with more aggressive clinicopathological features. In multivariate analyses, TD was an independent poor prognostic factor of overall survival (OS), disease-free survival (DFS), and local recurrence-free survival in all patients. In LN-negative patients, TD was an independent poor prognostic factor of OS, DFS and distant metastasis-free survival (DMFS). In LN-positive patients, TD has poor prognostic value only in patients with one positive LN. Three multivariate analyses according to three N staging methods showed that oN was not an independent prognostic factor, whereas n1N and n2N were independently associated with poor survival in OS, DFS and DMFS. The n2N method seemed to be better than n1N method. TD is an independent poor prognostic factor in LARC patients following neo-CRT, especially in patients with no more than one positive LN. TD probably should be considered as one positive LN when performing N staging.
| S-EPMC6488131 | biostudies-literature
Project description:Background:Inflammatory response and nutritional status are associated with cancer development and progression. The purpose of this study was to explore whether the preoperative fibrinogen-albumin ratio index (FARI) is related to prognosis and chemoradiotherapy outcome of radical surgery after neoadjuvant chemoradiotherapy (NCRT) in patients with locally advanced rectal cancer (LARC). Methods:In total, 123 patients with LARC who underwent radical surgery after NCRT between June 2012 and December 2018 were collected in this study. Time-dependent receiver operating characteristic (ROC) curve analysis was made to evaluate the ability of the markers for forecasting prognosis. The correlation between FARI and clinicopathological parameters was analyzed. The Kaplan-Meier survival analysis, univariate and multivariate analysis based on Cox proportional hazards models, and subgroup analysis were performed to evaluate overall survival (OS) and disease-free survival (DFS). A nomogram was constructed to evaluate the predictive role of FARI in DFS. Results:The ROC curve analysis showed that the ability of FARI on DFS prediction was superior to those of other inflammatory markers and carcinoembryonic antigen (CEA) (P<0.05). Based on the Youden's index, the optimal cut-off value of FARI was 8.8%. High FARI patients (>8.8%) showed a poor response to NCRT and a decreased DFS rate (P<0.05). In addition, multivariate analysis revealed that FARI (HR=3.098, P=0.033), neutrophil-to-lymphocyte ratio (NLR), and postoperative T stage were independent prognostic factors for DFS in TNM stage III LARC patients. However, FARI failed to distinguish patients with poor OS. Harrell's concordance index (C-index) of the nomogram containing FARI (0.807) was obviously higher than that without it (0.732) among LARC patients who underwent radical surgery after NCRT. Moreover, multivariate analysis revealed FARI (OR=3.044, P=0.012) as an independent predictor for response to NCRT. Conclusion:Among LARC patients who underwent radical surgery after NCRT, preoperative FARI is an independent prognostic factor for DFS and an independent predictor for response to NCRT.
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