Metabolic syndrome (MetS) has been shown to be associated with an increased risk of gastric cancer. However, the impact of MetS on gastric cancer mortality remains largely unknown. Here, we prospectively examined the prediction of preoperative MetS for gastric cancer mortality by analyzing a subset of data from the ongoing Fujian prospective investigation of cancer (FIESTA) study. This study was conducted among 3012 patients with gastric cancer who received radical gastrectomy between 2000 and 2010. The latest follow-up was completed in 2015. Blood/tissue specimens, demographic and clinicopathologic characteristics were collected at baseline. During 15-year follow-up, 1331 of 3012 patients died of gastric cancer. The median survival time (MST) of patients with MetS was 31.3 months, which was significantly shorter than that of MetS-free patients (157.1 months). The coexistence of MetS before surgery was associated with a 2.3-fold increased risk for gastric cancer mortality (P < 0.001). The multivariate-adjusted hazard ratios (HRs) were increased with invasion depth T1/T2 (HR = 2.78, P < 0.001), regional lymph node metastasis N0 (HR = 2.65, P < 0.001), positive distant metastasis (HR = 2.53, P < 0.001), TNM stage I/II (HR = 3.00, P < 0.001), intestinal type (HR = 2.96, P < 0.001), negative tumor embolus (HR = 2.34, P < 0.001), and tumor size ≤ 4.5 cm (HR = 2.49, P < 0.001). Further survival tree analysis confirmed the top splitting role of TNM stage, followed by MetS or hyperglycemia with remarkable discrimination ability. In this large cohort study, preoperative MetS, especially hyperglycemia, was predictive of significant gastric cancer mortality in patients with radical gastrectomy, especially for early stage of gastric cancer.
This prospective study sought to investigate the prediction of preoperative metabolic syndrome and its components for the risk of colorectal cancer (CRC) mortality by analyzing a subset of data from the ongoing Fujian prospective investigation of cancer (FIESTA) study. In total, 1,318 CRC patients who received radical resection were consecutively enrolled between January 2000 and December 2008. The median follow-up time was 58.6 months, with 412 deaths from CRC. The CRC patients with metabolic syndrome had significantly shorter median survival time (MST) than those without (50.9 vs. 170.3 months, p < 0.001). Among four components of metabolic syndrome, hyperglycemia was the strongest predictor and its presence was associated with shorter MST than its absence (44.4 vs. 170.3 months, p < 0.001). Moreover, the complication of metabolic syndrome in CRC patients was associated with a 2.98-fold increased risk of CRC mortality (hazard ratio [HR] = 2.98, 95% confidence interval [CI]: 2.40-3.69, p < 0.001) after adjusting for confounding factors. The magnitude of this association was especially potentiated in CRC patients with tumor-node-metastasis stage I/II (HR = 3.94, 95% CI: 2.65-5.85, p < 0.001), invasion depth T1/T2 (HR = 5.41, 95% CI: 2.54-11.50, p < 0.001), regional lymph node metastasis N0 (HR = 4.06, 95% CI: 2.85-5.80, p < 0.001) and negative distant metastasis (HR = 3.23, 95% CI: 2.53-4.12, p < 0.001). Further survival tree analysis reinforced the prognostic capability of fasting blood glucose in CRC survival. Our findings convincingly demonstrated that preoperative metabolic syndrome, especially hyperglycemia, was a robust predictor for CRC mortality, and the protection was more obvious in patients with Stage I/II.
Programmed death ligand 1 (PD-L1) expression is a predictive biomarker of the success of PD-1/PD-L1 inhibitor therapy for patients with advanced non-small cell lung cancer (NSCLC) but its role as a prognostic marker for early stage resectable NSCLC remains unclear. Here, we studied PD-L1 expression and tumor infiltrating lymphocytes (TILs) in surgically resectable NSCLC and correlate the finding with clinicopathological features and patient outcomes. Total of 170 archival samples of resectable NSCLC were probed for PD-L1 expression using the clone 22C3 pharmDx kit. The PD-L1 expression was determined by the Tumor Proportion Score (TPS) and classified into TPS <1%, TPS 1 to 49% and TPS ≥50%. The scoring of TILs was from hematoxylin & eosin stained tissue sections using a system for standardized evaluation of TILs in breast cancer. PD-L1 expression was compared with clinical pathological characteristics and survival outcome. Expression of PD-L1 scores of TPS ≥50%, TPS 1 to 49% and TPS <1% were observed in 10.6%, 24.7% and 64.7% of the 170 archival samples, respectively. Positive PD-L1 expression was significantly higher in patients with squamous carcinoma, in those with higher TNM stage and with the presence of TILs. Neither the PD-L1 expression, TIL status, nor their combination was an independent prognosis biomarker of survival when the data was subjected to either univariate or multivariate analysis. The incidence of PDL1 expression appears to be lower in patient with early stage resectable lung cancer. PD-L1 expression and TILs are not prognostic indicators of survival outcome in this population.
Small molecules targeting bromodomains of BET proteins possess strong anti-tumor activities and have emerged as potential therapeutics for cancer. However, the underlying mechanisms for the anti-proliferative activity of these inhibitors are still not fully characterized. In this study, we demonstrated that BET inhibitor JQ1 suppressed the proliferation and invasiveness of gastric cancer cells by inducing cellular senescence. Depletion of BRD4, which was overexpressed in gastric cancer tissues, but not other BET proteins recapitulated JQ1-induced cellular senescence with increased cellular SA-β-Gal activity and elevated p21 levels. In addition, we showed that the levels of p21 were regulated at the post-transcriptional level by BRD4-dependent expression of miR-106b-5p, which targets the 3′-UTR of p21 mRNA. Overexpression of miR-106b-5p prevented JQ1-induced p21 expression and BRD4 inhibition-associated cellular senescence, whereas miR-106b-5p inhibitor up-regulated p21 and induced cellular senescence. Finally, we demonstrated that inhibition of E2F suppressed the binding of BRD4 to the promoter of miR-106b-5p and inhibited its transcription, leading to the increased p21 levels and cellular senescence in gastric cancer cells. Our results reveal a novel mechanism by which BRD4 regulates cancer cell proliferation by modulating the cellular senescence through E2F/miR-106b-5p/p21 axis and provide new insights into using BET inhibitors as potential anticancer drugs.
Chemokine (C-X-C motif) ligand 1 (CXCL1) is a chemotactic cytokine known to regulate cancer progression and invasion. However, the prognostic significance of CXCL1 expression in colorectal cancer (CRC) has not been fully characterized. The present study explored the clinicopathological significance and potential role of CXCL1 in the carcinogenesis and progression of CRC. The protein expression of CXCL1 was measured immunohistochemically in tissue microarrays constructed from 276 CRC patients. CXCL1 expression levels and their associations with clinicopathological characteristics and patient survival were evaluated. The effect of CXCL1 on glycolysis was also examined. High CXCL1 expression was detected in 165 (59.8%) cases. CXCL1 expression was correlated with tumor diameter (P=0.002), T stage (P=0.044), N stage (P=0.005), M stage (P=0.001), lymphovascular invasion (P=0.010), and carcinoembryonic antigen status (P=0.019). High CXCL1 expression was validated as an independent prognostic factor for overall survival (OS) and disease-free survival (DFS) by both univariate and multivariate Cox regression analyses (both P<0.05). Experimentally, expression of CXCL1 was knocked down by stable transfected short hairpin RNA, resulting in a significantly decreased rate of glycolysis both in in vitro assays and in patients’ samples (P<0.05). Silencing the expression of CXCL1 decreased the levels of the glycolytic enzymes GLUT1, HK2, and LDHA. In conclusion, by inducing glycolysis, CXCL1 plays a crucial role in both cancer progression and metastasis in CRC patients. The CXCL1 expression level is an independent prognostic factor for both OS and DFS. Moreover, CXCL1 may serve as a new biomarker and potential therapeutic target for CRC treatment.
The Epstein–Barr virus (EBV) is associated with a variety of cancers, including gastric cancer, which has one of the highest mortality rates of all human cancers. Long non-coding RNAs (lncRNAs) have been suggested to have important causal roles in gastric cancer. However, the interaction between lncRNAs and EBV has not yet been studied. To this end, we sequenced 11,311 lncRNAs and 144,826 protein-coding transcripts from four types of tissue: one non-EBV-infected gastric carcinoma (EBVnGC) and its adjacent normal tissue, and one EBV-associated gastric carcinoma (EBVaGC) and its adjacent normal tissue. Five lncRNAs showed EBVaGC-specific expression; of those, one (SNHG8) was validated using real-time PCR in an independent cohort with 88 paired gastric cancer and adjacent tissue samples. To explore the functions of SNHG8, we identified its mRNA targets on the lncRNA–mRNA co-expression network of the Illumina Body Map, which contains the RNA sequencing data of mRNAs and lncRNAs from 16 normal human tissues. SNHG8 lncRNA was found to affect several gastric cancer-specific pathways and target genes of EBV. Our results reveal the intertwined tumorigenesis mechanisms of lncRNA and EBV and identify SNHG8 as a highly possible candidate biomarker and drug target of gastric cancer.
Some metabolic factors have been shown to be associated with an increased risk of esophageal cancer; however the association with its prognosis is rarely reported. Here, we assessed the prediction of preoperative metabolic syndrome and its single components for esophageal cancer mortality by analyzing a subset of data from the ongoing Fujian prospective investigation of cancer (FIESTA) study. Between 2000 and 2010, patients who underwent three-field lymphadenectomy were eligible for inclusion. Blood/tissue specimens, demographic and clinicopathologic data were collected at baseline. Metabolic syndrome is defined by the criteria proposed by Chinese Diabetes Society. In this study, analysis was restricted to esophageal squamous cell carcinoma (ESCC) due to the limited number of other histological types. The median follow-up in 2396 ESCC patients (males/females: 1822/574) was 38.2 months (range, 0.5–180 months). The multivariate-adjusted hazard ratio (HR) of metabolic syndrome for ESCC mortality was statistically significant in males (HR, 95% confidence interval, P: 1.45, 1.14–1.83, 0.002), but not in females (1.46, 0.92–2.31, 0.107). For single metabolic components, the multivariate-adjusted HRs were significant for hyperglycemia (1.98, 1.68–2.33, < 0.001) and dyslipidemia (1.41, 1.20–1.65, < 0.001) in males and for hyperglycemia (1.76, 1.23–2.51, < 0.001) in females, independent of clinicopathologic characteristics and obesity. In tree-structured survival analysis, the top splitting factor in both genders was tumor-node-metastasis stage, followed by regional lymph node metastasis. Taken together, our findings demonstrate that preoperative metabolic syndrome was a significant independent predictor of ESCC mortality in males, and this effect was largely mediated by glyeolipid metabolism disorder.
Diabetes as a latent risk factor for cancer has been extensively investigated, while its postoperative prognosis for esophageal cancer is rarely reported. We therefore sought to assess whether the elevated fasting blood glucose before surgery was associated with poor survival in esophageal cancer patients by eliciting a subset of data from the ongoing Fujian prospective investigation of cancer (FIESTA) study. Over 15-year follow-up, 2535 patients receiving three-field lymphadenectomy were assessable. Only patients with esophageal squamous cell carcinoma (ESCC) (n=2396) were analyzed due to the lower prevalence of the other histological types. In ESCC patients, the follow-up duration ranged from 0.5 to 180 months (median 38.2 months). The median survival time (MST) was remarkably shorter in males than in females (80.7 vs. 180+ months, Log-rank test: P<0.001). In males, the survival was worse in patients with diabetes than those without (MST: 27.9 vs. 111.1 months, Log-rank test: P<0.001). In females, the survivor was improved in patients with diabetes (MST: 71.5 months), but was still worse than patients without diabetes (MST: 180+ months, Log-rank test: P<0.001). The overall multivariate hazard ratio for per unit increment in fasting blood glucose was 1.11 (95% confidence interval or CI: 1.09-1.14, P<0.001) and 1.08 (95% CI: 1.03-1.13, P=0.002) in males and females, respectively. Further survival tree analysis consolidated the discrimination ability of fasting blood glucose for the survival of ESCC patients. Taken together, our findings convincingly demonstrated that the elevated preoperative fasting blood glucose can predict poor survival of ESCC patients, especially in males.
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