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.

Most cervical cancer patients worldwide receive surgical treatments, and yet the current International Federation of Gynecology and Obstetrics (FIGO) staging system do not consider surgical-pathologic data. We propose a more comprehensive and prognostically valuable surgical-pathologic staging and scoring system (SPSs).

This study aimed to investigate the role of B7-H3 in chemotherapy resistance of pancreatic cancer cells and discover the potential signal transduction pathway and molecular targets involved.

Lymph node metastasis commonly occurs in gastric cancer. Previous studies have demonstrated that the overexpression of lymphatic microvessel density (LVD) is correlated with various malignancies. To evaluate the potential role of LVD in various malignancies, we conducted a systematic review and meta-analysis to thoroughly investigate the association of LVD expression with tumor progression and survival in gastric cancer. We performed a comprehensive search of common databases and selected studies demonstrating the relationship between LVD expression and gastric cancer prognosis. Hazard ratios (HR) were used to determine the value of LVD for predicting gastric cancer metastasis and prognosis. The data were extracted from the included studies and pooled with the appropriate effects model using STATA 12.0. The results showed that high LVD expression obviously impacted the prognosis of gastric cancer, based on an overall survival (OS) HR of 2.58 (95% CI: 1.91-3.48, P < 0.001) and a disease-free survival (DFS) HR of 2.51 (95% CI: 1.35-4.68, P = 0.004) in the univariate analysis. In addition, the results of the multivariate analysis indicated a remarkable relationship between high LVD expression and gastric neoplasm prognosis. The pooled OS HR was 4.12 (95% CI: 3.45-4.91, P < 0.001). The current meta-analysis shows that high LVD is closely related to tumor metastasis and poor prognosis in gastric malignancy. LVD could be a key factor in tumor lymphatic metastasis. Moreover, LVD is likely a potential index and an effective biomarker for the prediction of patient prognosis.

U16-binding protein 4 (ULBP4), a human ligand for natural killer group 2, member D (NKG2D) receptor on NK cells and subsets of T cells, is thought to activate anticancer immune responses. However, the expression pattern and prognostic effect of ULBP4 in nasopharyngeal carcinoma (NPC) has not been investigated. We first compared ULBP4 expression between archival 15 NPC tissues and 8 normal nasopharynx (NP) tissues using qPCR. Then ULBP4 expression among 111 NPC specimens was validated on immunohistochemical examination. In addition, the association of ULBP4 expression with clinical characteristics and survival outcomes was analyzed. Furthermore, the impact of ULBP4 expression in NPC cells on the cytotoxic activity of NK cells was investigated. Both mRNA and protein ULBP4 expressions of NPC tissues were significantly lower than those in normal NP tissues. However, no association of ULBP4 expression with clinical characteristics was observed. Patients with NPC having decreased expression of UBLP4 had significantly poorer overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) than those with preserved levels of ULBP4. On multivariate analyses, low expression of ULBP4 was of borderline significance for OS, PFS, and DMFS (P = 0.060, 0.053, and 0.076, respectively). Further, LDH analysis demonstrated that the cytotoxic activitity of NK cells against C666-1 or 5-8F NPC cells with lenti-ULBP4 was considerably increased as compared to those with lenti-vector at various E/T ratios. Hence, restoration of ULBP4 expression may be a novel therapeutic strategy for treatment of NPC. However, further study is required to confirm these findings.

The oncogenic K-Ras can transform various mammalian cells and plays a critical role in development of pancreatic cancer. MicroRNAs (miRNA) have been shown to contribute to tumorigenic progression. However, the nature of miRNAs involved in K-Ras transformation remains to be investigated. Here, by using microarray we identified miR-155 as the most upregulated miRNA after both acute and prolonged activation of K-Ras in a doxycyline-inducible system. Pharmacological inhibition of MAPK and NF-κB pathway blocked the induction of miR-155 in response to K-Ras activation. Overexpression of miR-155 caused inhibition of Foxo3a, leading to decrease of major antioxidants including SOD2 and catalase, and enhanced pancreatic cell proliferation induced by ROS generation. Importantly, correlations of K-Ras, miR-155 and Foxo3a were also validated in human pancreatic cancer tissues. Therefore, we propose that miR-155 plays an important role in oncogenic K-Ras transformation mediated by cellular redox regulation.

KRAS is a frequently mutated oncogene in lung cancer and among the most refractory to EGFR targeted therapy. Recently, preclinical evidence in pancreatic cancer has demonstrated that mutant KRAS can be regulated by EGFR. However, the distinct correlation between the EGFR/HER family members and mutant KRAS has not been investigated. Here, we show that non-small cell lung cancer cell lines harboring differing isoforms of mutant KRAS, can be broadly divided into EGFR/HER dependent and EGFR/HER independent groups. Combined therapeutic targeting of EGFR, HER2 and HER3 in isoforms regulated by extracellular growth signals promotes in vitro and in vivo efficacy. We also provide evidence that depletion of EGFR via RNA interference specifically abolishes the EGFR/KRAS interaction in the dependent subset. Taken together, these findings suggest that upstream inhibition of the EGFR/HER receptors may be effective in treating a subset of KRAS mutant lung cancers.

In cancer cells, failure of chemotherapy is often caused by the ATP-binding cassette subfamily B member 1 (ABCB1), and few drugs have been successfully developed to overcome ABCB1-mediated multi-drug resistance (MDR). To suppress ABCB1 activity, we previously designed and synthesized a new series of derivatives based on 20(S)-protopanoxadiol (PPD). In the present study, we investigated the role of PPD derivatives in the function of ABC transporters. Non-toxic concentrations of the PPD derivative PPD12 sensitized ABCB1-overexpressing cells to their anti-cancer substrates better than either the parental PPD or inactive PPD11. PPD12 increased intracellular accumulation of adriamycin and rhodamine123 in resistant cancer cells. Although PPD12 did not suppress the expression of ABCB1 mRNA or protein, it stimulated the activity of ABCB1 ATPase. Because PPD12 is a competitive inhibitor, it was predicted to bind to the large hydrophobic cavity of homology-modeled human ABCB1. PPD12 also enhanced the efficacy of adriamycin against ABCB1-overexpressing KB/VCR xenografts in nude mice. In conclusion, PPD12 enhances the efficacy of substrate drugs in ABCB1-overexpressing cancer cells. These findings suggest that a combination therapy consisting of PPD12 with conventional chemotherapeutic agents may be an effective treatment for ABCB1-mediated MDR cancer patients.

In the present study, we conducted a comprehensive analysis on the clinical roles of p27 protein and p27 gene in digestive tract cancers (DTCs). First, we performed immunohistochemistry staining and found that p27 protein was down-regulated in DTCs. Then we collected 62 publications and calculated the combined hazard ratios (HRs), odds ratios (ORs) and 95% confidence intervals (95% CIs) to clarify the relationships of p27 protein expression with prognoses and clinicopathological parameters. The overall HRs indicated that the down-regulated p27 protein was an independent prognostic biomarker for overall survival (HR: 1.58, 95% CI: 1.38-1.81, P < 0.0001) but not for disease-free survival and cancer-specific survival. The combined ORs indicated that a low expression of p27 protein was positively related to lymph node metastasis (OR: 2.15, 95% CI: 1.57-2.96, P < 0.0001), distant metastasis (OR: 2.02, 95% CI: 1.12-3.63, P = 0.019) and pathology grading (OR: 2.14, 95% CI: 1.75-2.62, P < 0.0001). Additionally, 60 DTCs-related microarray and RNA-seq datasets were obtained to investigate the expression level and clinical value of p27 gene in DTCs patients. We found that the expression level of p27 gene in DTCs was similar to that in normal controls. And no significant associations of p27 gene expression with prognoses and clinicopathological factors were observed. In conclusion, according to our results, it was p27 protein, but not p27 gene, that can function as an effective biomarker to predict the clinical outcome in patients with DTCs. The down-regulation of p27 protein in DTCs may not result from the altered expression of p27 gene.

Astrocyte elevated gene-1 (AEG-1) is related to the tumorigenesis and deterioration of different cancers, including non-small cell lung cancer (NSCLC). However, the effect of AEG-1 in NSCLC remains unclear. In this study, we aimed to investigate the clinical significance and effect of AEG-1 on biological function of NSCLC.

Long non-coding RNAs have been shown to be associated with cancer development and progression, demonstrating potential applications as novel diagnostic or prognostic molecular markers in clinical management and treatment. However, the functional significance of lncRNAs in the development and malignant progression of gliomas is still unclear and needed to be further explored. we first obtained genome-wide lncRNA expression profiles in a large cohort of patients with gliomas from the Gene Expression Omnibus database using microarray probes repurposing method and investigated the lncRNA expression patterns during the tumorigenesis and malignant progression of gliomas. By using differential expression analysis, we identified a large number of lncRNAs that were associated with the tumorigenesis and malignant progression of gliomas in the training dataset and showed their robustness in the testing dataset. Subsequently, we identified a novel four-lncRNA signature which was closely related to the prognosis of patients with GBM. The prognostic value of this signature was verified in the test set of 80 patients. Functional analysis suggested that the four lncRNAs associated with survival of patients with GBM may be involved in cancer-related biological processes and pathways and their deregulation may lead to GBM tumorigenesis and progression. These novel lncRNA biomarkers will improve our understanding of the molecular mechanisms during the development and progression of glioma and provide novel diagnostic or prognostic markers and therapeutic targets for gliomas.

Pulmonary large cell carcinoma (LCC) was re-defined under the 2015 WHO classification criteria. However, the clinicopathological features and genetic mutation statuses of Chinese LCC patients based on the new classification have rarely been investigated. Twenty-four Chinese surgically resected LCC patients previously diagnosed under the 2004 WHO criteria were re-classified under the 2015 WHO criteria. Genetic analysis was performed using next-generation sequencing of 46 cancer-related genes. The correlation of clinicopathological and genetic data was further analyzed. Eight patients were re-defined as LCCs, and 16 patients were defined as non-LCCs under the refined criteria. All LCC patients were male, and 7 patients were smokers. No significant differences in age, gender, smoking status, primary site, TNM staging and overall survival were observed between the LCC and non-LCC patients under the refined criteria. Four of the 8 LCC patients presented TP53 mutations, and no somatic mutations were detected in the other 4 LCCs under the refined criteria. For the 16 non-LCCs, not only TP53 and KRAS but also EGFR, KIT, PIK3CA, PTEN, IDH1, APC, ATM and BRAF mutations were also observed. In addition, LCCs without TP53 mutations did not present any gene mutations under the 2004 or 2015 WHO criteria. Importantly, the patients with TP53 mutation exhibited a trend with a worse survival outcome at the time of follow-up. The new WHO diagnosis criteria have superior performance in precise molecular classification for LCC patients.

Growing evidence has shown that long non-coding RNAs (lncRNAs) can serve as prospective markers for survival in patients with colorectal adenocarcinoma. However, most studies have explored a limited number of lncRNAs in a small number of cases. The objective of this study is to identify a panel of lncRNA signature that could evaluate the prognosis in colorectal adenocarcinoma based on the data from The Cancer Genome Atlas (TCGA). Altogether, 371 colon adenocarcinoma (COAD) patients with complete clinical data were included in our study as the test cohort. A total of 578 differentially expressed lncRNAs (DELs) were observed, among which 20 lncRNAs closely related to overall survival (OS) in COAD patients were identified using a Cox proportional regression model. A risk score formula was developed to assess the prognostic value of the lncRNA signature in COAD with four lncRNAs (LINC01555, RP11-610P16.1, RP11-108K3.1 and LINC01207), which were identified to possess the most remarkable correlation with OS in COAD patients. COAD patients with a high-risk score had poorer OS than those with a low-risk score. The multivariate Cox regression analyses confirmed that the four-lncRNA signature could function as an independent prognostic indicator for COAD patients, which was largely mirrored in the validating cohort with rectal adenocarcinoma (READ) containing 158 cases. In addition, the correlative genes of LINC01555 and LINC01207 were enriched in the cAMP signaling and mucin type O-Glycan biosynthesis pathways. With further validation in the future, our study indicates that the four-lncRNA signature could serve as an independent biomarker for survival of colorectal adenocarcinoma.

Recent studies suggest that SF3B1 might be related to poor prognosis in CLL, but the results remain controversial. This meta-analysis was performed to clarify the relationship between SF3B1 mutation and prognosis in patients with CLL. The relevant published reports were searched in PubMed, EMBASE, and Web of Science. A total of 13 articles were included in this meta-analysis as they met the inclusion and exclusion criteria. The hazard ratios (HRs) and corresponding 95% confidence intervals (95%CIs) for progression free survival (PFS) and/or overall survival (OS) were extracted from each eligible study. The pooled HR evaluating SF3B1 mutation on PFS was 1.81(95%CI 1.33-2.46, I2=78.9%, P<0.001) and on on OS was 2.57(95%CI 1.68-3.94, I2=79.3%, P<0.001) by random effects model. In conclusion, SF3B1 mutation was significantly associated with poor PFS and OS in CLL. It could be consider as a potential prognostic factor in patients with CLL.

Scholars are striving to apply molecular biology involving long non-coding RNA (lncRNA) in the prognostication of papillary thyroid cancer (PTC). However, the clinical role of lncRNAs in the prognostic setting of PTC is still unclear. Herein, a comprehensive inquiry was performed to screen lncRNA expression profiling with 507 PTC patients from The Cancer Genome Atlas RNA-sequencing datasets. A total of 734 lncRNAs were detected to be aberrantly expressed, among which three novel lncRNAs including AC079630.2, CRNDE and CTD-2171N6.1 were markedly related to the progression and survival of PTC. Furthermore, the aberrant expression of these lncRNAs could be verified by other cohorts from gene expression omnibus (GEO) as detected by microarrays. Next, we established a three-lncRNA signature and divided the PTC patients into two subgroups of high- and low-risk. Interestingly, patients with high-risk tended to gain obviously poorer outcome. Most importantly, this three-lncRNA signature was an independent biomarker to predict the patient survival of PTC. The accurate molecular roles of these three lncRNAs remains unclarified and warrants further characterization, but our current data propose that they might play pivotal roles in PTC tumorigenesis and more importantly, these novel lncRNAs are closely related to patients' survival. These discoveries will have far-reaching consequences with respect to molecular prediction of PTC.

Individuals with ulcerative colitis (UC) are at a high risk for developing colorectal cancer (CRC). Huangqin Decoction (HQD), a traditional Chinese medicinal formula chronicled in the Shang Han Lun, is commonly used to treat gastrointestinal symptoms. However, experimental evidence for supporting the clinical practice is lacking. This study used modern biomedical approaches to investigate the protective/preventive effects of HQD in dextran sulfate sodium (DSS)-induced acute/chronic UC and azoxymethane (AOM)/DSS-induced CRC in mice. HQDs were prepared in 4 different ways: HQD-1 and HQD-2 were prepared in boiling water, whereas HQD-3 and HQD-4 were prepared in heated ethanol (70%). For HQD-1 and HQD-3, the 4 constituent herbs were processed together, whereas for HQD-2 and HQD4, these herbs were processed individually and then combined. The mice were administered 9.1 g/kg HQD via oral gavage daily. HQD-1 significantly inhibited DSS-induced acute UC, whereas HQD-3 and HQD-4 exhibited mild ameliorative effects; but HQD-2 had no protective effect and resulted in a higher mortality rate. This higher mortality rate may be due to the greater abundance of baicalein and wogonin in HQD-2 than HQD-1. Furthermore, HQD-1 protected against DSS-induced chronic UC and significantly inhibited AOM/DSS-induced CRC in mice. HQD-1 also inhibited the production of inflammatory cytokines and increased antioxidant capacity both in chronic DSS and AOM/DSS treated mice. Overall, HQD-1 inhibits the development of acute/chronic colitis and prevents colitis-associated CRC, possibly by inhibiting inflammation and preventing oxidative stress induced cellular damage.

This comprehensive investigation was performed to evaluate the expression level and potential clinical value of NEAT1 in digestive system malignancies. A total of 57 lncRNA datasets of microarray or RNA-seq and 5 publications were included. The pooled standard mean deviation (SMD) indicated that NEAT1 was down-regulated in esophageal carcinoma (ESCA, SMD = -0.35, 95% CI: -0.5~-0.20, P < 0.0001) and hepatocellular carcinoma (HCC, SMD = -0.47, 95% CI: -0.60~-0.34, P < 0.0001), while in pancreatic cancer (PC), NEAT1 was up-regulated (SMD = 0.45, 95% CI: 0.2~0.71, P = 0.001). However, NEAT1 expression in gastric cancer (GC), colorectal cancer (CRC), biliary tract cancer (BTC) and gallbladder carcinoma (GBC) showed no significant difference between cancer and control groups. The pooled area under the curve values for ESCA, GC, CRC, PC and HCC were 0.60, 0.89, 0.81, 0.77 and 0.69, respectively. Furthermore, our result demonstrated that a high expression of NEAT1 predicted an unfavorable prognosis in patients with digestive system malignancies (HR: 1.50, 95% CI: 1.28-1.76, P < 0.0001). Our study suggests that NEAT1 may play different roles in the initiation and progression of digestive system cancers and could be a potential diagnostic and prognostic biomarker in patients with digestive system carcinomas. Further and stricter studies with a larger number of cases are necessary to strengthen our conclusions.

Polo-like kinase 1 (PLK1) is a multi-functional protein and its aberrant expression is a driver of cancerous transformation and progression. To increase our understanding of the clinical value and potential molecular mechanism of PLK1 in gastric cancer (GC), we performed this comprehensive investigation. A total of 25 datasets and 12 publications were finally incorporated. Additional immunohistochemistry was conducted to validate the expression pattern of PLK1 in GC. The pooled standard mean deviation (SMD) indicated that PLK1 mRNA was up-regulated in GC (SMD=1.21, 95% CI: 0.65-1.77, P< 0.001). Similarly, the pooled odds ratio (OR) revealed that PLK1 protein was overexpressed in GC compared with normal gastric tissue (OR=12.12, 95% CI: 5.41-27.16, P<0.001). The area under the curve (AUC) of the summary receiver operating characteristic (SROC) curve was 0.86. Furthermore, our results demonstrated that GC patients with PLK1 overexpression were significantly associated with unfavorable overall survival (HR =1.54, 95% CI: 1.30-1.83, P<0.001), lymph node metastasis (OR = 1.78, 95% CI: 1.13-2.80, P=0.013) and advanced TNM stage (OR=1.48, 95% CI: 1.02-2.15, P=0.038). Altogether, 100 similar genes were identified by Gene Expression Profiling Interactive Analysis (GEPIA) and further with gene-set enrichment analysis. These genes were related to gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways relevant to the cell cycle. Gene set enrichment analysis (GSEA) indicated that PLK1 is associated with various cancer-related pathways. Collectively, this study suggests that PLK1 overexpression could play vital roles in the carcinogenesis and deterioration of GC via regulating tumor-related pathways.

The prognostic value of long non-coding RNAs (lncRNAs) in patients with soft-tissue sarcoma has rarely been unraveled. The aim of the study was to find a lncRNA signature to predict the clinical outcome and survival in soft-tissue sarcoma based on the high-throughput RNA-seq data from The Cancer Genome Atlas (TCGA) database. The lncRNAs which closely correlated with overall survival in 258 soft-tissue sarcoma patients were identified with Cox proportional regression model. Ten lncRNAs, including RP11-560J1.2, AP001432.14, RP4-665J23.1, LINC00680, AC006129.2, RP11-230G5.2, BACH1-IT2, RP11-274B21.9, RP11-504A18.1 and RP11-713P17.3, were selected to calculate a risk score. The risk score could effectively predict patients' outcome, such as the status of mitotic count of tumor cells, person neoplasm cancer and residual tumor. More inspiringly, the risk score generated from the 10-lncRNA signature was an independent prognostic indicator for soft-tissue sarcoma patients. Overall, this 10-lncRNA signature gains the potential as an effective prognostic tool for soft-tissue sarcoma as part of the integrated clinical RNA-seq program.

The alterations in microenvironment upon chronic arsenic exposure may contribute to arsenic-induced lung carcinogenesis. Immune cells, such as macrophages, play an important role in mediating the microenvironment in the lungs. Macrophages carry out their functions after activation. There are two activation status for macrophages: classical (M1) or alternative (M2); the latter is associated with tumorigenesis. Our previous work showed that long-term arsenic exposure induces transformation of lung epithelial cells. However, the crosstalk between epithelial cells and macrophages upon arsenic exposure has not been investigated. In this study, using a co-culture system in which human lung epithelial cells are cultured with macrophages, we determined that long-term arsenic exposure polarizes macrophages towards M2 status through ROS generation. Co-culture with epithelial cells further enhanced the polarization of macrophages as well as transformation of epithelial cells, while blocking macrophage M2 polarization decreased the transformation. In addition, macrophage M2 polarization decreased autophagy activity, which may account for increased cell transformation of epithelial cells with co-culture of macrophages.