Cigarette smoking-related OLC1 overexpression associated with poor prognosis in bladder urothelial carcinoma.

AIMS: To explore the clinical significance of OLC1 and cigarette smoking in bladder urothelial carcinoma (UBC). MATERIALS AND METHODS: OLC1 mRNA expression was detected in 106 UBC samples by mRNA array or reverse real-time PCR. OLC1 protein expression in 114 UBC samples was detected by immunohistochemical staining. Wild-type C57BL/6J mice were injected with cigarette smoke condensate (n = 12) or exposed to cigarette smoke (n = 6) to investigate the correlations between cigarette smoking and OLC1 expression using mRNA array. KEY FINDINGS: The mRNA and protein expression of OLC1 were higher in tumor samples (p < 0.01) and significantly correlated with tumor stage (p < 0.05). OLC1 protein expression and smoking history were correlated with disease-free survival (p < 0.05). OLC1 expression was significantly elevated in smoking patients with higher smoking intensity on both mRNA and protein levels (p < 0.05). Cigarette smoke exposure experiments revealed that OLC1 mRNA overexpressed in bladder uroepithelium of mice. SIGNIFICANCE: OLC1 could serve as a potential prognosis biomarker of UBC, especially for smoking patients.

Screening microRNAs as potential prognostic biomarkers for lung adenocarcinoma.

OBJECTIVE: To screen and identify microRNAs (miRNAs) associated with the prognosis of lung adenocarcinoma (LUAD) using clinical samples and construct a prediction model for the prognosis of LUAD. METHODS: 160 patient samples were used to screen and identify miRNAs associated with the prognosis of LUAD. Differentially expressed miRNAs were analyzed using gene chip technology. The selected miRNAs were validated using samples from the validation sample group. Cox proportional hazards regression was used to construct the model and Kaplan-Meier was used to plot survival curves. Model power was assessed by testing the prognosis of the constructed model using real-time polymerase chain reaction (RT-PCR) data. RESULTS: The data showed that miR-1260b, miR-21-3p and miR-92a-3p were highly expressed in the early recurrence and metastasis group, while miR-2467-3p, miR-4659a-3p, miR-4514, miR-1471 and miR-3621 were lowly expressed. It was further confirmed that miR-21-3p was significantly highly expressed in the early recurrence and metastasis group (p = 0.02). Receiver operating characteristic (ROC) curve results showed cut-off point value of 0.0172, sensitivity of 88.2% and specificity of 100%. The predictive results of the constructed model were in good agreement with the actual prognosis of patients by using the validation sample test (Kappa = 0.426, p < 0.001), with a model sensitivity of 74.4%, a specificity of 68.3%, and an accuracy of 71.3%. CONCLUSION: miRNAs associated with the prognosis of patients with stage I LUAD were screened and validated, and a risk model for predicting the prognosis of patients was constructed. This model has good consistency with the actual prognosis of patients.

Radiomics Signature to Predict Prognosis in Early-Stage Lung Adenocarcinoma (≤3 cm) Patients with No Lymph Node Metastasis.

OBJECTIVES: To investigate the predictive ability of radiomics signature to predict the prognosis of early-stage primary lung adenocarcinoma (≤3 cm) with no lymph node metastasis (pathological stage I). MATERIALS AND METHODS: This study included consecutive patients with lung adenocarcinoma (≤3 cm) with no lymph node metastasis (pathological stage I) and divided them into two groups: good prognosis group and poor prognosis group. The association between the radiomics signature and prognosis was explored. An integrative radiomics model was constructed to demonstrate the value of the radiomics signature for individualized prognostic prediction. RESULTS: Six radiomics features were significantly different between the two prognosis groups and were used to construct a radiomics model. On the training and test sets, the area under the receiver operating characteristic curve value of the radiomics model in discriminating between the two groups were 0.946 and 0.888, respectively, and those of the pathological model were 0.761 and 0.798, respectively. A radiomics nomogram combining sex, tumor size and rad-score was built. CONCLUSION: The radiomics signature has potential utility in estimating the prognosis of patients with pathological stage I lung adenocarcinoma (≤3 cm), potentially enabling a step forward in precision medicine.

Exploration of a Novel Prognostic Risk Signature and Its Effect on the Immune Response in Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic carcinoma with different molecular characteristics and clinical outcomes. In this work, we aimed to establish a novel gene signature that could predict the prognosis of NPC patients. A total of 13 significant genes between the recurrence/metastasis (RM) group and the no recurrence/metastasis (no-RM) group were identified by machine learning from RNA-Seq data including 60 NPC tumor biopsies. Based on these genes, a 4-mRNA signature (considering U2AF1L5, TMEM265, GLB1L and MLF1) was identified. Receiver operating characteristic (ROC) and Kaplan-Meier (K-M) analyses indicated that this signature had good prognostic value for NPC. The overall survival (OS) and progression-free survival (PFS) of the patients in the high-risk group were significantly shorter than those of the patients in the low-risk group (p = 0.00126 and p = 0.000059, respectively). The area under the ROC curve (AUC) values of the 4-mRNA signature were higher than those of T stage and N stage for OS (0.893 vs 0.619 and 0.582, respectively) and PFS (0.86 vs 0.538 and 0.622, respectively). Furthermore, the 4-mRNA signature was closely associated with cell proliferation and the immune response. The expression of GLB1L and TMEM265 was associated with the level of tumor-infiltrating immune cells (r > 0.4, p < 0.05). We have validated the model through measuring the expression levels of the 4-mRNA signature by qRT-PCR, in an independent cohort of NPC patients. Here, we report a novel gene signature that can serve as a new tool for predicting the prognosis of NPC patients.

CYR61 as a potential biomarker for the preoperative identification of muscle-invasive bladder cancers.

BACKGROUND: The biological behaviors, clinical treatment, prognosis of non-muscle-invasive bladder cancers (NMIBCs) and muscle-invasive bladder cancers (MIBCs) are distinct. Accurate staging is pivotal in optimal therapy planning for bladder cancers (BCs). However, it is insufficient for urologists in preoperative determining whether the tumor has invaded within the muscularis propria through cystoscope and imaging methods (CT or MRI). Therefore, searching for ideal biomarkers from the tumor tissues and urine is important for identifying the MIBCs preoperatively. METHODS: Differentially expressed genes between NMIBCs and MIBCs were identified by microarray analysis and validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemical analysis. The correlation between cysteine-rich angiogenic inducer 61 (CYR61) expression and Kaplan-Meier test evaluated patients' overall survival (OS). CYR61 protein levels were measured using enzyme-linked immunosorbent assay (ELISA) in preoperatively collected urine samples from BC patients. The receiver-operating characteristic (ROC) curve analyzed the diagnostic accuracy of uric CYR61. The siRNA mediated silencing of CYR61 in bladder carcinoma cells was performed using Lipofectamine 2000. Cell migration and invasion were assessed using wound healing and transwell assay, respectively. RESULTS: Differential gene expression analysis using microarray between 14 MIBCs and 16 NMIBCs human tumor samples revealed a significant increase (P<0.001) in the expression of CYR61 in MIBCs compared with NMIBCs. Higher expression of CYR61 in MIBCs was found in additional 54 tumor samples using qRT-PCR. Therefore, the overexpression of CYR61 in MIBCs could be used as a potential biomarker to distinguish between MIBCs and NMIBCs. ELISA detected elevated levels of CYR61 in the urine samples of MIBC patients (average 2.5-fold) compared with NMIBCs, with 72.7% sensitivity and 86.0% specificity to distinguish MIBCs from NMIBCs. Wound healing and transwell assays using CYR61-silenced carcinoma cells indicated the role of CYR61 in cell migration and invasion. CONCLUSIONS: CYR61 expression is higher in MIBCs compared with NMIBCs and can serve as a promising biomarker for the preoperative diagnosis of MIBCs with prognostic value; however, multicentric prospective validation is essential for the further evaluation of CYR61.

Copy Number Variations of CEP63, FOSL2 and PAQR6 Serve as Novel Signatures for the Prognosis of Bladder Cancer.

BACKGROUND: Finding effective prognostic signatures is of great urgency due to the high risk of recurrence and progression of bladder cancer (BC). Although a lot of genetic alterations are involved in the carcinogenesis, none of them were referred in the current risk group stratifications. In this study, we aimed to find significant copy number variations (CNVs) to predict prognosis for BC patients. METHODS: CNVs with high aberration frequencies in BC were explored by array-based comparative genomic hybridization in 65 tumor samples. Candidates were validated in independent groups of BC tumor samples (n=219) and urine samples (n=123). 3D digital PCR was applied for detecting accurate gene copy numbers in BC urine. In order to explore the prognostic value of candidate CNVs, all enrolled patients were followed up for the disease-free survival (DFS). Cox proportional hazards regression analysis was performed to find the independent prognostic factors for DFS. RESULTS: CNVs of CEP63, FOSL2 and PAQR6 with high aberration frequencies (67.7%, 56.9% and 60.0%, respectively) were found in BC tumors. Copy numbers of CEP63, FOSL2 and PAQR6 were gained in 219 tumor samples. CNVs of CEP63 and FOSL2 were correlated with advanced tumor stage and high grade. Retrospective analysis (median follow-up time: 69 months) revealed that CNVs of CEP63 and FOSL2 were independent prognostic factors for DFS of non-muscle-invasive bladder cancer (NMIBC) patients, while CNVs of FOSL2 and PAQR6 were independent prognostic factors for DFS of muscle-invasive bladder cancer (MIBC) patients. Models for predicting DFS were constructed based on CNVs of three genes. Patients with high prognostic indexes tended to have poor DFS. Prognostic index can also help to identify those with worse outcomes among high risk NMIBC patients. Copy number gains of CEP63 and FOSL2 in urine were found to be significantly correlated with poor DFS of NMIBC patients. CONCLUSIONS: CNVs of CEP63, FOSL2 and PAQR6 were capable of predicting DFS and may serve as promising signatures for prognosis of BC.

Abnormally localized DLK1 interacts with NCOR1 in non-small cell lung cancer cell nuclear.

Delta-like homolog 1 (DLK1) regulates noncanonical Notch signaling pathway as ligand. DLK1 was abnormally expressed in a variety of tumors, affecting tumorigenesis and developments. The biological function of DLK1 toward cell proliferation and signaling activation was controversial across different cell types. Two currently known isoforms of DLK1, which are membrane-tethered isoform and soluble isoform, are believed to be the key of DLK1 dual behaviors. While these isoforms are not enough to explain the phenomena, our observations offer the possibility of a third isoform of DLK1. In the present study, we verified the nuclear localization of DLK1 in lung cancer cells. The nuclear localized DLK1 was observed in 107 of 351 non-small cell lung cancer (NSCLC) samples and was associated with tissue differentiation and tumor size. Through co-immunoprecipitation (co-IP) combined mass spectrometry (MS), we identified nuclear receptor corepressor 1 (NCOR1) as DLK1's novel interaction protein and confirmed their interaction in nuclear. We analyzed the expression of NCOR1 in two independent cohorts and demonstrated that NCOR1 is a tumor suppressor and has prognosis potential in lung squamous carcinomas. At last, we analyzed the colocalization of DLK1 and NCOR1 in 147 NSCLC samples by immunohistochemistry (IHC). The result indicated NCOR1 might participate with nuclear localized DLK1 in regulating cell differentiation.

Post-surgical resection prognostic value of combined OPN, MMP7, and PSG9 plasma biomarkers in hepatocellular carcinoma.

Biomarkers for hepatocellular carcinoma (HCC) following curative resection are not currently sufficient for prognostic indication of overall survival (OS) and disease-free survival (DFS). The aim of this study was to investigate the prognostic performance of osteopontin (OPN), matrix metalloproteinase 7 (MMP7), and pregnancy specific glycoprotein 9 (PSG9) in patients with HCC. A total of 179 prospective patients with HCC provided plasma before hepatectomy. Plasma OPN, MMP7, and PSG9 levels were determined by enzyme-linked immunosorbent assay. Correlations between plasma levels, clinical parameters, and outcomes (OS and DFS) were overall analyzed. High OPN ( ⩾ 149.97 ng/mL), MMP7 ( ⩾ 2.28 ng/mL), and PSG9 ( ⩾ 45.59 ng/mL) were prognostic indicators of reduced OS (P < 0.001, P < 0.001, and P = 0.007, respectively). Plasma PSG9 protein level was an independent factor in predicting OS (P = 0.008) and DFS (P = 0.038). Plasma OPN + MMP7 + PSG9 elevation in combination was a prognostic factor for OS (P < 0.001). OPN was demonstrated to be a risk factorassociated OS in stage I patients with HCC and patients with low α-fetoprotein levels ( < 20 ng/mL). These findings suggested that OPN, MMP7, PSG9 and their combined panels may be useful for aiding in tumor recurrence and mortality risk prediction of patients with HCC, particularly in the early stage of HCC carcinogenesis.

Systems biology analysis of the lung cancer­related secretome.

Tumorigenesis is closely and highly associated with developmental biology. The present study aimed to discover and identify marker proteins strongly associated with the occurrence and development of non­small cell lung cancer (NSCLC) in humans and to provide new ideas for investigating lung cancer markers by combining biological analyses of embryonic development. We established primary cultures for samples of tumor and control tissues from 9 patients with NSCLC and collected conditioned medium (CM). Subsequently, we used liquid chromatography and linear ion trap (LTQ) mass spectrometry to isolate and identify proteins in CM samples. Data mining of free proteins was conducted using the analogous analysis strategy in systems biology to obtain important lung cancer­associated proteins (plasma markers). Proteins with significant plasma enrichment in lung cancer patients were detected via enzyme­linked immunosorbent assay (ELISA). We identified 987 high­confidence proteins and established a primary database of free proteins associated with lung cancer. Furthermore, 511 high­confidence proteins were present in CM from primary tissue cultures from at least 2 of the 9 examined cases of lung cancer. Analysis using Gene Set Enrichment Analysis (GSEA) software revealed significant enrichment for 197 proteins from the CM of lung cancer samples in maternal­placental interface expression profiles for a mid­term placenta with strong invasiveness relative to RNA expression profiles for a human full­term placenta after delivery. ELISA results demonstrated that hypoxanthine phosphoribosyltransferase 1 (HPRT1) was associated with worse rates of disease­free survival (DFS) and overall survival (OS). The biological behaviors of embryonic implantation are similar to those of tumor invasion and metastasis, and the information obtained regarding developmental biology could facilitate the interpretation of tumor invasion and metastasis. Therefore, similar biological behaviors combined with analyses at different molecular levels from the perspective of systems biology will provide new ideas for tumor research.

Proliferation genes in lung development associated with the prognosis of lung adenocarcinoma but not squamous cell carcinoma.

There are many similarities between embryonic development and tumorigenesis, and gene expression profiles show that certain correlations exist between the gene signature during development and the clinical phenotypes of different cancers. Our group previously reported the gene expression profiles of human lung development, and the expression of one group of proliferation-related genes (PTN1 genes) steadily decreased during lung development. Here, we examined the prognostic value of PTN1 genes in 5 independent lung adenocarcinoma (ADC) and 5 lung independent squamous cell carcinoma (SCC) microarray datasets and found that the expression levels of PTN1 genes were associated with survival in lung ADC but not lung SCC. All of the lung ADC datasets contained a set of highly correlated genes from PTN1 genes, but the lung SCC datasets had no similar set of genes. We identified 63 unique core genes from the PTN1 genes in the 5 lung ADC datasets: 17 of these core genes appeared in at least 4 of the lung ADC datasets, and the 17 corresponding proteins clearly interacted more strongly with each other in lung ADC than in lung SCC. Moreover, 16 of the 17 core genes play major roles in the G2 /M phase of the cell cycle. These data indicate that proliferation-related genes in lung development have a significant prognostic value for lung ADC; the synergistic effects of the 17 core genes play an important role in lung ADC prognosis. These genes may have significant clinical implications for the treatment and prognosis of lung ADC.

Prognostic value of molecular events from negative surgical margin of non-small-cell lung cancer.

It is hypothesized that the molecular status in negative surgical margin (NSM) is associated with prognosis of cancer patients. In this study, the prognostic relevance of Epithelial-to-Mesenchymal Transition (EMT) molecular events in NSMs in patients with NSCLC was investigated. EMT model was developed, in which the mesenchymal transition of human immortalized bronchial epithelial cell line was induced by TGF-beta1. Gene expression of EMT-induced cells and NSMs from 60 lung squamous cell carcinoma (SCC) patients was profiled by microarray and validated by quantitative RT-PCR. Two independent cohorts (lung SCC, n = 50; NSCLC, n = 54) were employed to validate the prognostic value of candidate genes. A set of 1490 genes were identified in EMT model in vitro. An EMT-like gene-expression pattern by 33 essential genes was optimized in NSMs, and was significantly associated with tumor progression. The 33 genes also exhibited a site-dependent field cancerization effect in the normal-appearing airways adjacent to NSCLCs. In the independent lung SCC cohort, the EMT-like active pattern indicated poor outcome of patients (n = 50, log-rank p = 0.009). Furthermore, in the NSCLC cohort, patients with EMT-like active pattern had shorter predictive survival time (n = 54, log-rank p = 0.02). In conclusion, the existence of EMT-like gene expression in NSMs, may play critical role in tumor progression and be a potential biomarker for prognosis in patients with NSCLC.

[Overexpression of OLC1 in Lung Squamous Cell Carcinoma Tissues is Associated with Poor Prognosis of Patients].

BACKGROUND: OLC1 (overexpressed in lung cancer 1), screened out and cloned in our previous research, is a new gene associated with lung cancer. It is highly expressed in lung cancer and many other malignant tumors, and is associated with poor prognosis of esophageal squamous cell carcinoma, ovarian cancer, breast cancer and colorectal cancer. The aim of this research was to detect the expression level of OLC1 in the tumor tissues of lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) and explore its relationship with the prognosis of lung cancer patients. METHODS: Lung cancer tissues of 108 SCC and 90 ADC was dealed with immunohistochemical staining to detect the expression level of OLC1. The relationship between the expression level of OLC1 and clinical parameters and prognosis was analyzed. RESULTS: The rate of high expression of OLC1 staining in ADC was significantly higher than that in SCC (87.5% vs 55.3%, P<0.001). The overexpression of OLC1 in tumor tissues did not have a significant relationship with the prognosis of patients with ADC, but it was related with a poor prognosis of SCC patients as the univariate analysis showed. However the multivariate regression analysis showed that correlation between the overexpression of OLC1 and poor prognosis of SCC patients did not have a statistical significance (P=0.05). CONCLUSIONS: The expression of OLC1 in ADC might be higher than that in SCC. A higher score of OLC1 staining in tumor tissue was associated with a poorer prognosis of patients with SCC, but could not be an independent predictor for a shorter overall survival in patients with SCC.

PSG9 promotes angiogenesis by stimulating VEGFA production and is associated with poor prognosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant solid tumor characterized by rich vascularization. Pregnancy-specific glycoprotein 9 (PSG9) is a member of the carcinoembryonic antigen (CEA)/PSG family and is produced at high levels during pregnancy. We previously identified PSG9 as an HCC-related protein. However, the expression of PSG9 and its regulation during HCC carcinogenesis remain poorly explored. In the present study, we first found that the levels of PSG9 protein were significantly increased in the plasma of HCC patients. PSG9 overexpression also increased the proliferation ability of an HCC cell line. High expression of PSG9 was associated with angiogenesis by accelerating VEGFA expression. In addition, Cox's proportional hazards model analysis revealed that the plasma level of PSG9 was an independent prognostic factor for overall survival. We propose that PSG9 is a novel indicator of prognosis in patients with HCC and could serve as a novel therapeutic target for HCC. Furthermore, our results indicate that PSG9 protein may facilitate the development of HCC by fostering angiogenesis via promoting VEGFA production in cancer cells.

Genomic heterogeneity of multiple synchronous lung cancer.

Multiple synchronous lung cancers (MSLCs) present a clinical dilemma as to whether individual tumours represent intrapulmonary metastases or independent tumours. In this study we analyse genomic profiles of 15 lung adenocarcinomas and one regional lymph node metastasis from 6 patients with MSLC. All 15 lung tumours demonstrate distinct genomic profiles, suggesting all are independent primary tumours, which are consistent with comprehensive histopathological assessment in 5 of the 6 patients. Lung tumours of the same individuals are no more similar to each other than are lung adenocarcinomas of different patients from TCGA cohort matched for tumour size and smoking status. Several known cancer-associated genes have different mutations in different tumours from the same patients. These findings suggest that in the context of identical constitutional genetic background and environmental exposure, different lung cancers in the same individual may have distinct genomic profiles and can be driven by distinct molecular events.

Urine gamma-synuclein as a biomarker for the diagnosis of bladder cancer.

Gamma-synuclein (SNCG) is secreted from tumor cells and elevated in the urine of bladder cancer (BCa) patients, however, the diagnostic and prognostic values of urine SNCG for BCa remain unknown. Here, we used enzyme immunoassay and western blotting to measure urine SNCG levels. Patients with BCa or other urological diseases and healthy controls were enrolled at four Chinese hospitals from April 2010 to November 2014. Diagnostic performance was evaluated by analyzing the area under receiver operating characteristic curves (AUROCs). The AUROC was 0.903 ± 0.019 (95% confidence interval [CI], 0.867 - 0.940) for the test and 0.929 ± 0.015 (95% CI, 0.901 - 0.958) for the validation cohort. The optimal cutoff value yielded sensitivities of 68.4%, 62.4% and specificities of 97.4%, 97.8% for the test and validation cohort, respectively. Urine SNCG levels were decreased after tumor resection, but were higher in BCa patients with recurrence than those without (P = 0.001). The urine SNCG levels in patients with urological benign diseases were significantly lower than BCa patients (all P < 0.05) but higher than healthy controls (all P < 0.05). Hematuria did not interfere with the SNCG detection by spiking urine specimens with whole blood. Compared with a nuclear-matrix-protein-22 assay in an additional cohort excluding hematuria, SNCG showed a similar sensitivity and higher specificity. In summary, our results demonstrated that urine SNCG can discriminate BCa from urinary diseases, and is a useful prognosticator of postsurgical recurrence.

[Hsp90AB1 Protein is Overexpressed in Non-small Cell Lung Cancer Tissues 
and Associated with Poor Prognosis in Lung Adenocarcinoma Patients].

BACKGROUND: Heat shock protein 90 kDa alpha, class B member 1 (Hsp90AB1) is highly conserved ATP-dependent molecular chaperone, and over-expressed in a variety of tumor cells. Some molecules that play important roles in tumor development signaling pathways such as epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2 (HER2) are Hsp90AB1 client proteins. Hsp90AB1 interact with these client proteins and participate in a variety of pathophysiological processes of cells. The aim of this study is to detect the expression of Hsp90AB1 in non-small cell lung cancer (NSCLC) tissues, and explore its clinical significance. METHODS: The expression of Hsp90AB1 in 213 NSCLC tissues and 147 normal lung tissues was detected by tissue microarray and immunohistochemical staining method, and the relationship of Hsp90AB1 expression with clinicopathological parameters and prognosis of NSCLC patients were analyzed. RESULTS: The expression level of Hsp90AB1 in lung cancer tissues (positive rate of 54.0%) was significantly higher than that in normal lung tissue (positive rate of 0.0%, P<0.001). The positive expression rate of Hsp90AB1 in lung adenocarcinoma tissues (61.2%) was significantly higher than that in lung squamous cell carcinoma tissues (37.9%)(P=0.002), and its over-expression was associated with poor prognosis in lung adenocarcinoma patients (P=0.032). The expression level of Hsp90AB1 had no significant correlation with clinical stage, lymph node metastasis, pathological grade or other factors (P>0.05). CONCLUSIONS: Hsp90AB1 protein was over-expressed in NSCLC tissues, and was associated with lung cancer pathological type and overall survival in lung adenocarcinoma patients.

[Protein levels and its clinical significance of septin-9 and clusterin in peripheral blood of epithelial ovarian cancer patients].

OBJECTIVE: To evaluate septin-9 and clusterin protein levels in the peripheral blood samples from epithelial ovarian cancer patients, and explore its clinical significance. METHODS: Clinical data of 200 patients in Cancer Hospital, Chinese Academy of Medical Sciences from Jan. 29, 2008 to Feb. 1, 2010 were collected. The peripheral blood samples were obtained from 137 epithelial ovarian cancer patients, 12 borderline ovarian tumor patients, 10 benign ovarian tumor patients, 41 benign pelvic lesion patients and 58 healthy women. The septin-9 and clusterin protein levels in the plasma were measured by double antibody sandwich ELISA or ELISA. The clinical significance of clusterin and septin-9 in plasma was analyzed. The diagnostic efficacy of septin-9 and clusterin protein in the detection of ovarian cancer was evaluated by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: Double antibody sandwich ELISA showed: the mean levels of plasma septin-9 in epithelial ovarian cancer patients or benign pelvic lesion patients were significantly higher than that in healthy women detedted by double antibody sandwich ELISA (P < 0.01). The mean levels of plasma septin-9 in epithelial ovarian carcinoma patients with tumor family history or distance metastasis were significantly higher than those patients without (P < 0.05). While the expression level of septin-9 protein in peripheral blood of ovarian cancer patients was not related to the patient age, pathologic stage, pathologic differentiation, smoking history, treatment history (including surgery, radiotherapy and chemotherapy) and lymph node metastasis (all P > 0.05). ELISA showed: the mean level of plasma clusterin in epithelial ovarian cancer patients was significantly higher than that in healthy women deteded by ELISA (P = 0.021). The expression level of clusterin protein in peripheral blood of ovarian cancer patients was not related to the above clinical pathological parameters (all P > 0.05). To distinguish between ovarian cancer patients and healthy women by septin-9 protein expression level in plasma, when AUC was 0.712 and cut off was 0.28, the sensitivity of detection ovarian cancer by septin-9 protein expression was 82.5%, and the specificity was 50.0%. To distinguish between ovarian cancer patients and healthy women by clusterin protein expression level in plasma, when AUC was 0.636 and cut off was 87.96 pg/L, the sensitivity of detection ovarian cancer by clusterin protein expression was 71.5%, and the specificity was 41.4%. CONCLUSIONS: The expression of septin-9 and clusterin protein in peripheral blood of ovarian cancer patients is increased, especially the expression level of septin-9 protein with related to the distant metastasis. The study results shown that the detection of septin-9 and clusterin in plasma has a certain diagnosis value in ovarian cancer, which may be a potential markers for ovarian cancer.

Exposure to airborne PM2.5 suppresses microRNA expression and deregulates target oncogenes that cause neoplastic transformation in NIH3T3 cells.

Long-term exposure to airborne PM2.5 is associated with increased lung cancer risk but the underlying mechanism remains unclear. We characterized global microRNA and mRNA expression in human bronchial epithelial cells exposed to PM2.5 organic extract and integrally analyzed microRNA-mRNA interactions. Foci formation and xenograft tumorigenesis in mice with NIH3T3 cells expressing genes targeted by microRNAs were performed to explore the oncogenic potential of these genes. We also detected plasma levels of candidate microRNAs in subjects exposed to different levels of air PM2.5 and examined the aberrant expression of genes targeted by these microRNAs in human lung cancer. Under our experimental conditions, treatment of cells with PM2.5 extract resulted in downregulation of 138 microRNAs and aberrant expression of 13 mRNAs (11 upregulation and 2 downregulation). In silico and biochemical analyses suggested SLC30A1, SERPINB2 and AKR1C1, among the upregulated genes, as target for miR-182 and miR-185, respectively. Ectopic expression of each of these genes significantly enhanced foci formation in NIH3T3 cells. Following subcutaneous injection of these cells into nude mice, fibrosarcoma were formed from SLC30A1- or SERPINB2-expressing cells. Reduced plasma levels of miR-182 were detected in subjects exposed to high level of PM2.5 than in those exposed to low level of PM2.5 (P = 0.043). Similar results were seen for miR-185 although the difference was not statistically significant (P = 0.328). Increased expressions of SLC30A1, SERPINB2 and AKR1C1 were detected in human lung cancer. These results suggest that modulation of miR-182 and miR-185 and their target genes may contribute to lung carcinogenesis attributable to PM2.5 exposure.

Decreased Interferon Alpha/Beta Signature Associated with Human Lung Tumorigenesis.

Accumulating evidence suggests that interferon (IFN) alpha/beta are involved in antitumor immunity and cancer immunoediting, but information on the antitumor effects of IFN alpha/beta in lung cancer is limited. In our study, we elucidated the IFN alpha/beta signature during both human fetal lung development and lung tumorigenesis. Our findings indicated gradual upregulation in the IFN alpha/beta signature during human fetal lung development. In addition, this signature was progressively downregulated in normal human airway epithelial cells from lung cancer patients, in immortalized human bronchial epithelial cell lines from later passages, in late-stage lung squamous cell carcinoma (LSCC) tissues, and in LSCC tissues exhibiting lymph node metastasis. Therefore, from its earliest stages, lung tumorigenesis may be associated with a decreased IFN alpha/beta signature. This association may provide insight to guide the detection of high-risk lung cancer patients.