5-mRNA-based prognostic signature of survival in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common non-small-cell lung cancer, with a high incidence and a poor prognosis. AIM: To construct effective predictive models to evaluate the prognosis of LUAD patients. METHODS: In this study, we thoroughly mined LUAD genomic data from the Gene Expression Omnibus (GEO) (GSE43458, GSE32863, and GSE27262) and the Cancer Genome Atlas (TCGA) datasets, including 698 LUAD and 172 healthy (or adjacent normal) lung tissue samples. Univariate regression and LASSO regression analyses were used to screen differentially expressed genes (DEGs) related to patient prognosis, and multivariate Cox regression analysis was applied to establish the risk score equation and construct the survival prognosis model. Receiver operating characteristic curve and Kaplan-Meier survival analyses with clinically independent prognostic parameters were performed to verify the predictive power of the model and further establish a prognostic nomogram. RESULTS: A total of 380 DEGs were identified in LUAD tissues through GEO and TCGA datasets, and 5 DEGs (TCN1, CENPF, MAOB, CRTAC1 and PLEK2) were screened out by multivariate Cox regression analysis, indicating that the prognostic risk model could be used as an independent prognostic factor (Hazard ratio = 1.520, P < 0.001). Internal and external validation of the model confirmed that the prediction model had good sensitivity and specificity (Area under the curve = 0.754, 0.737). Combining genetic models and clinical prognostic factors, nomograms can also predict overall survival more effectively. CONCLUSION: A 5-mRNA-based model was constructed to predict the prognosis of lung adenocarcinoma, which may provide clinicians with reliable prognostic assessment tools and help clinical treatment decisions.

Circular RNA-DPP4 serves an oncogenic role in prostate cancer progression through regulating miR-195/cyclin D1 axis.

BACKGROUND: Recently, more and more studies have highlighted the critical regulatory roles of circular RNAs (circRNAs), a class of non-coding RNAs, in the progression of many human cancers, including prostate cancer (PCa). circRNA microarray analysis was performed to identify circRNAs that are differentially expressed in PCa tissues. METHODS: 104 pairs of PCa tissues and matched adjacent normal prostate tissues (at least 2 cm distal to the tumor margin) were obtained. circRNA microarray analysis was performed on four pairs of PCa tissues and matched adjacent normal prostate tissues to investigate the potential involvement of circRNAs in PCa. Flow cytometric analysis was performed to investigate whether the effect of circDPP4 on PCa cell proliferation was associated with the alteration in cell cycle progression. The role of circDPP4 in PCa tumor growth was further explored in vivo. RESULTS: We found that circDPP4 was overexpressed in PCa tissues and cell lines, and its expression was closely associated with Gleason score and clinical stage of PCa patients. In vitro loss- and gain-of-function experiments demonstrated that circDPP4 knockdown inhibited, whereas circDPP4 overexpression promoted the proliferation, migration, invasion and cell cycle progression of PCa cells. Knockdown of circDPP4 also suppressed PCa tumor growth in vivo. We further found that circDPP4 functioned as a competing endogenous RNA (ceRNA) for miR-195 in PCa cells, and miR-195 negatively regulated the expression of oncogenic cyclin D1. Rescue experiments suggested that restoration of miR-195 blocked the oncogenic role of circDPP4 in PCa cells. CONCLUSIONS: Taken together, our findings revealed a novel regulatory mechanism between circDPP4 and miR-195/cyclin D1 axis, and offered novel strategies for the treatment of PCa.

Identification of Specific Long Non-Coding Ribonucleic Acid Signatures and Regulatory Networks in Prostate Cancer in Fine-Needle Aspiration Biopsies.

Prostate cancer (PCa) is one of the most common tumors in men and can be lethal, especially if left untreated. A substantial majority of PCa patients not only are diagnosed based on fine needle aspiration (FNA) biopsies, but their treatment choices are also largely driven by the pathological findings obtained with these FNA specimens. It is widely believed that lncRNAs have strong biological significance, but their specific functions and regulatory networks have not been elucidated. LncRNAs may serve as key players and regulators of PCa carcinogenesis and could be novel biomarkers of this cancer. To identify potential markers for early detection of PCa, in this study, we employed a competing endogenous RNA (ceRNA) microarray to identify differentially expressed lncRNAs (DelncRNAs) in PCa tissue and quantitative real-time PCR (qRT-PCR) analysis to validate these DelncRNAs in FNA biopsies. We demonstrated that a total of 451 lncRNAs were differentially expressed in four pairs of PCa/adjacent tissues, and upregulation of the lncRNAs RP11-33A14.1, RP11-423H2.3, and LAMTOR5-AS1 was confirmed in FNA biopsies of PCa by qRT-PCR and was consistent with the ceRNA array data. The association between the expression of the lncRNA LAMTOR5-AS1 and aggressive cancer was also investigated. Regulatory network analysis of DelncRNAs showed that the lncRNAs RP11-33A14.1 and RP11-423H2.3 targeted miR-7, miR-24-3p, and miR-30 and interacted with the RNA binding protein FUS. Knockdown of these DelncRNAs in PCa cells also demonstrated the effects of RP11-423H2.3 on miR-7/miR-24/miR-30 or LAMTOR5-AS1 on miR-942-5p/miR-542-3p via direct interaction. The results of these studies indicate that these three specific lncRNA signatures and regulatory networks might serve as risk prediction and diagnostic biomarkers for prostate cancer, even in biopsies obtained by FNA.

Hepatomas are exquisitely sensitive to pharmacologic ascorbate (P-AscH-).

Rationale: Ascorbate is an essential micronutrient known for redox functions at normal physiologic concentrations. In recent decades, pharmacological ascorbate has been found to selectively kill tumour cells. However, the dosing frequency of pharmacologic ascorbate in humans has not yet been defined. Methods: We determined that among five hepatic cell lines, Huh-7 cells were the most sensitive to ascorbate. The effects of high-dose ascorbate on hepatoma were therefore assessed using Huh-7 cells and xenograft tumour mouse model. Results: In Huh-7 cells, ascorbate induced a significant increase in the percentage of cells in the G0/G1 phase, apoptosis and intracellular levels of ROS. High doses of ascorbate (4.0 pmol cell-1), but not low doses of ascorbate (1.0 pmol cell-1), also served as a pro-drug that killed hepatoma cells by altering mitochondrial respiration. Furthermore, in a Huh-7 cell xenograft tumour mouse model, intraperitoneal injection of ascorbate (4.0 g/kg/3 days) but not a lower dose of ascorbate (2.0 g/kg/3 days) significantly inhibited tumour growth. Gene array analysis of HCC tumour tissue from xenograft mice given IP ascorbate (4.0 g/kg/3 days) identified changes in the transcript levels of 192 genes/ncRNAs involved in insulin receptor signalling, metabolism and mitochondrial respiration. Consistent with the array data, gene expression levels of AGER, DGKK, ASB2, TCP10L2, Lnc-ALCAM-3, and Lnc-TGFBR2-1 were increased 2.05-11.35 fold in HCC tumour tissue samples from mice treated with high-dose ascorbate, and IHC staining analysis also verified that AGER/RAGE and DGKK proteins were up-regulated, which implied that AGER/RAGE and DGKK activation might be related to oxidative stress, leading to hepatoma cell death. Conclusions: Our studies identified multiple mechanisms are responsible for the anti-tumour activity of ascorbate and suggest high doses of ascorbate with less frequency will act as a novel therapeutic agent for liver cancer in vivo.

Identification of novel biomarkers for hepatocellular carcinoma using transcriptome analysis.

Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer in the world. To comprehensively investigate the utility of microRNAs (miRNAs) and protein-encoding transcripts (messenger RNAs [mRNAs]) in HCC as potential biomarkers for early detection and diagnosis, we exhaustively mined genomic data from three available omics datasets (GEO, Oncomine, and TCGA), analyzed the overlaps among gene expression studies from 920 hepatocellular carcinoma samples and 508 healthy (or adjacent normal) liver tissue samples available from six laboratories, and identified 178 differentially expressed genes (DEGs) associated with HCC. Paired with miRNA and lncRNA data, we identified 23 core genes that were targeted by nine differentially expressed miRNAs and 21 HCC-specific lncRNAs. We further demonstrated that alterations in these 23 genes were quite frequent, with five genes altered in over 5% of the population. Patients with high levels of YWHAZ, ENAH, and HMGN4 tended to have high-grade tumors and shorter overall survival, suggesting that these genes could be promising candidate biomarkers for disease and poor prognosis in patients with HCC. Our comprehensive mRNA, miRNA, and lncRNA omics analyses from multiple independent datasets identified robust molecules that may be used as biomarkers for early HCC detection and diagnosis.

Circular RNA Expression Profiling Identifies Prostate Cancer- Specific circRNAs in Prostate Cancer.

BACKGROUND/AIMS: Prostate cancer (PCa) is one of the main cancers that damage males' health severely with high morbidity and mortality, but there is still no ideal molecular marker for the diagnosis and prognosis of prostate cancer. METHODS: To determine whether the differentially expressed circRNAs in prostate cancer can serve as novel biomarkers for prostate cancer diagnosis, we screened differentially expressed circRNAs using SBC-ceRNA array in 4 pairs of prostate tumor and paracancerous tissues. A circRNA-miRNA-mRNA regulatory network for the differential circRNAs and their host genes was constructed by Cytoscape3.5.1 software. Quantitative real-time polymerase chain reaction analysis (qRT-PCR) was performed to confirm the microarray data. RESULTS: We found 1021 differentially expressed circRNAs in PCa tumor using SBC-ceRNA array and confirmed the expression of circ_0057558, circ_0062019 and SLC19A1 in PCa cell lines and tumor tissues through qRT-PCR analysis. We demonstrated that combination of PSA level and two differentially expressed circRNAs showed significantly increased AUC, sensitivity and specificity (0.938, 84.5% and 90.9%, respectively) than PSA alone (AUC of serum PSA was 0.854). Moreover, circ_0057558 was correlated positively with total cholesterol. The functional network of circRNA-miRNA-mRNA analysis showed that circ_0057558 and circ_0034467 regulated miR-6884, and circ_0062019 and circ_0060325 regulated miR-5008. CONCLUSION: Our results demonstrated that differentially expressed circRNAs (circ_0062019 and circ_0057558) and host gene SLC19A1 of circ_0062019 could be used as potential novel biomarkers for prostate cancer.

Molecular Changes of Lung Malignancy in HIV Infection.

Malignancy of the lung is a major source of morbidity and mortality in persons with human immunodeficiency virus infection; as the most prevalent non-acquired immunodeficiency syndrome-defining malignancy, it represents an important and growing problem confronting HIV-infected patients. To evaluate the molecular changes of lung malignancy in HIV infection, we analyzed differential gene expression profiles and screened for early detection biomarkers of HIV-associated lung cancer using Affymetrix arrays and IPA analysis. A total of 59 patients were diagnosed with HIV-associated lung cancer from Jan 2010 to May 2018. The primary outcome was a significant difference in survival outcome between stages III-IV (10.46 ± 1.87 months) and I-II (17.66 ± 2.88 months). We identified 758 differentially expressed genes in HIV-associated lung cancer. The expression levels of SIX1 and TFAP2A are specifically increased in HIV-associated lung cancer and are associated with poorly differentiated tumor tissue. We also found decreased ADH1B, INMT and SYNPO2 mRNA levels in HIV lung cancer. A comprehensive network and pathway analysis of the dysregulated genes revealed that these genes were associated with four network functions and six canonical pathways relevant to the development of HIV-associated lung cancer. The molecular changes in lung malignancy may help screen the growing population of HIV patients who have or will develop this malignancy.

Molecular analyses of prostate tumors for diagnosis of malignancy on fine-needle aspiration biopsies.

Prostate cancer (PCa) is a common cancer and remains the second-leading cause of cancer-associated mortality in men, but diagnosis of PCa remains a main clinical challenge. To investigate the involvement of differentially expressing genes in PCa with deregulated pathways to allow earlier diagnosis of the disease, transcriptomic analyses of differential expression genes in fine-needle aspiration (FNA) biopsies helped to discriminate PCa from benign prostatic hyperplasia (BPH). We identified 255 genes that were deregulated in prostate tumors compared with BPH tissues. qRT-PCR was conducted to examine the expression levels of the four genes in FNA biopsies and confirmed that ITGBL1 was significantly up-regulated and HOXA7, KRT15 and TGM4 were down-regulated in the PCa compared to the BPH, with a sensitivity of 87.1% and a specificity of 87.8%; the area under the receiver operating characteristic curve was estimated at 0.94, which was significantly improved compared with PSA alone (AUC = 0.82). Moreover, the increased expression of ITGBL1 correlated with total cholesterol, triglyceride and PSA. Our results demonstrated that transcriptomic analyses in FNA biopsies could facilitate rapid identification of potential targets for therapy and diagnosis of PCa.

Clinically relevant circulating microRNA profiling studies in pancreatic cancer using meta-analysis.

BACKGROUND: Pancreatic cancer (PaCa) is the most lethal gastrointestinal (GI) tumor. Although many studies on differentially expressed miRNAs as candidate biomarkers of pancreatic cancer have been published, reliability of these findings generated from investigations performed in single laboratory settings remain unclear. RESULTS: There were 29 articles with a total of 2,225 patients and 1,618 controls included in this meta-analysis. The pooled sensitivity was 82% (95% CI, 79-85%); the specificity was 85% (95% CI, 79-89%); and area under the curve (AUC) was 0.89 (95% CI, 0.86-0.92). Subgroup analyses indicated that there were significant divergences between Caucasian and Asian subgroups for circulating miRNA analysis. MATERIALS AND METHODS: To comprehensively investigate the potential utility of miRNAs as biomarkers of the disease, we searched publications diagnosing PaCa using miRNAs from PubMed, Medline, Embase, Google Scholar and Chinese National Knowledge Infrastructure (CNKI) databases. The sensitivity (SEN), specificity (SPE), and summary receiver operating characteristic (SROC) curve were used to examine the overall test performance, and heterogeneity was analyzed with the I2 test. CONCLUSIONS: Our analysis demonstrated that multiple miRNAs (SEN: 85%; SPE: 89%; AUC: 0.93) were more accurate for diagnosing PaCa than a single miRNA (SEN: 78%; SPE: 79%; AUC: 0.84), and future studies are still needed to confirm the diagnostic value of these pooled miRNAs for PaCa.