Insights into the involvement of long non-coding RNAs in doxorubicin resistance of cancer.

Doxorubicin is one of the most classical chemotherapeutic drugs for the treatment of cancer. However, resistance to the cytotoxic effects of doxorubicin in tumor cells remains a major obstacle. Aberrant expression of long non-coding RNAs (lncRNAs) has been associated with tumorigenesis and development via regulation of chromatin remodeling, transcription, and post-transcriptional processing. Emerging studies have also revealed that dysregulation of lncRNAs mediates the development of drug resistance through multiple molecules and pathways. In this review, we focus on the role and mechanism of lncRNAs in the progress of doxorubicin resistance in various cancers, which mainly include cellular drug transport, cell cycle disorder, anti-apoptosis, epithelial-mesenchymal transition, cancer stem cells, autophagy, tumor microenvironment, metabolic reprogramming and signaling pathways. This review is aimed to provide potential therapeutic targets for future cancer therapy, especially for the reversal of chemoresistance.

Long non-coding RNA H19: a potential biomarker and therapeutic target in human malignant tumors.

Long non-coding RNAs play important roles in cellular functions and disease development. H19, as a long non-coding RNA, is pervasively over-expressed in almost all kinds of human malignant tumors. Although many studies have reported that H19 is closely associated with tumor cell proliferation, apoptosis, invasion, metastasis, and chemoresistance, the role and mechanism of H19 in gene regulation and tumor development are largely unclear. In this review, we summarized the recent progress in the study of the major functions and mechanisms of H19 lncRNA in cancer development and progression. H19 possesses both oncogenic and tumor-suppressing activities, presumably through regulating target gene transcription, mRNA stability and splicing, and competitive inhibition of endogenous RNA degradation. Studies indicate that H19 may involve in cell proliferation and apoptosis, tumor initiation, migration, invasion, metastasis and chemoresistance and may serve as a potential biomarker for early diagnosis, prognosis, and novel molecular target for cancer therapy.

Vibrio vulnificus infection attributed to bee sting: a case report.

Vibrio vulnificus is a pathogenic marine bacteria associated with high mortality. Changes in climate and the global seafood trade have increased the prevalence of marine and freshwater systems affected by V. vulnificus. As a result, the incidence of land animals, plants, and insects contacting V. vulnificus and acting as disease vectors is on the rise. We report the case of a 53-year-old male who was infected with V. vulnificus as the result of a bee sting. The patient had no history of contact with the sea or fresh water or aquatic organisms or products. Due to bacterial pathogenicity and the patient's underlying diseases, his condition deteriorated rapidly and eventually resulted in death. Here, we review the pathogenic mechanisms and treatment of V. vulnificus. We determined that V. vulnificus has spread from seawater to freshwater and that individuals may become infected from insects, even in the absence of direct contact with infected water. This case report will inform clinicians about the possible sources of V. vulnificus infection and indicates the possibility that more insects may transmit V. vulnificus in the future.

Effects of CORO2A on Cell Migration and Proliferation and Its Potential Regulatory Network in Breast Cancer.

Coronin 2A (CORO2A) is a novel component of the N-CoR (nuclear receptor co-repressor) complex. Abnormal CORO2A expression is associated with carcinogenesis. We used databases from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and analyzed CORO2A expression and gene regulation networks in breast cancer. Expression was analyzed using GEO and TCGA database and further validated in breast cancer samples collected in our clinic. The prognostic value of CORO2A was explored by using the Kaplan-Meier survival analysis and Cox proportional hazards regression analysis. LinkedOmics was used to identify coexpressed genes associated with CORO2A. After analyzing the intersection of coexpressed genes correlated with CORO2A and differentially expressed genes after CORO2A silencing, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of the intersecting genes were conducted by using FunRich software. Transwell assays were performed in breast cancer cells to determine the effect of CORO2A on cell migration. MTS, colony formation, and cell cycle distribution assays were performed in breast cancer cells to determine the effect of CORO2A on cell proliferation. Gene enrichment analysis was employed to explore the target networks of transcription factors and miRNAs. We found that CORO2A was upregulated and that the elevated expression of CORO2A was associated with poor overall survival (OS) and relapse-free survival (RFS) in TNBC patients. Further bioinformatics analysis of public sequencing data and our own RNA-Seq data revealed that CORO2A was probably involved in the epithelial-to-mesenchymal transition process and might have a significant effect on the migration of breast cancer cells, which might be mediated via pathways involving several miRNAs and MYC transcription factors. Functionally, the knockdown of CORO2A inhibited cell migration, decreased viability, and colony formation and induced cell cycle arrest in the G0/G1 phase in breast cancer cells. These results demonstrate that bioinformatics-based analysis efficiently reveals information about CORO2A expression and its potential regulatory networks in breast cancer, laying a foundation for further mechanistic research on the role of CORO2A in carcinogenesis. Moreover, CORO2A promotes the migration and proliferation of breast cancer cells and may have an important function in breast cancer progression. CORO2A is a potential prognostic predictor for TNBC patients. Targeting CORO2A may provide promising therapy strategies for breast cancer treatment.

Identification of Candidate Genes Associated with Breast Cancer Prognosis.

Breast cancer (BC) is the most malignant tumor in women. The molecular mechanisms underlying tumorigenesis still need to be further elucidated. It is necessary to investigate novel candidate genes involved in breast cancer progression and prognosis. In this study, we commit to explore candidate genes that associate with prognosis and therapy in BC by a comprehensive bioinformatic analysis. Four GEO datasets (GSE5764, GSE7904, GSE20711, and GSE29431) and the BC-related transcriptome data in TCGA database were downloaded and used to identify the differently expressed genes (DEGs). The function of DEGs was analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis. The protein-protein interaction (PPI) network of DEGs was constructed to identify hub genes. Prognostic candidate genes were identified through survival analysis. In addition, potential therapeutic targets were identified by constructed gene-drug interaction network through Comparative Toxicogenomics Database. A total of 547 DEGs (302 up and 245 down) were identified. Three core-subnetwork and 25 hub genes were identified in PPI network. Seven genes (namely COL12A1, QPRT, MRPL13, KRT14, KRT15, LAMB3, and MYBPC1) were identified as crucial prognostic candidate genes, which significantly associated with breast cancer overall survival. Furthermore, two representative candidate genes (COL12A1 and LAMB3) were optionally chosen for verification by reverse transcription and quantitative real-time polymerase chain reaction (RT-PCR). What's more, the gene-drugs interaction analysis indicates several antitumor drugs that could affect the expression of these prognostic markers, such as doxorubicin, cisplatin, and tamoxifen. These results identified seven crucial candidate genes that may serve as prognosis biomarkers and novel therapeutic targets of breast cancer, which may facilitate further understanding the molecular pathogenesis and providing potential therapeutic strategies for BC.

Statins induce cell apoptosis through a modulation of AKT/FOXO1 pathway in prostate cancer cells.

BACKGROUND: In recent years, statins have been frequently investigated in neoplasms. However, the potential roles of statins on prostate cancer cells and the underlying mechanisms have not been fully elucidated. In current study, we explored the effect and molecular mechanism of statins on cell proliferation and apoptosis in prostate cancer cells. METHODS: Prostate cancer cell were treated with gradient doses of simvastatin and fluvastatin for 24-72 h. Cell proliferation was analyzed by using MTS assay and colony formation. Cell apoptosis was measured by Hoechst staining, flow cytometry and caspase-3 activity. Western blotting was used to evaluate the proteins levels. RESULTS: Both simvastatin and fluvastatin produced a dose- and time-dependent inhibition of cell viability and colony formation while a promotion of cell apoptosis as evident with increases in caspase-3 activity, cleaved-caspase-3, cleaved-caspase-8 and cleaved-PARP levels in PC3 cells. Similar statin effects were observed in DU145 prostate cancer cells. Furthermore, statins produced a time- and dose-dependent reduction of phosphorylated-AKT and phosphorylated-FOXO1 levels in PC3 cells, and pretreatment of cells with an AKT phosphorylation inhibitor, MK2206, potentiated statins' effect. CONCLUSION: Statins decrease cell proliferation and induce cell apoptosis, probably mediated via a downregulation of AKT/FOXO1 phosphorylation in prostate cancer cells, which may have a potential benefit in prostate cancer prevention and therapy.

Long non-coding RNAs in prostate cancer: Functional roles and clinical implications.

Long noncoding RNAs (lncRNAs) are defined as RNA transcripts longer than 200 nucleotides that do not encode proteins. LncRNAs have been documented to exhibit aberrant expression in various types of cancer, including prostate cancer. Currently, screening for prostate cancer results in overdiagnosis. The consequent overtreatment of patients with indolent disease in the clinic is due to the lack of appropriately sensitive and specific biomarkers. Thus, the identification of lncRNAs as novel biomarkers and therapeutic targets for prostate cancer is promising. In the present review, we attempt to summarize the current knowledge of lncRNA expression patterns and mechanisms in prostate cancer. In particular, we focus on lncRNAs regulated by the androgen receptor and the specific molecular mechanism of lncRNAs in prostate cancer to provide a potential clinical therapeutic strategy for prostate cancer.

Identification of Potential Crucial Genes and Key Pathways in Breast Cancer Using Bioinformatic Analysis.

Background: The molecular mechanism of tumorigenesis remains to be fully understood in breast cancer. It is urgently required to identify genes that are associated with breast cancer development and prognosis and to elucidate the underlying molecular mechanisms. In the present study, we aimed to identify potential pathogenic and prognostic differentially expressed genes (DEGs) in breast adenocarcinoma through bioinformatic analysis of public datasets. Methods: Four datasets (GSE21422, GSE29431, GSE42568, and GSE61304) from Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) dataset were used for the bioinformatic analysis. DEGs were identified using LIMMA Package of R. The GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses were conducted through FunRich. The protein-protein interaction (PPI) network of the DEGs was established through STRING (Search Tool for the Retrieval of Interacting Genes database) website, visualized by Cytoscape and further analyzed by Molecular Complex Detection (MCODE). UALCAN and Kaplan-Meier (KM) plotter were employed to analyze the expression levels and prognostic values of hub genes. The expression levels of the hub genes were also validated in clinical samples from breast cancer patients. In addition, the gene-drug interaction network was constructed using Comparative Toxicogenomics Database (CTD). Results: In total, 203 up-regulated and 118 down-regulated DEGs were identified. Mitotic cell cycle and epithelial-to-mesenchymal transition pathway were the major enriched pathways for the up-regulated and down-regulated genes, respectively. The PPI network was constructed with 314 nodes and 1,810 interactions, and two significant modules are selected. The most significant enriched pathway in module 1 was the mitotic cell cycle. Moreover, six hub genes were selected and validated in clinical sample for further analysis owing to the high degree of connectivity, including CDK1, CCNA2, TOP2A, CCNB1, KIF11, and MELK, and they were all correlated to worse overall survival (OS) in breast cancer. Conclusion: These results revealed that mitotic cell cycle and epithelial-to-mesenchymal transition pathway could be potential pathways accounting for the progression in breast cancer, and CDK1, CCNA2, TOP2A, CCNB1, KIF11, and MELK may be potential crucial genes. Further, it could be utilized as new biomarkers for prognosis and potential new targets for drug synthesis of breast cancer.

Neurexophilin and PC-esterase domain family member 4 (NXPE4) and prostate androgen-regulated mucin-like protein 1 (PARM1) as prognostic biomarkers for colorectal cancer.

Owing to the high morbidity and mortality, novel biomarkers in the occurrence and development of colorectal cancer (CRC) are needed nowadays. In this study, the CRC-related datasets were downloaded from the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database. After screening the differentially expressed genes (DEGs) in R software, a total of 238 upregulated and 199 downregulated DEGs were revealed simultaneously. Then the Kaplan-Meier survival analysis and Cox regression analysis were used to reveal the prognostic function of these DEGs. Neurexophilin and PC-esterase domain family member 4 (NXPE4) and prostate androgen-regulated mucin-like protein 1 (PARM1) were two outstanding independent overall survival (OS) and relapse-free survival (RFS) prognostic genes of CRC in TCGA database. We next verified the expression of NXPE4 and PARM1 messenger RNA (mRNA) levels were significantly lower in CRC tumor tissue than in the adjacent noncancerous tissue in our clinical samples, and NXPE4 mRNA expression level was related to the tumor location and tumor size, while PARM1 was related to tumor location, lymph nodes metastasis, and tumor size. This study demonstrated that NXPE4 and PARM1 might be two potential novel prognostic biomarkers for CRC.

Polymorphisms in IGF2/H19 gene locus are associated with platinum-based chemotherapeutic response in Chinese patients with epithelial ovarian cancer.

AIM: The present study aimed to assess the association between IGF2/H19 genetic variants and susceptibility to platinum-based chemotherapy in epithelial ovarian cancer (EOC). METHODS: A total of 43 platinum-resistant (PR) and 138 platinum-sensitive (PS) EOC patients were recruited in our study. 21 polymorphisms in IGF2/H19 locus were genotyped by Sequenom MassARRAY assay. RESULTS: The frequencies of GG genotype in both rs3842761(C/G) and rs4244809(A/G) were significantly lower in PR group compared with those in PS group (9.76 vs 23.36%, p = 0.049; 9.76 vs 26.09%, p = 0.045; respectively). Compared with the AA genotype, rs4244809 GG genotype was associated with significantly reduced risk of platinum resistance (adjusted OR: 0.30; 95% CI: 0.10-0.91; p = 0.033). Further stratified analyses revealed that the SNPs of rs3842761 and rs4244809 were greatly related to PR risk in FIGO stage III-IV (rs3842761GG/CC+CG: adjusted OR: 0.15; 95% CI: 0.02-1.21; rs4244809 GG/AA+AG: adjusted OR: 0.24; 95% CI: 0.07-0.84; respectively) and serous adenocarcinoma subgroups (rs3842761 GG/CC+CG: adjusted OR: 0.21; 95% CI: 0.05-0.94; rs4244809 GG/AA+AG: adjusted OR: 0.19; 95% CI: 0.04-0.5; respectively), while rs7924316 polymorphism was associated with reduced risk of PR in serous adenocarcinoma subgroup as analyzed by a recessive model (rs7924316 GG/TT+TG: adjusted OR: 0.22; 95% CI: 0.05-0.98). In addition, both TCT haplotypes of rs3741206/rs3842761/rs7924316 and TC haplotype of rs3741206/rs3842761 were associated with elevated risk of PR (for the TCT haplotype of rs3741206/rs3842761/rs7924316: p = 0.049; OR: 1.69; 95% CI: 1.00-2.87; for the TC haplotype of rs3741206/rs3842761: p = 0.044; OR: 1.71; 95% CI: 1.01-2.88). CONCLUSION: These results suggest that polymorphisms in IGF2/H19 gene locus are associated with PR risk in EOC.

Emerging role of long non-coding RNAs in cisplatin resistance.

Cisplatin (CDDP) is one of the most commonly used chemotherapy drugs for the treatment of various cancers. Although platinum-based therapies are highly efficacious against rapidly proliferating malignant tumors, the development of CDDP resistance results in significant relapse as well as decreased overall survival rates, which is a significant obstacle in CDDP-based cancer therapy. Long non-coding RNAs (lncRNAs) are involved in cancer development and progression by the regulation of processes related to chromatin remodeling, transcription, and posttranscriptional processing. Emerging evidence has recently highlighted the roles of lncRNAs in the development of CDDP resistance. In this review, we discuss the roles and mechanisms of lncRNAs in CDDP chemoresistance, including changes in cellular uptake or efflux of a drug, intracellular detoxification, DNA repair, apoptosis, autophagy, cell stemness, and the related signaling pathways, aiming to provide potential lncRNA-targeted strategies for overcoming drug resistance in cancer therapy.

LncRNA H19 is a major mediator of doxorubicin chemoresistance in breast cancer cells through a cullin4A-MDR1 pathway.

Development of chemoresistance is a persistent problem during cancer treatment. Long non-coding RNAs (LncRNAs) are currently emerging as an integral functional component of the human genome and as critical regulators of cancer development and progression. In the present study, we investigated the role and molecular mechanism of H19 lncRNA in chemoresistance development by using doxorubicin (Dox) resistance in breast cancer cells as a model system. H19 lncRNA expression was significantly increased in anthracycline-treated and Dox-resistant MCF-7 breast cancer cells. This H19 overexpression was contributed to cancer cell resistance to anthracyclines and paclitaxel as knockdown of H19 lncRNA by a specific H19 shRNA in Dox-resistant cells significantly improved the cell sensitivity to anthracyclines and paclitaxel. Furthermore, gene expression profiling analysis revealed that a total of 192 genes were associated with H19-mediated Dox resistance. These genes were enriched in multiple KEGG pathways that are related to chemoresistance. Using genetic and pharmacological approaches, we demonstrated that MDR1 and MRP4 were major effectors of H19-regulated Dox resistance in breast cancer cells as MDR1 and MRP4 expression was markedly elevated in Dox-resistant cells while dramatically reduced when H19 was knocked down. Moreover, we found that CUL4A, an ubiquitin ligase component, was a critical factor bridging H19 lncRNA to MDR1 expression, and a high tumor CUL4A expression was associated with low survival in breast cancer patients treated with chemotherapy. These data suggest that H19 lncRNA plays a leading role in breast cancer chemoresistance, mediated mainly through a H19-CUL4A-ABCB1/MDR1 pathway.

[Spatiotemporal changes of potential evapotranspiration in Songnen Plain of Northeast China].

Based on the daily meteorological data from 72 weather stations from 1961-2003, a quantitative analysis was conducted on the spatiotemporal changes of the potential evapotranspiration in the Plain. The Penman-Monteith model was applied to calculate the potential evapotranspiration; the Mann-Kendall test, accumulative departure curve, and climatic change rate were adopted to analyze the change trend of the evapotranspiration; and the spatial analysis function of ArcGIS was used to detect the spatial distribution of the evapotranspiration. In 1961-2003, the mean annual potential evapotranspiration in the Plain was 330 - 860 mm, and presented an overall decreasing trend, with the high value appeared in southwest region, low value in surrounding areas of southwest region, and a ring-belt increasing southwestward. The climatic change rate of the annual potential evapotranspiration was -0.21 mm x a(-1). The annual potential evapotranspiration was the highest in 1982, the lowest in 1995, and increased thereafter. Seasonally, the climatic change rate of the potential evapotranspiration in spring, summer, autumn, and winter was -0.19, 0.01, -0.05, and 0.03 mm x a(-1), respectively, suggesting that the potential evapotranspiration had a weak increase in winter and summer and a slight decrease in spring and autumn.

[Variation characteristics of runoff coefficient of Taizi River basin in 1967-2006].

Based on the daily precipitation and runoff data of six main embranchments (Haicheng River, Nansha River, Beisha River, Lanhe River, Xihe River, and Taizi River south embranchment) of Taizi River basin in 1967-2006, this paper analyzed the variation trend of runoff coefficient of the embranchments as well as the relationship between this variation trend and precipitation. In 1967-2006, the Taizi River south embranchment located in alpine hilly area had the largest mean annual runoff coefficient, while the Haicheng River located in plain area had the relatively small one. The annual runoff coefficient of the embranchments except Nansha River showed a decreasing trend, being more apparent for Taizi River south embranchment and Lanhe River. All the embranchments except Xihe River had an obvious abrupt change in the annual runoff coefficient, and the beginning year of the abrupt change differed with embranchment. Annual precipitation had significant effects on the annual runoff coefficient.

[Energy balance and evapotranspiration in broad-leaved Korean pine forest in Changbai Mountains].

Based on the continuous measurements of an open-path eddy covariance system, this paper analyzed the characteristics of energy balance components and evapotranspiration in a broad-leaved Korean pine forest in Changbai Mountains in 2008, as well as the differences of energy balance components and evapotranspiration between growth season and dormant season. For the test forest, the year-round energy balance closure was 72%, being at a medium level, compared to the other studies in the Fluxnet community. The energy balance components had significant differences in their diurnal and seasonal variations. In growth season, turbulent energy exchange was dominated by upward latent heat flux, accounting for 66% of available energy; while in dormant season, the turbulent energy exchange was dominated by upward sensible heat flux, accounting for 63% of available energy. The accumulated annual evapotranspiration in the study site in 2008 was 484.7 mm, occupying 87% of the precipitation at the same time period (558.9 mm), which demonstrated that evapotranspiration was the main water loss item in temperate forests of northern China.