Upregulation of TMEM40 is associated with the malignant behavior and promotes tumor progression in cervical cancer.

OBJECTIVE: Recent studies indicated that transmembrane protein 40 (TMEM40) is associated with several types of cancers but is not clear in cervical cancer (CC). The study aimed to examine the role of TMEM40 in CC and related mechanisms. METHODS: The expression of TMEM40 in CC tissues and cell lines was studied with western blot and real-time quantitative RT-PCR. The effect of TMEM40 on proliferation was evaluated by CCK-8, EdU and colony formation assay. The migration, invasion, cell cycle and apoptosis of CC cells were studied with wound healing, transwell assays and flow cytometry. Tumor growth was evaluated in vivo using a xenogenous subcutaneously implant model. RESULTS: The results revealed that the TMEM40 elevation in CC tissues and cell lines was closely correlated with tumor size and lymph node metastasis in clinical patients. Upregulation of TMEM40 with OE-TMEM40 vector promoted the invasion, migration and proliferation, inhibited the apoptosis and led to distinct S cell cycle arrest in CC cell lines. Silencing TMEM40 with shRNA inhibited the invasion, migration and proliferation, promoted apoptosis and led to a G0/G1 cell cycle arrest in CC cell lines. Silence of TMEM40 downregulated the expression of c-MYC, Cyclin D1, matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-9 (MMP-9), but in contrast, activated p53 and several apoptosis related proteins such as p53, Caspase-3, Caspase-9 and PARP1. In addition, TMEM40 silencing dramatically decreased tumor growth in mice models. CONCLUSION: The present study demonstrates that TMEM40 upregulation can be a potential prognostic biomarker and contribute to CC development.

Elevated expression of myosin VI contributes to breast cancer progression via MAPK/ERK signaling pathway.

Breast cancer (BC) is one of the most common malignancies occurring in women worldwide, and its incidence is increasing each year. Accumulating evidence indicated that Myosin VI (MYO6) functions as a gene associated with tumor progression in several cancers. However, the potential role of MYO6 and its underlying mechanisms in the development and progression of BC remains unknown. Herein, we examined the expression levels of MYO6 in BC cells and tissues by western blot and immunohistochemistry. Loss- and gain-of-function investigations in vitro were performed to determine the biological functions of MYO6. And in vivo effects of MYO6 on tumorigenesis were investigated in nude mice. Our findings showed that the expression of MYO6 was up-regulated in breast cancer, and its high expression was correlated with poor prognosis. Further investigation exhibited that silencing the expression of MYO6 significantly inhibited cell proliferation, migration and invasion, whereas overexpression of MYO6 enhanced these abilities in vitro. Also, reduced expression of MYO6 significantly retarded the tumor growth in vivo. Mechanistically, Gene Set Enrichment Analysis (GSEA) revealed that MYO6 was involved in mitogen-activated protein kinase (MAPK) pathway. Moreover, we proved that MYO6 enhanced BC proliferation, migration and invasion via increasing the expression of phosphorylated ERK1/2. Taken together, our findings highlight the role of MYO6 in promoting BC cell progression through MAPK/ERK pathway, suggesting it may be a new potential therapeutic and prognostic target for BC patients.

Myo1b promotes tumor progression and angiogenesis by inhibiting autophagic degradation of HIF-1α in colorectal cancer.

Myosin 1b (Myo1b) is an important single-headed membrane-associated motor of class I myosins that participate in many critical physiological and pathological processes. Mounting evidence suggests that the dysregulation of Myo1b expression has been extensively investigated in the development and progression of several tumors. However, the functional mechanism of Myo1b in CRC angiogenesis and autophagy progression remains unclear. Herein, we found that the expression of Myo1b was upregulated in CRC tissues and its high expression was correlated with worse survival. The overexpression of Myo1b promoted the proliferation, migration and invasion of CRC cells. Conversely, silencing of Myo1b suppressed tumor progression both in vitro and in vivo. Further studies indicated that Myo1b inhibited the autophagosome-lysosome fusion and potentiated the VEGF secretion of CRC cells to promote angiogenesis. Mechanistically, Myo1b blocked the autophagic degradation of HIF-1α and then led to the accumulation of HIF-1α, thus enhancing VEGF secretion and then promoting tumor angiogenesis in CRC. Together, our study provided novel insights into the role of Myo1b in CRC progression and revealed that it might be a feasible predictive biomarker and promising therapeutic target for CRC patients.

Long noncoding RNA MIR210HG is induced by hypoxia-inducible factor 1α and promotes cervical cancer progression.

Increasing evidence has indicated that long noncoding RNAs (lncRNAs) play essential roles in various types of cancer, especially the ability of tumor cells to adapt to hypoxia conditions. However, only a few of them have been experimentally validated in cervical squamous cell carcinoma (CSCC). In the current study, we identified a hypoxia-induced lncRNA MIR210HG was excessively expressed in CSCC tissues and regulated by human papillomavirus (HPV) type 16 E6 and E7 via hypoxia-inducible factor 1α (HIF-1α). Functional assays revealed the role of MIR210HG in promoting proliferation, migration and invasion of CSCC cells in vitro under normoxia as well as hypoxia conditions. Meanwhile, stable MIR210HG silencing dramatically repressed tumor growth and pulmonary metastasis in vivo. Mechanistically, the depletion of MIR210HG or HIF-1α decreased each other's expression level, while silencing MIR210HG or HIF-1α respectively downregulated the expression levels of phosphoglycerate kinase 1 (PGK1), one of key metabolic enzymes in the glycolysis pathway. Furthermore, decreased expression of PGK1 by HIF-1α knockdown was reversed through the overexpression of MIR210HG. Also, we demonstrated HIF-1α can activate the transcription of MIR210HG via binding its promoter. Taken together, these results expand our understanding of the cancer-associated functions of hypoxia-induced lncRNAs, and highlight MIR210HG forms a feedback loop with HIF-1α contributing to cervical carcinogenesis, with potential implications for therapeutic targeting.

LncRNA HIF1A-AS2 modulated by HPV16 E6 regulates apoptosis of cervical cancer cells via P53/caspase9/caspase3 axis.

BACKGROUND: Plentiful evidence proves that lncRNAs play a crucial role in tumor development. However, the function and mechanism that were mediated by lncRNA HIF1A-AS2 in cervical cancer remain unclear. METHODS: The lncRNA HIF1A-AS2 was identified via high-throughput microarray analysis of three HPV 16-positive cervical squamous cell carcinoma (CSCC) samples and three HPV-negative normal controls. The expression of HIF1A-AS2 was detected by qRT-PCR in clinical tissues and cancer cells. In vitro and in vivo assays were performed through downregulation or upregulation of HIF1A-AS2. The possible mechanisms of HIF1A-AS2 in cervical cancer cells were explored by western blot, flow cytometric analysis and rescue assays. RESULTS: HIF1A-AS2 was significantly increased in cervical cancer tissue, and in the HPV- positive cervical cancer cells. Further investigation showed that the inhibition of HIF1A-AS2 suppressed cell proliferation, migration, invasion, and induced apoptosis, while up-regulation of HIF1A-AS2 revealed opposite results. In terms of mechanism, we found that HIF1A-AS2 was mediated by HPV16 E6 and regulated cell apoptosis via P53/caspase 9/caspase 3 axis. CONCLUSION: Our findings demonstrate that HIF1A-AS2 functions as a carcinogenic lncRNA that promotes tumor development, and serves as a candidate prognostic factor, which may contribute to the treatment of cervical cancer.

Myosin 1b promotes migration, invasion and glycolysis in cervical cancer via ERK/HIF-1α pathway.

BACKGROUND: Increasing evidence indicated that metabolic reprograming is essential and has been regarded as a hallmark of cancer. Although the biological functions of Myosin 1b (Myo1b) have been reported in several malignancies, the correlation between Myo1b and cancer metabolism, and its underlying mechanisms remain elusive, particularly in cervical cancer (CC). METHODS: Myo1b and other glycolytic enzymes expression levels were examined in CC cells and tumor tissues from xenograft models by quantitative real-time PCR, Western blot and immunohistochemistry. The biological impacts and regulatory mechanisms of Myo1b on cell migration, invasion and glycolysis were explored. Also, the effects of Myo1b on carcinogenesis and metastasis in nude mice were investigated. RESULTS: Upregulation of Myo1b was found in CC tissues and associated with poor prognosis. Overexpressed Myo1b not only significantly elevated CC cell glycolysis, migration and invasion in vitro, but also promoted tumorigenesis and metastasis in vivo. Conversely, Myo1b knockdown had opposite consequences. Moreover, our study suggested that Myo1b stimulated ERK/HIF-1α pathway and its downstream glycolysis associated genes to modulate the glycolysis, migration and invasion of CC. CONCLUSION: These findings provide evidence that Myo1b regulates migration, invasion and glycolysis in CC through ERK/HIF-1α pathway, suggesting a promising remedial target in treatment of CC.

Long noncoding RNA SNHG12 modulated by human papillomavirus 16 E6/E7 promotes cervical cancer progression via ERK/Slug pathway.

Recently, long noncoding RNA SNHG12 has been reported to be dysregulated in various types of cancer. This study investigated its biological function and the underlying molecular mechanism in cervical squamous cell carcinoma (CSCC). We found that SNHG12 was significantly overexpressed in CSCC tissues. Further evidence showed that human papillomavirus (HPV) type 16 E6 and E7 might regulate the expression level of SNHG12 by modulating transcription factor c-Myc. Functional experiments suggested that SNHG12 knockdown dramatically repressed CSCC cells proliferation, migration, and invasion while induced apoptosis in vitro as well as suppressed tumor growth in vivo. In addition, SNHG12 could facilitate epithelial-mesenchymal transition through ERK/Slug/E-cadherin pathway at least in part. Our findings highlight SNHG12 functions as an oncogenic long noncoding RNA in malignant phenotype and tumorigenesis of CSCC, which implicate it may be a potential target for CSCC treatment.

Human papillomavirus 16 E7 oncoprotein alters the expression profiles of circular RNAs in Caski cells.

Cervical cancer is one of the most common cancer in female worldwide. The expression of high-risk human papillomavirus E7 oncogene is necessary for the maintenance of malignant phenotypes and transformation. Accumulating studies of this protein has been explored in cervical cancer, however, there are fewer studies on how E7 expression affects the expression of global circular RNA. CircRNA, a promising biomarker and even therapeutic target, has become a star molecular in research after miRNA and long non-coding RNA. Our aim of this study was to investigate the global circRNA levels modulated by HPV E7 expression and identified the potential consequences for mechanism studies. Here we investigated the expression profiles of circRNAs by transfecting E7 siRNA in Caski cells with high-throughput microarray technology. In total, we identified 526 dysregulated circRNAs with fold change ≥2 or≤0.5, and p< 0.05. Among them, 352 were up-regulated and 174 were down-regulated. In addition, 8 selected circRNAs confirmed using qRT-PCR was in line with the results of microarray analysis. Furthermore, bioinformatic analyses indicated that differently expressed circRNAs might implicate in the mTOR signaling pathway, proline metabolism and glutathione metabolism. In conclusion, this study showed the expression profiles of circRNAs regulated by HPV16 E7 in cervical cancer cells and provides novel insights into the new potential candidates for future mechanism studies.

Myosin 1b promotes cell proliferation, migration, and invasion in cervical cancer.

OBJECTIVE: Recent evidence suggests an important role of Myosin 1b (Myo1b) in the progression of several cancers, including prostate cancer and head and neck squamous cell carcinoma (HNSCC). However, the contribution of Myo1b to cervical cancer (CC) remains elusive. METHODS: Quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry and western blotting assays were used to confirm the expression of Myo1b in CC tissues compared with matched non-tumor tissues and CC cells, and analyze its clinical significance. In vitro, RNA interference (siRNA or shRNA) was used to investigate the biological function and underlying mechanism of Myo1b in cervical carcinogenesis. Furthermore, tumor growth was evaluated in vivo using a xenogenous subcutaneously implant model. RESULTS: Here, for the first time we reported that Myo1b expression was significantly increased in human CC, compared to cervical intraepithelial neoplasia (CIN) and normal cervical tissues and that the upregulation of Myo1b was significantly correlated with FIGO Stage, HPV infection, lymph node metastasis and pathological grade. In vitro, knockdown of Myo1b significantly suppressed proliferation, migration, and invasion of CaSki and SiHa cells, and markedly decreased the MMP1/MMP9 activities. Also, silencing the expression of Myo1b dramatically repressed tumor growth in a mouse xenograft model. Further investigations showed that HPV16 E6 or E7 could enhance the expression of Myo1b via upregulating c-MYC. CONCLUSION: Taken together, our data suggested a potential role of Myo1b in cervical carcinogenesis and tumor progression and provided novel insights into the mechanism of how this factor promotes cell proliferation, migration, and invasion in CC cells.

High expression of TMEM40 is associated with the malignant behavior and tumorigenesis in bladder cancer.

BACKGROUND: Bladder cancer (BCa) is one of the most common cancers in the urinary system among the world. Previous studies suggested that TMEM40 expression level was significantly associated with clinicopathological parameters including histological grade, clinical stage and pT status of bladder cancer. However, the molecular mechanism of TMEM40 in BCa remains poorly understood. METHODS: Real-time quantitative RT-PCR (qRT-PCR) and western blot (WB) were used to examine the expression levels of TMEM40 in BCa tissues, paired non-cancer tissues and cell lines. A series of experiments, including CCK-8, wound healing, flow cytometry, transwell and EdU assays were performed to assess the effects of TMEM40 on cell proliferation, cell cycle and apoptosis, migration and invasion. In addition, tumor growth was evaluated in vivo using a xenogenous subcutaneously implant model. All statistical analyses were executed by using the SPSS 20.0 software. All experimental data from three independent experiments were analyzed by Student's t test and results were expressed as mean ± standard deviation. RESULTS: In this study, we identified the role of TMEM40 in the tumorigenesis of bladder cancer and found that it was upregulated in bladder cancer tissues and cell lines, compared with their normal counterparts. The results demonstrated that effective silence of TMEM40 expression suppressed cell proliferation, blocked G1-to-S cell cycle transition, and inhibited cell migration and invasion in human bladder 5637 and EJ cell lines. Consistently, in vivo data showed that TMEM40 silencing could dramatically decreased tumor growth. Further study revealed that TMEM40 knockdown resulted in accumulation of p53 and p21 protein and decrease of c-MYC and cyclin D1 protein. CONCLUSION: These data suggest that TMEM40 represents a potential oncogene, which exert a crucial role in the proliferation and apoptosis via the p53 signaling pathway in BCa, thus probably serve as a novel candidate biomarker and a potential therapeutic target for patients with BCa.

Low expression of PinX1 is associated with malignant behavior in basal-like breast cancer.

Human Pinx1 protein, associated with shelterin proteins, is widely revealed as a haploinsufficient tumor suppressor. Growing evidence has manifested the deregulation of PinX1 in distinct cancers. Nonetheless, the loss status of PinX1 and its diagnostic, prognostic and clinicopathological significance in Basal-like breast cancer are still unclear. In the present study, the PinX1 expression levels of breast cancer tissues were investigated by qRT-PCR and immunoblotting assays. Then immunohistochemistry (IHC) was performed to detect PinX1 expression on a tissue microarray. The optimal threshold for PinX1 positivity was determined by receiver operating characteristic (ROC) curve analysis. To clarify the probable role of PinX1 in BLBC, the PinX1 knockout and stably over-expressed MDA-MB-231 cell lines were constructed by the CRISPR-Cas9 system and gene transfection. The association of PinX1 expression with cell proliferation, migration and apoptosis of MDA-MB-231 cells were observed by CCK-8 assay, wound healing assay, transwell assay, flow cytometric analysis and immunoblotting of the cleaved caspase-3 protein level. Our results showed that both PinX1 mRNA and protein expression were downregulated in breast cancer tissues (P<0.05). In IHC analysis, the optimal cut-off parameter for PinX1 positive expression was 62.5% (the AUC was 0.749, P<0.01). PinX1 positivity was 76.9% (10/14) in luminal subtypes, 50% (5/10) in Her2-enriched breast cancer and 27.3% (9/33) in basal-like subtypes. Besides, in 59 invasive ductal breast carcinomas, PinX1 expression was inversely related to histology grade (P<0.05) while it was positively associated with PR status (P<0.05) and ER status (P<0.05). These results indicated that low expression of PinX1 correlated with aggressive clinicopathological significance of breast cancer, especially in the basal-like subtype. Besides, we identified that overexpression of PinX1 inhibited the proliferation rates and migration ability and increased the apoptosis rates of BLBC. Our findings demonstrated that low expression of PinX1 was associated with malignant behaviors in basal-like subtype of breast cancer. PinX1 is likely a feasible biomarker and molecular target of BLBC.

Expression of TMEM40 in bladder cancer and its correlation with clinicopathological parameters.

Transmembrane protein 40 (TMEM40) is a 23-kDa protein in cell membrane. There is no report that TMEM40 is associated with cancer. However, our study found that TMEM40 was high expressed in bladder cancer tissues. Immunohistochemical analyses of TMEM40 expression were performed on a tissue microarray including 72 transitional cell carcinomas and 43 normal bladder tissues to investigate the expression and clinical significance of TMEM40 in bladder cancer. We adopted receiver operating characteristic (ROC) analysis to select the optimal cut-off score. TMEM40 expression was defined positive if above 62.5% of cells were stained, and below it was negative. Then, the expression of TMEM40 in bladder cancer cells was evaluated by quantitative real-time PCR and western blot analysis. A significantly high level of TMEM40 in bladder cancer cells was proved. On the basis of ROC curve analysis, TMEM40 expression was positive in 68.1% (n=49) and negative in 31.9% (n=23) of bladder cancer cases. TMEM40 staining was positive in 2.3% (n=1) and negative in 97.7% (n=42) of normal bladder tissues. It showed that TMEM40 was up-regulated in bladder cancer tissues compared to normal bladder tissues. Moreover, TMEM40 expression was significantly associated with histological grade (P<0.05), clinical stage (P<0.05), pT status (P<0.05), but not age. Our study demonstrates that high TMEM40 expression is associated with bladder cancer, and it could be a diagnostic biomarker for bladder cancer.

Association between APE1 Asp148Glu polymorphism and the risk of urinary cancers: a meta-analysis of 18 case-control studies.

BACKGROUND: Several observational studies suggested that APE1 Asp148Glu was significantly associated with urinary cancers; however, the results of published studies are inconsistent. MATERIALS AND METHODS: The PubMed and EMBASE were searched for case-control studies regarding the association between Asp148Glu and the risk of urinary cancers with a time limit of September 12, 2015. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association between Asp148Glu and the risk of developing prostate cancer, kidney cancer, bladder cancer, as well as all urinary cancers combined. RESULTS: A total of 18 case-control studies were included in the analysis. Our meta-analysis revealed that the inheritance of at least one APE1 148Glu among Asian men was associated with a 1.26-fold increase in the risk of developing urinary cancers. Meanwhile, APE1 Asp148Glu was significantly associated with the risk of prostate cancer. However, there were no significant relationships between the APE1 SNP (single nucleotide polymorphism) and all urinary cancers combined and bladder cancer and kidney cancer among the men of Caucasian/Asian/African descent or all racial/ethnic groups combined. When stratified by the quality score, no significant association was found in high-quality studies (score ≥7), but a significant increased risk of urinary cancers was observed in lower quality studies (score <7) (dominant model: OR=1.27, 95% CI=1.11-1.45). CONCLUSION: Our meta-analysis suggests that APE1 Asp148Glu was not associated with the risk of urinary cancers but might increase the risk of urinary cancers among Asians. Stratification by cancer type identified a significant association of Asp148Glu with prostate cancer.

MiR-519d facilitates the progression and metastasis of cervical cancer through direct targeting Smad7.

BACKGROUND: MicroRNAs (miRNAs) play pivotal roles in the development of various cancer types, including cervical cancer. METHODS AND RESULTS: In this study, we showed that miR-519d, a miRNA within the chromosome 19 miRNA cluster, was significantly upregulated in cervical cancer tissues, compared with non-tumorous cervical samples. Suppression of miR-519d markedly attenuated the migration and invasion of HeLa and SiHa cervical cancer cells. Additionally, miR-519d inhibited the apoptosis of cervical cancer cells, and the proliferation of cervical cancer cells was also affected following transfection of miR-519d inhibitor. Moreover, we identified Smad7 to be a novel target of miR-519d in cervical cancer cells. MiR-519d matched the 3'-UTR of Smad7 mRNA. Transfection with miR-519d mimics led to apparent downregulation of Smad7 both at the mRNA and protein levels. Luciferase reporter analysis revealed that miR-519d reduced the luciferase activity of Smad7 mRNA 3'-UTR through matching site-dependent manner. And more notably, suppression of Smad7 remarkably restored the migration and invasion of miR-519d-depleted cervical cancer cells. CONCLUSION: Taken together, these findings implicated that miR-519d promoted the progression and metastasis of cervical cancer through targeting Smad7.

Association between three exonuclease 1 polymorphisms and cancer risks: a meta-analysis.

To date, the results of studies exploring the relation between exonuclease 1 (Exo1) polymorphisms and cancer risks have differed. In this study, we performed a meta-analysis to investigate the effect of the three most extensively studied Exo1 polymorphisms (Pro757Leu, Glu589Lys, and Glu670Gly) on cancer susceptibility. The related studies published before August 5, 2015, were collected by searching the PubMed and EMBASE databases. We found 16 publications containing studies that were eligible for our study, including 10 studies for Pro757Leu polymorphism (4,093 cases and 3,834 controls), 12 studies for Glu589Lys polymorphism (6,479 cases and 6,550 controls), and 7 studies for Glu670Gly polymorphism (3,700 cases and 3,496 controls). Pooled odds ratios and 95% confidence intervals were used to assess the strength of the associations, and all the statistical analyses were calculated using the software program STATA version 12.0. Our results revealed that the Pro757Leu polymorphism was significantly associated with a reduced cancer risk, whereas an inverse association was found for the Glu589Lys polymorphism. Furthermore, subgroup analysis of smoking status indicated that the Glu589Lys polymorphism was significantly associated with an increased cancer risk in smokers, but not in nonsmokers. However, no evidence was found for an association between the Glu670Gly polymorphism and cancer risk. In conclusion, this meta-analysis suggests that the Pro757Leu polymorphism may provide protective effects against cancer, while the Glu589Lys polymorphism may be a risk factor for cancer. Moreover, the Glu670Gly polymorphism may have no influence on cancer susceptibility. In the future, large-scaled and well-designed studies are needed to achieve a more precise and comprehensive result.

Anti-tumor activity of phenoxybenzamine hydrochloride on malignant glioma cells.

Phenoxybenzamine hydrochloride (PHEN) is a selective antagonist of both α-adrenoceptor and calmodulin that exhibits anticancer properties. The aim of this study was to explore the anti-tumor function of PHEN in glioma. Cell proliferation assay was used to assess glioma cell growth. Migration and invasion capacity of glioma cells was monitored by wound-healing and transwell assay, respectively. Neurosphere formation test was adopted for the tumorigenesis of glioma cells, which was also confirmed by soft agar cloning formation test in vitro and a nude mouse model in vivo. Finally, we explored the potential pathway utilized by PHEN using Western blot and immunofluoresce staining. PHEN exhibited a significant inhibitory effect on the proliferation of both U251 and U87MG glioma cell lines in a positive dose-dependent manner. PHEN apparently attenuated the malignancy of glioma in terms of migration and invasion and also suppressed the tumorigenic capacity both in vitro and in vivo. Mechanism study showed that PHEN promoted tumor suppression by inhibiting the TrkB-Akt pathway. The results of the present study demonstrated that PHEN suppressed the proliferation, migration, invasion, and tumorigenesis of glioma cells, induced LINGO-1 expression, and inhibited the TrkB-Akt pathway, which may prove to be the mechanisms underlying the anti-tumor effect of PHEN on glioma cells.

Differential lncRNA expression profiles in recurrent gliomas compared with primary gliomas identified by microarray analysis.

Glioma, especially high-grade glioma, is highly malignant with high rate of recurrence and poor prognosis. The mechanisms of glioma progression and recurrence have not been elucidated. Previous studies showed that long non-coding RNAs (lncRNAs) involved in the development and progression of glioma. However, the roles of lncRNAs in the recurrence of glioma remain unknown. We use high throughput microarray to screen the differentially expressed lncRNAs and mRNAs in recurrence gliomas compared with primary gliomas. We found a total of 1,111 lncRNAs were differentially expressed in recurrent group. Among these, 639 lncRNAs were up-regulated, while 472 lncRNAs were down-regulated (fold Change ≥2.0). GO (Gene ontology) and pathway analysis revealed that the potential functions of differentially expressed lncRNAs were closely connected with the processes of cancer progression and pathogenesis. LncRNA classification and subgroup analysis further identified three important clusters of differentially expressed lncRNA-mRNA pairs which have potential gene regulatory functions. This study for the first time showed abundant differentially expressed lncRNAs in recurrent gliomas. Some lncRNAs may play important roles in glioma recurrence, such as previously reported H19, CRNDE, HOTAIRM1 or unreported AC016745.3, XLOC_001711, RP11-128A17.1. Moreover, this study set a basis for future researches on specific lncRNA which may contribute to the recurrence of glioma. Further studies on these lncRNAs will help to elucidate the mechanism of glioma recurrence at genetic level and find therapeutic targets for glioma patients.

Expression of HERC4 in lung cancer and its correlation with clinicopathological parameters.

BACKGROUND: Growing evidence suggests that the members of the ubiquitin-proteasome system (UPS) are important for tumorigenesis. HERC4, one component, is a recently identified ubiqutin ligase. However, the expression level and function role of HERC4 in lung cancer remain unknown. Our objective was to investigate any correlation between HERC4 and development of lung cancer and its clinical significance. MATERIALS AND METHODS: To determine HERC4 expression in lung cancer, an immunohistochemistry analysis of a tissue microarray containing samples of 10 lung normal tissues, 15 pulmonary neuroendocrine carcinomas, 45 squamous epithelial cancers and 50 adenocarcinomas was conducted. Receiver operating characteristic (ROC) curve analysis was applied to obtain a cut-off point of 52.5%, above which the expression of HERC4 was regarded as "positive". RESULTS: On the basis of ROC curve analysis, positive expression of HERC4 was detected in 0/10 (0.0%) of lung normal tissues, in 4/15 (26.7%) of pulmonary neuroendocrine carcinomas, in 13/45 (28.9%) of squamous epithelial cancers and in 19/50 (38.0%) of adenocarcinomas. It showed that lung tumors expressed more HERC4 protein than adjacent normal tissues (χ2=4.675, p=0.031). Furthermore, HERC4 positive expression had positive correlation with pT status (χ2=44.894, p=0.000), pN status (χ2=43.628, p=0.000), histological grade (χ2=7.083, p=0.029) and clinical stage (χ2=72.484, p=0.000), but not age (χ2=0.910, p=0.340). CONCLUSIONS: Our analysis suggested that HERC4 is likely to be a diagnostic biomarker for lung cancer.

Comprehensive assessment of associations between ERCC2 Lys751Gln/Asp312Asn polymorphisms and risk of non- Hodgkin lymphoma.

BACKGROUND: Excision repair crossing-complementing group 2 (ERCC2), also called xeroderma pigmentosum complementary group D (XPD), plays a crucial role in the nucleotide excision repair (NER) pathway. Previous epidemiological studies have reported associations between ERCC2 polymorphisms and non-Hodgkin lymphoma (NHL) risk, but the results have remained controversial. MATERIALS AND METHODS: We conducted this meta- analysis based on eligible case-control studies to investigate the role of two ERCC2 polymorphisms (Lys751Gln and Asp312Asn) in determining susceptibility to NHL. Ten case-control studies from several electronic databases were included in our study up to August 14, 2014. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- or random-effects models to estimate the association strength. RESULTS: The combined results based on all studies did not show any association between Lys751Gln/Asp312Asn polymorphisms and NHL risk for all genetic models. Stratified analyses by histological subtype and ethnicity did not indicate any significant association between Lys751Gln polymorphism and NHL risk. However, a significant reduced risk of NHL was found among population-based studies (Lys/Gln versus Lys/Lys: OR=0.87, 95% CI=0.77-0.99, P=0.037) but not hospital-based studies. As for Asp312Asn polymorphism, there was no evidence for the association between this polymorphism and the risk of NHL in all subgroup analyses. CONCLUSIONS: This meta-analysis suggests that there may be no association between Lys751Gln/Asp312Asn polymorphism and the risk of NHL and its two subtypes, whereas ERCC2 Lys751Gln heterozygote genotype may provide protective effects against the risk of NHL in population-based studies. Therefore, large-scale and well-designed studies are needed to clarify the effects of haplotypes, gene-gene, and gene-environment interactions on these polymorphisms and the risk of NHL and its different histological subtypes in an ethnicity specific population.