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Simple Summary: Bladder cancer (BLCA) stands as the predominant malignancy within the global urinary system. Small Cajal body-specific RNAs (scaRNAs), constituting a distinct subset of small nucleolar RNAs (snoRNAs), have recently recognized as crucial players in various physiological and pathological processes. The aim of our retrospective study was to elucidate the potential role and mechanism of SCARNA12 in BLCA, offering a foundational understanding the functionalities of scaRNAs. Employing integrated transcriptomic and single-cell proteomic analyses, we comprehensively investigate the impact of SCARNA12 on extracellular matrix (ECM) signaling pathways. Biological experiments provide additional insights into the oncogenic nature of SCARNA12, highlighting its interaction with the transcription factor H2AFZ as a pivotal factor in contributing to the carcinogenesis and progression of BLCA. This study suggests SCARNA12 as a promising diagnostic biomarker and therapeutic target, unveiling its involvement in BLCA through modulation of ECM signaling and interaction with H2AFZ. Background: Small Cajal body-specific RNAs (scaRNAs) are a specific subset of small nucleolar RNAs (snoRNAs) that have recently emerged as pivotal contributors in diverse physiological and pathological processes. However, their defined roles in carcinogenesis remain largely elusive. This study aims to explore the potential function and mechanism of SCARNA12 in bladder cancer (BLCA) and to provide a theoretical basis for further investigations into the biological functionalities of scaRNAs. Materials and Methods: TCGA, GEO and GTEx data sets were used to analyze the expression of SCARNA12 and its clinicopathological significance in BLCA. Quantitative real-time PCR (qPCR) and in situ hybridization were applied to validate the expression of SCARNA12 in both BLCA cell lines and tissues. RNA sequencing (RNA-seq) combined with bioinformatics analyses were conducted to reveal the changes in gene expression patterns and functional pathways in BLCA patients with different expressions of SCARNA12 and T24 cell lines upon SCARNA12 knockdown. Single-cell mass cytometry (CyTOF) was then used to evaluate the tumor-related cell cluster affected by SCARNA12. Moreover, SCARNA12 was stably knocked down in T24 and UMUC3 cell lines by lentivirus-mediated CRISPR/Cas9 approach. The biological effects of SCARNA12 on the proliferation, clonogenic, migration, invasion, cell apoptosis, cell cycle, and tumor growth were assessed by in vitro MTT, colony formation, wound healing, transwell, flow cytometry assays, and in vivo nude mice xenograft models, respectively. Finally, a chromatin isolation by RNA purification (ChIRP) experiment was further conducted to delineate the potential mechanisms of SCARNA12 in BLCA. Results: The expression of SCARNA12 was significantly up-regulated in both BLCA tissues and cell lines. RNA-seq data elucidated that SCARAN12 may play a potential role in cell adhesion and extracellular matrix (ECM) related signaling pathways. CyTOF results further showed that an ECM-related cell cluster with vimentin+, CD13+, CD44+, and CD47+ was enriched in BLCA patients with high SCARNA12 expression. Additionally, SCARNA12 knockdown significantly inhibited the proliferation, colony formation, migration, and invasion abilities in T24 and UMUC3 cell lines. SCARNA12 knockdown prompted cell arrest in the G0/G1 and G2/M phase and promoted apoptosis in T24 and UMUC3 cell lines. Furthermore, SCARNA12 knockdown could suppress the in vivo tumor growth in nude mice. A ChIRP experiment further suggested that SCARNA12 may combine transcription factors H2AFZ to modulate the transcription program and then affect BLCA progression. Conclusions: Our study is the first to propose aberrant alteration of SCARNA12 and elucidate its potential oncogenic roles in BLCA via the modulation of ECM signaling. The interaction of SCARNA12 with the transcriptional factor H2AFZ emerges as a key contributor to the carcinogenesis and progression of BLCA. These findings suggest SCARNA12 may serve as a diagnostic biomarker and potential therapeutic target for the treatment of BLCA. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is one of the main blood disorders threatening human health today. This study aimed to examine the expression of BCL-2/adenovirus E1B 19 kDa-interacting protein 3-like (BNIP3L) in patients with MM and explore its mechanisms in silico. Bone marrow samples (n = 36 from patients with MM and n = 12 from healthy donors) were used to conduct BNIP3L expression analysis using immunohistochemistry. Microarray or RNA sequencing data from the Sequence Read Archive, Gene Expression Omnibus, and ArrayExpress databases were used to appraise BNIP3L expression and its prognostic role in patients with MM. The co-expressed genes of BNIP3L were identified for enrichment and protein-protein interaction (PPI) analyses to determine the associated signaling pathways. Immunohistochemistry indicated that BNIP3L expression in bone marrow of patients with MM was significantly lower than that in bone marrow of healthy donors. BNIP3L mRNA expression was also significantly lower in patients with MM than in healthy donors. The overall standard mean difference (SMD) for downregulation of BNIP3L was −0.62 [−1.17, −0.06], and the area under the curve was 0.81 [0.78, 0.85] based on a total of 694 MM cases. The overall survival analysis demonstrated that BNIP3L levels could act as an independent protective indicator of MM patient survival (HR = 0.79). Moreover, 261 co-expressed genes of BNIP3L were confirmed and found to be mainly involved in the adipocytokine signaling pathway. We preliminarily proved that downregulation of BNIP3L may play an important role in the occurrence and development of MM, and the promoting cancer capacity may be related to the pathway of adipocytokine signaling pathway. [ABSTRACT FROM AUTHOR]

Purpose: Multiple myeloma (MM) is characterized by the malignant proliferation of plasma cells, which produce a monoclonal immunoglobulin protein. The role of 5‐aminoimidazole‐4‐carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC) has not yet been well studied in the area of MM. Thus, in the current study, we sought to examine the expression levels, including mRNA and protein levels of ATIC in MM. Methods: Multiple myeloma microarray and RNA‐seq data were screened from the SRA, GEO, ArrayExpress, and Oncomine databases. The mRNA level of ATIC was extracted from the high throughput data, and the prognostic value was studied. The protein level of ATIC was also detected by in‐house immunohistochemistry on a tissue microarray. Potential signaling pathways were enriched with ATIC‐related genes in MM. Results: Both the mRNA and protein levels of ATIC were significantly upregulated in MM samples as compared to normal samples. Furthermore, the summarized Standardized Mean Difference was 1.66 with 674 cases of MM based on 10 independent studies including the in‐house tissue microarray. The overall hazard ratio of ATIC in MM was 1.7 with 1631 cases of MM based on five microarrays. In the KEGG pathway analysis, the ATIC‐related genes were mainly enriched in the pathway of complement and coagulation cascades. Conclusion: We provided the first evidence supporting the upregulation of ATIC may play an essential part in the tumorigenesis and development of MM. The promoting cancer capacity may be related to the pathway of complement and coagulation cascades. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the main causes of tumor-related deaths worldwide. Due to the lack of obvious early symptoms and the lack of sensitive screening indicators in the early stage of HCC, the vast majority of patients are diagnosed with advanced or metastatic HCC, resulting in dissatisfactory treatment result. Therefore, it is urgent to determine effective and sensitive diagnostic and prognostic indicators and to determine new therapeutic targets. Circular RNA (circRNA) is a type of non-coding RNA that has been neglected for a long time. In recent years, it has been proved to play an important role in the development of many human diseases. Increasing evidence shows that change in circRNA expression has an extensive effect on the biological behavior of HCC. In this study, we comprehensively tracked the latest progress of circRNA in the pathogenesis of HCC, and reviewed its role as a biomarker for diagnosis and prognosis prediction in patients with HCC. In addition, we also summarized the potential of circRNA as therapeutic target in HCC and its relationship with HCC drug resistance, providing clues for the clinical development of circRNA-based therapeutic strategies. [ABSTRACT FROM AUTHOR]

Previous studies have investigated the association between HOXA13 and non‑small cell lung cancer. However, the role of HOXA13 expression in the occurrence and progression of lung adenocarcinoma (LUAD) has not yet been investigated. In the present study, HOXA13‑related data mining of The Cancer Genome Atlas (TCGA), polymerase chain reaction (PCR) data from our cases and the case information in Oncomine was conducted for validation. The expression data of HOXA13 in lung cancer cell lines were also collected from the Cancer Cell Line Encyclopedia (CCLE) database for further verification. A comprehensive meta‑analysis of the expression of HOXA13 was also performed, integrating the data of TCGA, in‑house PCR and Oncomine. Genes that were co‑expressed with HOXA13 were subsequently identified through cBioPortal and Multi Experiment Matrix (MEM), and the potential role and mechanism of HOXA13 in LUAD was investigated. The expression value of HOXA13 in the LUAD group, which comprised 237 cases, was 3.74±2.694, significantly higher than its expression value in the non‑cancerous group (0.92±0.608, P<0.001). The pooled SMD for HOXA13 was 0.346 (95% CI, 0.052‑0.640; P=0.068; I2=51.3%; P=0.021), The meta‑analysis of diagnostic tests revealed that the area under the summary receiver operating characteristic curve (SROC) was 0.78 (95% CI, 0.75‑0.82). The results demonstrated that HOXA13 is highly expressed in LUAD. In addition to the studies on HOXA13 expression in tissues, the expression data of HOXA13 in lung cancer cell lines were also collected from the CCLE database for further verification of these conclusions. Genes that were co‑expressed with HOXA13 were identified for pathway analysis. The most enriched Gene Ontology terms in the genes co‑expressed with HOXA13 were positive regulation of transcription from RNA polymerase II promoter, signal transduction and positive regulation of GTPase activity in biological process; cytoplasm, integral component of membrane and plasma membrane in cellular component; and significantly involved in protein binding, transcription factor activity, sequence‑specific DNA binding and sequence‑specific DNA binding in molecular function. Kyoto Encyclopedia of Genes and Genomes analysis revealed that these target genes were clearly involved in Pathways in cancer, Proteoglycans in cancer and cAMP signaling pathway. The hub genes obtained from the four protein‑protein interaction networks were associated with HOXA13. The results of the bioinformatics research in the present study revealed that HOXA13 may influence the expression of these hub genes in such a way as to promote the occurrence and development of LUAD. In conclusion, the expression of HOXA13 in patients with LUAD and its potential clinical value were analyzed comprehensively in the present study using data from a variety of sources. Through bioinformatics analysis, evidence that HOXA13 may promote the occurrence and development of LUAD was obtained. [ABSTRACT FROM AUTHOR]

There has been accumulative evidence that microRNAs (miRNAs) play essential roles in the tumorigenesis and progression of bladder cancer. However, individual studies and small sample size caused discrepant outcomes. Thus, the current study focused on a comprehensive profiling of all differentially expressed miRNAs in a total of 519 bladder cancer tissue samples, based on miRNA microarray data. Altogether, 11 prioritized miRNAs stated by 21 published microarray datasets, including five down-regulated (miR-133a-3p, miR-1-3p, miR-99a-5p, miR-490-5p, and miR-133b) and six up-regulated candidate miRNAs (miR-182-5p, miR-935, miR-518e-3p, miR-573, miR-100-3p, and miR-3171) were analyzed with vote-counting strategy and a Robust Rank Aggregation method. Subsequently, miRNA in silico target prediction and potential pathway enrichment analysis were performed to investigate the prospective molecular mechanism of miRNAs in the tumorigenesis of bladder cancer. We found that most of the relative pathways of the aberrantly expressed miRNAs found in the current study were closely correlated with different biological processes, cellular components, molecular functions, cancer pathogeneses, and some cell signalings, such as Wnt signaling, insulin/IGF, PI3 kinase, and FGF signaling pathways. Hence, a comprehensive overview on the miRNA expression pattern in bladder cancer tissues was gained by the current study. These miRNAs might be involved in the tumorigenesis and deterioration of bladder cancer. [ABSTRACT FROM AUTHOR]

Background. Aberrant expression of microRNA-146a (miR-146a) has been found in several classes of cancers. However, its expression and clinicopathological contribution in hepatocellular carcinoma (HCC) has not been fully elucidated. Objective. To explore the clinicopathological significance of the miR-146a level in HCC formalin-fixed paraffin-embedded (FFPE) tissue. Methods. Eighty-five HCC samples and their para-cancerous normal liver tissues were collected. Total mRNA including miRNA was extracted, and miR-146a expression was determined using real-time RT-PCR. Furthermore, the correlation between the miR-146a expression and clinicopathological parameters was investigated. Results. MicroRNA-146a expression in HCC tissues was lower compared with that in adjacent non-cancerous hepatic tissues. MicroRNA-146a expression was also related to clinical TNM stage, metastasis, portal vein tumor embolus, and number of tumor nodes. Conclusions. Down-regulation of miR-146a is related to HCC carcinogenesis and deterioration of HCC. MicroRNA-146a may act as a suppressor miRNA of HCC, and it is therefore a potential prognostic biomarker for HCC patients. [ABSTRACT FROM AUTHOR]

Neutrophil extracellular traps (NETs) are promising promoters in venous thromboembolism (VTE). In the present study, we have investigated the potential thrombogenic role of NETs in colorectal cancer (CRC). A total of 583 patients with gastrointestinal malignancies who were diagnosed with or without VTE by extremities arteriovenous ultrasound and computed tomography were enrolled. The incidence of VTE in CRC was as high as 17.53%. In serological ELISA experiments, Cit-H3, MPO and cfDNA were significantly overexpressed in CRC patients with VTE compared to CRC patients without VTE and healthy individuals. Neutrophils from CRC patients with VTE produced appreciable amounts of NETs after stimulation with phorbol-12-myristate-13-acetate, which were lacking in CRC patients without VTE and healthy individuals. CfDNA was positively correlated with plasmin-α2-antiplasmin complex and tissue plasmin activator inhibitor-1 complex, and Cit-H3 was positively correlated with plasmin-α2-antiplasmin complex, suggesting that NETs are associated with increased fibrinolytic activity. We screened some NETs-related genes by analysing several high-throughput sequencing datasets of VTE and NETs. FCGR1A was identified as the optimal target gene by pan-cancer expression analysis and survival analysis. FCGR1A was significantly overexpressed in the peripheral blood of CRC patients without VTE compared to healthy individuals and showed a positive correlation with cfDNA. Neutrophil-derived NETs were significantly reduced by FCGR1A inhibitor exposure. These findings indicate that NETs are actively involved in VTE in CRC. NETs are promising thrombotic marker and therapeutic target in CRC to prevent the thrombotic consequences of cancer., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Immune infiltration is a prognostic marker to clinical outcomes in various solid tumors. However, reports that focus on bone and soft tissue sarcoma are rare. The study aimed to analyze and identify how immune components influence prognosis and develop a novel prognostic system for sarcomas., Methods: We retrieved the gene expression data from 3 online databases (GEO, TCGA, and TARGET). The immune fraction was estimated using the CIBERSORT algorithm. After that, we re-clustered samples by K-means and constructed immunoscore by the least absolute shrinkage and selection operator (LASSO) Cox regression model. Next, to confirm the prognostic value, nomograms were constructed., Results: 334 samples diagnosed with 8 tumor types (including osteosarcoma) were involved in our analysis. Patients were next re-clustered into three subgroups (OS, SAR1, and SAR2) through immune composition. Survival analysis showed a significant difference between the two soft tissue groups: patients with a higher proportion of CD8+ T cells, macrophages M1, and mast cells had favorable outcomes (p=0.0018). Immunoscore models were successfully established in OS and SAR2 groups consisting of 12 and 9 cell fractions, respectively. We found immunosocre was an independent factor for overall survival time. Patients with higher immunoscore had poor prognosis (p<0.0001). Patients with metastatic lesions scored higher than those counterparts with localized tumors (p<0.05)., Conclusions: Immune fractions could be a useful tool for the classification and prognosis of bone and soft tissue sarcoma patients. This proposed immunoscore showed a promising impact on survival prediction.

Cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) has been reported in cancers but its role and potential molecular mechanism in hepatocellular carcinoma (HCC) is unclear. Therefore, we aimed to investigate the clinical value and molecular mechanism of CELSR3 in HCC using an in vitro experiment, a meta-analysis and bioinformatics. The in vitro experiment determined the promoting effect of CELSR3 in the proliferation, invasion, and migration of HCC cells. CELSR3 knockout causes S-phage arrest in HCC cells. CELSR3 can also inhibit the apoptosis of HCC cells. The expression of the CELSR3 gene and protein was significantly elevated in HCC. Elevated CELSR3 was correlated to the bigger tumor size, higher pathological stage, and the worse overall survival of HCC. Methylation analysis revealed that the hypomethylation of CELSR3 regulated by DNMT1, DNMT3A, and DNMT3B may be the underlying mechanism of upregulated CELSR3. Biological enrichment analysis uncovered that the cell cycle, DNA replication, and PI3K-Akt signaling pathways were important pathways regulated by CELSR3 and its co-expressed genes in HCC. Taken together, upregulated CELSR3 is an important regulator in the progression and prognosis of HCC. The hypomethylation of CELSR3 and its regulation in the cell cycle may be the potential molecular mechanism in HCC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

[This corrects the article on p. 1295 in vol. 10, PMID: 29887946.].

Background: Recent studies have reported that an elevated intracellular glutathione (GSH) level is associated with resistance of non-small cell lung cancer (NSCLC) cell lines to cisplatin (CDDP). It is well-known that GSH is widely used in the clinic as a hepatoprotective agent. However, whether exogenous GSH can affect the sensitivity of NSCLC cells to CDDP remains unclear. The aim of this study is to evaluate the role of exogenous GSH in the resistance of A549 cells to CDDP., Methods: The effect of GSH and CDDP on the proliferation of A549 cells was analyzed by MTT assay. Subsequent experiments were conducted in A549 cells divided into four groups: control group (untreated cells), GSH group (treated with 120 μg/ml GSH for 48 h), CDDP group (treated with 10 μg/ml CDDP for 48 h) and CDDP+GSH group (treated with 10 μg/ml CDDP+120 μg/ml GSH for 48 h). Apoptosis was detected by flow cytometry. Light microscopy, fluorescence microscopy and electron microscopy were performed to study morphologic and ultrastructural differences among the four groups of cells. Intracellular GSH level and γ-GCS expression were determined by immunohistochemistry (IHC). Cellular platinum uptake was assessed by inductively coupled plasma mass spectrometry (ICP-MS). Quantitative RT-PCR analysis was performed to measure the expression of caspase3, caspase9, bax, bcl-2 and MDR-1. Western blot analysis was conducted to examine the protein levels of GST-π, MRP-1 and P-gp., Results: Growth inhibition and apoptosis were reduced in A549 cells in the CDDP+GSH group compared to those in the CDDP group 48 h post-treatment. Alterations in cellular morphology and ultrastructure, as well as typical characteristics of apoptosis, were observed. Intracellular GSH and γ-GCS levels were elevated by exogenous administration of GSH; in contrast, cellular platinum concentration fell rapidly. Relative to the CDDP group, the CDDP+GSH group exhibited 47.92%, 47.82% and 63.75% downregulation in caspase3, caspase9 and bax mRNA expression, respectively, and a 2.17-fold increase in bcl-2 mRNA level. In addition, there were 1.58-fold and 2.67-fold increases in the level of GST-π and MRP-1, respectively; however, the changes in MDR-1 and P-gp levels were not statistically significant., Conclusions: Our data demonstrated that exogenous GSH used as hepatinica in the clinic could induce resistance of A549 cells to CDDP by inhibiting apoptosis, elevating cellular GSH levels, inactivating the mitochondria-mediated signaling pathway, and increasing the expression of GST-π, γ-GCS and MRP1 to increase CDDP efflux., Competing Interests: None.

Management of prostate cancer, especially advanced prostate cancer, remains clinically challenging and requires the identification of new biomarkers and therapeutic targets that can be exploited to improve patient outcome. Galectin-3 (gal-3) is a carbohydrate-binding protein involved in cancer progression and metastasis, including prostate tissues. Gal-3 function is regulated by proteolytic cleavage and the cleaved gal-3 is implicated in tumor progression. This study is the first to determine gal-3 expressions with two monoclonal anti-gal-3 antibodies in prostate tissues to distinguish expression patterns between intact and cleaved gal-3 and analyze their clinical relevance. Our results showed gal-3 cleavage occurred in prostate cancer but not normal prostate. Gal-3 presented in tumor tissues was mainly the cleaved form that can be detected by the anti-gal-3 antibody targeting C terminal. The cleaved gal-3, but not the intact gal-3, was increased in prostate cancer compared to normal prostate tissues and positively associated with malignance, tumor progression and metastasis. In addition, the expression of cleaved gal-3 was closely related to PSA level, indicating a PSA-mediated degradation of intact gal-3 in prostate cancer. In summary, our findings suggested the cleaved gal-3 could be a valuable diagnostic biomarker and a therapeutic target for the treatment of prostate cancer, especially advanced metastatic prostate cancer., Competing Interests: None., (IJCEP Copyright © 2018.)

The clinical significance of p90-kDa ribosomal S6 kinase (RSK) family members in lung adenocarcinoma (LUAD) is unknown. The aim of this study was to analyze genomic alterations in RSK family membersand investigate the expression and clinicopathological significance of RSK4 in LUAD tissues. Genomic calterations of RSK family, overall survival, andinteraction networks were analyzed in patients with LUAD (n=522), using data from The Cancer Genome Atlas (TCGA) database. The expression of RSK4 protein was investigated in an independent cohort of patients with LUAD (n=127) by immunohistochemistry, and relationships between RSK4 protein levels and clinicopathological parameters of LUAD were analyzed. Patients with LUAD with RSK genomic alterations had significantly better overall survival than patients without alterations (P=0.026). RSK4 mRNA was overexpressed in LUAD compared with noncancerous lung tissue (P=0.013), and the diagnostic value of RSK4 expression was moderate, as evaluated by a value of 0.603 for the area under the receiver operator characteristic curve (95% CI, 0.551-0.655; P=0.01). RSK4 protein levels were significantly higher in LUAD than in para-carcinoma tissue (P=0.002); moreover, RSK4 protein expression was closely associated with TNM stage (P<0.001), tumor diameter (P<0.001), lymphatic metastasis (P<0.001), and distant metastasis (P=0.003). In conclusion, alterations to RSK family members may affect tumor progression in LUAD. RSK4 is a potentially useful molecular biomarker for LAUD diagnosis and may predict disease progression in patients with this condition., Competing Interests: None., (IJCEP Copyright © 2017.)

The presence of nonalcoholic fatty liver disease (NAFLD) is a strong risk predictor for type 2 diabetes (T2D). A reduction in sex hormone-binding globulin (SHBG) is associated with NAFLD. Low SHBG is also associated with insulin resistance (IR). However, very limited data are available for the association of SHBG and IR in patients with NAFLD. The study aims to clarify the association between SHBG and IR in patients with NAFLD. In this cross-sectional study, 334 men with NAFLD were recruited. SHBG, total testosterone, free testosterone, total cholesterol, triglyceride, insulin, and glucose concentrations were measured. Homeostatic model assessment (HOMA)-IR and HOMA-β were calculated. Spearman's correlations and multiple linear regressions were used to analyze the association between SHBG and IR. Men with moderate-severe NAFLD had higher waist circumference, BMI, total cholesterol, triglyceride, insulin, HOMA-IR, HOMA-β, and free testosterone, but lower SHBG than the mild NAFLD. The moderate-severe NAFLD group exhibited higher HOMA-IR (2.38±1.35 vs. 4.16±2.84, p<0.001) and lower SHBG (25.89±11.89 vs. 30.13±12.97 nmol/l, p<0.001) than the other group. SHBG value was negatively correlated with insulin, and HOMA-IR, but was not significantly correlated with glucose and testosterone. The multiple linear regression analysis showed that SHBG was significantly associated with insulin (β=- 0.241, p<0.001), and HOMA-IR (β=- 0.229, p<0.001), even adjusting for potential confounders. In conclusion, low serum SHBG is associated with IR in men with NAFLD., (© Georg Thieme Verlag KG Stuttgart · New York.)

Recent studies found that metadherin (MTDH) played an essential role in hepatocellular carcinoma (HCC). Nevertheless, the exact function of MTDH in the pathogenesis of HCC was unclarified. In the present study, we aimed to investigate the clinical significance of MTDH in HCC and its effect on HCC cells. Immunohistochemistry (IHC) was performed to detect MTDH expression in HCC tissues. Data from The Cancer Genome Atlas (TCGA) and ONCOMINE was obtained to examine MTDH expression in HCC and its clinical significance. Meta-analysis was conducted to assess the correlation between MTDH expression and both the prognosis (Overall Survival (OS) or Disease-free Survival (DFS)) and clinicopathological features of HCC via STATA 12.0. In vitro experiments were performed to investigate the role of MTDH in cell growth, caspase-3/7 activity and apoptosis in HCC cells. The MTDH staining was remarkably stronger in HCC tissues than in non-cancer tissues from IHC, TCGA and ONCOMINE data. Moreover, MTDH-positive expression was significantly correlated with pathological grade, distant metastasis and hepatitis B virus (HBV) infection by IHC. For meta-analysis, MTDH expression was indicative of poor OS without heterogeneity in HCC patients. Additionally, MTDH expression was correlated with high-grade histological differentiation, non-vascular invasion and metastasis in HCC. In vitro experiments revealed that MTDH could the inhibit cell growth and activate caspase-3/7 activity and apoptosis in the four HCC cell lines. In conclusion, MTDH expression may serve as a novel targeting strategy for HCC due to its clinical significance and oncogenic function in HCC cells., Competing Interests: None.

Although miR-132 has been studied in various human tumors, few studies have investigated the role of miR-132 in hepatocellular carcinoma (HCC). The present study aimed to evaluate the associations between miR-132 and clinicopathological parameters, including recurrence, in patients with HCC. Reverse transcription-quantitative polymerase chain reaction analysis was used to detect the expression levels of miR-132 in 95 cases of HCC and their corresponding non-cancerous liver tissues. Th e associations between miR-132 expression levels and clinicopathological characteristics, including recurrence, were investigated in patients with HCC. miR-132 expression levels were significantly reduced in HCC tissues, as compared with adjacent non-cancerous tissues (1.9245±0.7564 vs. 2.7326±1.1475; P<0.001). The area under curve (AUC) of receiver operating characteristic (ROC) used to distinguish cancerous and non-cancerous tissues was 0.711 for miR-132 expression (95% confidence interval, 0.637-0.785; P<0.001) and the optimal cut-off value was 2.25. Expression levels of miR-132 were significantly reduced in the distant metastasis (P=0.031), advanced clinical TNM stage (P=0.022), hepatitis B virus-positive (P<0.001), NM23-expressed (P=0.034), high Ki-67 labeling index (LI; P=0.005) and tumor infiltration or no capsule groups (P=0.026). Spearman correlation analysis demonstrated that miR-132 was significantly correlated with hepatitis B virus infection ( r =-0.351; P<0.001), NM23 ( r =-0.220; P=0.032), Ki-67 LI ( r =-0.264; P=0.010) and tumor capsule ( r =-0.207; P=0.044). Kaplan-Meier analysis with the log-rank test indicated an approximate difference of 8 months, although miR-132 may exhibit inferior values for the prediction of recurrence in HCC patients (50.95 vs. 58.68 months; P=0.512). Therefore, the findings of the present study indicated that miR-132 is downregulated in HCC and may serve as a tumor suppressor in its progression.

There has been accumulative evidence that microRNAs (miRNAs) play essential roles in the tumorigenesis and progression of bladder cancer. However, individual studies and small sample size caused discrepant outcomes. Thus, the current study focused on a comprehensive profiling of all differentially expressed miRNAs in a total of 519 bladder cancer tissue samples, based on miRNA microarray data. Altogether, 11 prioritized miRNAs stated by 21 published microarray datasets, including five down-regulated (miR-133a-3p, miR-1-3p, miR-99a-5p, miR-490-5p, and miR-133b) and six up-regulated candidate miRNAs (miR-182-5p, miR-935, miR-518e-3p, miR-573, miR-100-3p, and miR-3171) were analyzed with vote-counting strategy and a Robust Rank Aggregation method. Subsequently, miRNA in silico target prediction and potential pathway enrichment analysis were performed to investigate the prospective molecular mechanism of miRNAs in the tumorigenesis of bladder cancer. We found that most of the relative pathways of the aberrantly expressed miRNAs found in the current study were closely correlated with different biological processes, cellular components, molecular functions, cancer pathogeneses, and some cell signalings, such as Wnt signaling, insulin/IGF, PI3 kinase, and FGF signaling pathways. Hence, a comprehensive overview on the miRNA expression pattern in bladder cancer tissues was gained by the current study. These miRNAs might be involved in the tumorigenesis and deterioration of bladder cancer.

Background: Decoy receptor 3 (DcR3) has been reported to be involved in different cancers. However, few related researches have been accomplished on the role of DcR3 in lung cancer., Objective: To explore the expression level and clinicopathological implication of DcR3 protein in lung cancer tissues., Materials and Methods: Immunohistochemistry was used to examine DcR3 protein expression in lung cancer (n=365) and normal lung tissues (n=26). The relationships between DcR3 expression and clinical parameters were further investigated. Furthermore, the diagnostic and clinicopathological value of DcR3 mRNA was analyzed based on The Cancer Genome Atlas database in lung cancer patients., Results: Compared to normal lung tissues, DcR3 expression was significantly higher in lung cancer (P=0.007) tissues, including small-cell lung cancer (P=0.001) and non-small-cell lung cancer (P=0.008). In addition, DcR3 expression was related to tumor-node-metastasis (TNM) stage (P<0.001), tumor diameter (P=0.007), distant metastasis (P<0.001), and lymph node metastasis (P<0.001) in lung cancers. When concerning non-small-cell lung cancer, consistent correlations between DcR3 expression and TNM stage (P<0.001), tumor diameter (P=0.019), distant metastasis (P<0.001), and lymph node metastasis (P<0.001) were found. Simultaneously, in small-cell lung cancer, TNM stage (P=0.004) and lymph node metastasis (P=0.005) were also associated with DcR3 expression. Additionally, receiver operator characteristic curve revealed that the area under curve (AUC) of DcR3 was 0.637 (95% confidence interval [CI] 0.531-0.742) for lung cancer. Furthermore, DcR3 was overexpressed in both adenocarcinoma and squamous cell carcinoma tissues than in noncancerous lung tissues (all P<0.0001) based on the data from The Cancer Genome Atlas. AUC of DcR3 was 0.726 (95% CI 0.644-0.788) for lung adenocarcinoma patients and 0.647 (95% CI 0.566-0.728) for squamous cell carcinoma patients. DcR3 expression was also related to the overall survival (P<0.001) and disease-free survival (P<0.001) of lung adenocarcinoma according to the data from The Cancer Genome Atlas., Conclusion: Our study confirms that DcR3 might be involved in the tumorigenesis and deterioration of lung cancer. Therefore, the detection of DcR3 gains the potential to be applied in the clinic for screening and progression prediction of lung cancer.

BACKGROUND DcR3 (decoy receptor 3) has been proposed be involved in development and prognosis of female reproductive cancers, including cervical cancer, ovarian cancer, and breast cancer. The purpose of this meta-analysis was to explore the evidence for the correlation between DcR3 and the clinicopathological characteristics, as well as the overall survival time, in female reproductive cancers. MATERIAL AND METHODS Relevant studies were searched for in PubMed, Wiley Online Library, Web of Science, Science Direct, Cochrane Central Register of Controlled Trials, Google Scholar, EMBASE, Ovid, LILACS, Chinese CNKI, Chong Qing VIP, Wan Fang, and China Biology Medicine disc up to 30 September 2015. Data on the relationship between DcR3 expression and TNM stage, differentiation, lymph node metastasis, age, and overall survival time were extracted. Pooled odds ratios (ORs) and 95% CIs (confidence intervals) were estimated by forest plot. RESULTS Twelve studies with 1127 patients met the inclusion criteria for this meta-analysis. Overexpression of DcR3 was significantly related to the risk of female reproductive cancers (OR=10.69, 95% CI: 6.33-18.05), TNM stage (OR=5.51, 95% CI: 2.83-10.71), differentiation (OR=4.16, 95% CI: 2.28-7.60), lymph node metastasis (OR=5.89, 95% CI: 3.16-10.9), age (OR=0.85, 95% CI: 0.51-1.44), and overall survival time (OR=1.84, 95% CI: 0.58-5.83). Subgroup analyses showed that overexpression of DcR3 in cervical, ovarian, and breast cancer all had similar relationships with these clinicopathological parameters. CONCLUSIONS Our meta-analysis suggests that overexpression of DcR3 may play vital roles in the tumorigenesis and deterioration of female reproductive cancers. However, the relationship between DcR3 expression and prognosis needs further investigation.

Ki-67 is considered as one of prime biomarkers to reflect cell proliferation and immunohistochemical Ki-67 staining has been widely applied in clinical pathology. To solve the widespread controversy whether Ki-67 reactivity significantly predicts clinical prognosis of bladder carcinoma (BC), we performed a comprehensive meta-analysis by combining results from different literature. A comprehensive search was conducted in the Chinese databases of WanFang, China National Knowledge Infrastructure and Chinese VIP as well as English databases of PubMed, ISI web of science, EMBASE, Science Direct, and Wiley online library. Independent studies linking Ki-67 to cancer-specific survival (CSS), disease-free survival (DFS), overall survival (OS), progression-free survival (PFS), and recurrence-free survival (RFS) were included in our meta-analysis. With the cut-off values literature provided, hazard ratio (HR) values between the survival distributions were extracted and later combined with STATA 12.0. In total, 76 studies (n = 13,053 patients) were eligible for the meta-analysis. It was indicated in either univariate or multivariate analysis for survival that high Ki-67 reactivity significantly predicted poor prognosis. In the univariate analysis, the combined HR for CSS, DFS, OS, PFS, and RFS were 2.588 (95% confidence interval [CI]: 1.623-4.127, P < 0.001), 2.697 (95%CI: 1.874-3.883, P < 0.001), 2.649 (95%CI: 1.632-4.300, P < 0.001), 3.506 (95%CI: 2.231-5.508, P < 0.001), and 1.792 (95%CI: 1.409-2.279, P < 0.001), respectively. The pooled HR of multivariate analysis for CSS, DFS, OS, PFS, and RFS were 1.868 (95%CI: 1.343-2.597, P < 0.001), 2.626 (95%CI: 2.089-3.301, P < 0.001), 1.104 (95%CI: 1.008-1.209, P = 0.032), 1.518 (95%CI: 1.299-1.773, P < 0.001), and 1.294 (95%CI: 1.203-1.392, P < 0.001), respectively. Subgroup analysis of univariate analysis by origin showed that Ki-67 reactivity significantly correlated with all 5 clinical outcome in Asian and European-American patients (P < 0.05). For multivariate analysis, however, the pooled results were only significant for DFS, OS, and RFS in Asian patients, for CSS, DFS, PFS, and RFS in European-American patients (P < 0.05). In the subgroup with low cut-off value (<20%), our meta-analysis indicated that high Ki-67 reactivity was significantly correlated with worsened CSS, DFS, OS, PFS, and RFS on univariate analysis (P < 0.05). For multivariate analysis, the meta-analysis of literature with low cut-off value (<20%) demonstrated that high Ki-67 reactivity predicted shorter DFS, PFS, and RFS in BC patients (P < 0.05). In the subgroup analysis of high cut-off value (≥20%), our meta-analysis indicated that high Ki-67 reactivity, in either univariate or multivariate analysis, significantly correlated with all five clinical outcomes in BC patients (P < 0.05). The meta-analysis indicates that high Ki-67 reactivity significantly correlates with deteriorated clinical outcomes in BC patients and that Ki-67 can be considered as an independent indicator for the prognosis by the meta-analyses of multivariate analysis.

Background: MiR-30a-5p has been reported to play vital roles in the carcinogenesis and progression of various malignancies via different molecular mechanisms. However, the role and target genes of miR-30a-5p in hepatocellular carcinoma (HCC) remain still unclear. In silico analysis finds that there are complementary sequences between the 3'-untrasnlated region of astrocyte elevated gene 1 (AEG-1) and miR-30a-5p. Herein, we investigated the biological function of miR-30a-5p, as well as the potential molecular mechanism via targeting AEG-1 in HCC cells., Materials and Methods: MiR-30a-5p inhibitor, miR-30a-5p mimic, AEG-1 siRNAs, as well as their negative controls were transfected into HCC cell lines HepG2, SMMC-7221, HepB3 and SNU449. Then, the in vitro influence and mechanism of miR-30a-5p on cell viability, proliferation, caspase-3/7 activity and apoptosis were studied, as assessed by different methods, including spectrophotometry, fluorimetry, fluorescence microscopy of Hoechst 33342/propidium iodide double chromatin staining, western blot and dual luciferase reporter assay, respectively., Results: MiR-30a-5p mimic markedly inhibited cell growth, also induced caspase-3/7 activity and apoptosis in all four HCC cell lines tested. The strongest effect was observed in HepG2 and SMMC-7721 cells. However, this effect was slightly weaker than that of AEG-1 siRNAs. Transfection of miR-30a-5p mimic led to a markedly reduced AEG-1 protein level and further dual luciferase reporter assay confirmed that AEG-1 was one of the target genes of miR-30a-5p in HCC cells., Conclusions: MiR-30a-5p may play an essential role in the cell growth and apoptosis of HCC cells, partially via targeting AEG-1.

Background: Recent reports have suggested that miR-30a plays a tumor-suppressive role in various cancers. However, miR-30a has not been completely studied in non-small lung cancer (NSCLC). Thus, the aim of the present study was to clarify the association between the expression of miR-30a and the clinicopathological features in NSCLC patients., Material and Methods: Total RNA of miR-30a was extracted from 125 pairs of NSCLC patients (male 75, female 50) and their matching normal tissues. The miR-30a level was detected by using quantitative real-time polymerase chain reaction (qRT-PCR). Simultaneously, the 2-ΔCq method was used to calculate the correlation between miR-30a expression and the clinicopathological parameters and prognosis of NSCLC patients., Results: MiR-30a expression was significantly down-regulated in NSCLC tissues (4.0696±2.4178) compared to their non-tumor lung tissues (7.4530±3.0561, P<0.001). Level of miR-30a was negatively correlated to tumor size (r=-0.197, P=0.028), lymphatic metastasis (r=-0.312, P<0.001), clinical TNM stage (r=-0.299, P=0.001), pathological grading (I/II vs. III, r=-0.224, P=0.001), and histological classification (r=-0.299, P=0.001). Survival time was 3.23±2.18 months in the low miR-30a expression group, remarkably shorter than that of the high expression group (20.72±11.63 months, P<0.001)., Conclusions: MiR-30a may be regarded as a tumor suppressor in NSCLC, and it could become a prognostic marker and potential therapeutic target for NSCLC.

Purpose: Recent evidence suggests that the rs2910164 variant of miR-146a is associated with the development of certain types of malignancies. Hence, the aim of this study was to investigate the association between this genetic variant and the susceptibility of squamous cell carcinoma (SCC)., Methods: We performed a systematic search using PubMed, EMBASE, ISI Web of Science, Cochrane Central Register of Controlled Trials, ScienceDirect, Wiley Online Library and Chinese National Knowledge Infrastructure (CNKI) databases with the last search updated on November 15, 2014. Studies were pooled and summary odds ratios (ORs) were calculated. Potential sources of heterogeneity were sought out via subgroup analysis., Results: A total of 12 studies (5192 cases and 9945 controls) were found to be eligible for meta-analysis. Overall, no significant associations were found between miR-146a G/C polymorphism and SCC risk when all studies were pooled into the meta-analysis. In the subgroup analysis by cancer location, statistically significantly increased risks were found for cervical SCC/CSCC (CC vs CG+GG:OR = 0.521, 95% CI=0.412-0.657,p<0.001; CC+CG vs GG:OR=1.583, 95%CI=1.215-2.062,p=0.001); and for skin SCC (GC vs CC+GG:OR=2.533, 95% CI=1.989-3.224, p<0.001). In addition, the C allele and CC genotype of rs2910164 were found to be associated with an inverse risk of nasopharyngeal carcinoma (GG vs CC:OR=0.586, 95% CI=0.405-0.847, p=0.005; CC vs CG+GG:OR=1.496, 95% CI=1.189-1.881, p=0.001). Similarly, CC genotpe of rs2910164 was found to be inversely related to susceptibility of oral SCC (CC+CG vs. GG: OR=0.726, 95% CI=0.607-0.869, p<0.001)., Conclusions: The miR-146a rs2910164 polymorphism is associated with increased risk for cervical and skin SCC. In contrast, rs2910164 in miR-146a is related to decreased risk for nasopharyngeal and oral SCC.

Background: Despite present studies which suggested miR-133a as a promising biomarker for several cancers, there still exist no articles concerning the validated clinical significance of miR-133a in non-small cell lung cancer (NSCLC). Therefore, in this study, we targeted the correlation between miR-133a expression and clinicopathological significance in NSCLC patients., Methods: The expression of miR-133a in 125 cases of NSCLC and their paired adjacent non-cancerous tissues was evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Meanwhile, the relationship between miR-133a expression and several clinicopathological parameters and patient survival was analyzed., Results: The relative level of miR-133a was 2.0108 ± 1.3334 in NSCLC tissues, significantly lower than that of the adjacent non-cancerous lung tissues (3.6430 ± 2.2625, P = 0.019). The area under curve (AUC) of low expression of miR-133a to diagnose NSCLC was 0.760 (95% CI: 0.702 ~ 0.819, P < 0.001). MiR-133a expression was negatively correlated to lymphatic metastasis (r = -0.182, P = 0.042), tumor size (r = -0.253, P = 0.04), clinical TNM stages (r = -0.154, P = 0.087), and EGFR protein expression (r = -0.612, P < 0.001)., Conclusions: MiR-133a serves as a tumor-suppressive miRNA in human NSCLC, and its downregulation suggests deterioration in NSCLC patients.

Lung cancer is the most common malignant tumor worldwide. MicroRNA has become an ideal biomarker for cancer diagnosis, prognosis and therapy. The relationship between microRNA-141 and non-small cell lung cancer (NSCLC) is contradictory. Thus, in current study, we aimed to investigate the level of microRNA-141 in NSCLC tissues and to evaluate its potential clinical value. This study enrolled 125 NSCLC patients (75 males and 50 females) with a median age of 61 years (range, 23-90 years). NSCLC patients included 23 squamous cell carcinomas (SCCs), 101 adenocarcinomas (ADCs) and 1 large cell carcinoma. The expression level of microRNA-141 was significantly higher in NSCLC tissues than in adjacent lung tissues (P < 0.001), detected by real time RT-PCR. Receiver operating characteristic (ROC) exhibited a moderate diagnostic value of microRNA-141 for NSCLC with the area under curve of 0.707. The microRNA-141 expression increased with the larger tumor size (P = 0.002), lymph node metastasis (P = 0.018) and advanced stage (P = 0.022) in NSCLC patients. For subgroup analysis, microRNA-141 expression in SCC was correlated with tumor size (r = 0.490, P = 0.018), and in ADC, microRNA-141 level was positively associated with tumor size (r = 0.222, P = 0.026), lymph node metastasis (r = 0.242, P = 0.015) and TNM stage (r = 0.210, P = 0.035). Furthermore, univariate analysis revealed that the expression of microRNA-141 was an independent prognostic indicator of ADC. In conclusion, microRNA-141 is a potential biomarker for the molecular diagnosis and risk stratification of NSCLC.

Background: Aberrant expression of microRNA-148a (miR-148a) has been reported in several types of malignancies. However, its expression and clinicopathological significance in hepatocellular carcinoma (HCC) has not been entirely clarified. Our objective was to investigate the clinicopathological contribution of the miR-148a expression in HCC formalin-fixed paraffin-embedded (FFPE) tissues., Methods: Eighty-nine HCC and their para-cancerous liver tissues were recruited. Total mRNA including miRNA was isolated and miR-148a expression was determined by using real time RT-qPCR. Furthermore, the relationship between the miR-148a level and clinicopathological features was explored., Results: Significantly lower miR-148a expression in HCC tissues was observed than that in adjacent noncancerous hepatic tissues. miR-148a expression was also correlated to clinical TNM stage, metastasis, status of capsular infiltration and numbers of tumor nodes., Conclusions: Underexpression of miR-148a might be associated with HCC tumorigenesis and deterioration of HCC. miR-148a might act as a suppressor miRNA of HCC and it therefore has a potential role in prognosis of HCC patients.

Previously, we found that the expression of microRNA-146a (miR-146a) was downregulated in hepatocellular carcinoma (HCC) formalin-fixed paraffin-embedded (FFPE) tissues compared to the adjacent noncancerous hepatic tissues. In the current study, we have explored the in vitro effect of miR-146a on the malignant phenotypes of HCC cells. MiR-146a mimic could suppress cell growth and increase cellular apoptosis in HCC cell lines HepG2, HepB3, and SNU449, as assessed by spectrophotometry, fluorimetry, and fluorescence microscopy, respectively. Furthermore, western blot showed that miR-146a mimic downregulated EGFR, ERK1/2, and stat5 signalings. These effects were less potent compared to that of a siRNA targeting EGFR, a known target gene of miR-146a. Moreover, miR-146a mimic could enhance the cell growth inhibition and apoptosis induction impact of various EGFR targeting agents. The most potent combination was miR-146a mimic with cetuximab, presenting a synergistic effect. In conclusion, miR-146a plays a vital role in the cell growth and apoptosis of HCC cells and inducing miR-146a level might be a critical targeted molecular therapy strategy for HCC.