Purpose: Whether N-telopeptide of type I collagen (NTx) can be applied for diagnosis and prognostic prediction of bone metastasis in human cancers is still conflicting. This study aimed to investigate the diagnostic and prognostic value of NTx for cancer patients with bone metastasis. Methods: Embase, PubMed, Chinese National Knowledge Infrastructure and Wanfang databases were retrieved to collect related publications. In diagnostic meta-analysis, the sensitivity (SEN) and specificity (SPE) were calculated. Hazard ratio (HR) with 95% confidence interval (95% CI) was used in the prognostic meta-analysis. Sensitivity and publication analyses were conducted for potential heterogeneity sources. Results: The pooled SEN and SPE were 77% (72-81%) and 80% (75-84%) for 45 diagnostic studies. A higher diagnostic efficacy was obtained from NTx combining with other markers (AUC: 0.94 (0.92-0.96)) for bone metastasis of human cancers, especially for lung cancer (AUC: 0.87 (0.84-0.90)), breast cancer (AUC: 0.83 (0.79-0.86)) and prostate cancer (AUC: 0.88 (0.85-0.90)) in Asian people (AUC: 0.86 (0.83-0.89)). For the value of NTx on prognosis of human cancers with bone metastasis, the pooled HR was 2.12 (1.74-2.58) for high versus low NTx level, indicating high NTx level would increase the risk of poor overall survival. Conclusion: Our results indicated serum NTx combining with other markers can become a feasible biomarker for the diagnosis and prognosis prediction for bone metastasis of different cancers, including lung cancer, breast cancer and prostate cancer in Asian people.

Hypoxia-exposed lung cancer-released exosomal microRNA-23a (miR-23a) has been shown to enhance angiogenesis as well as vascular permeability, contributing to the close correlation between exosomal miR-23a and tumorigenesis. The current study aimed to investigate whether gastric cancer (GC) cell-derived exosomal miR-23a could induce angiogenesis and to elucidate the potential mechanisms associated with the process. Differentially expressed miRNAs in GC were initially screened from the Gene Expression Omnibus database. Target genes were selected following miRNA-mRNA prediction and subsequently verified by dual luciferase reporter assay. RT-qPCR was conducted to detect miR-23a and PTEN expression in GC tissues, cells and exosomes. Human umbilical venous endothelial cells (HUVECs) were co-cultured with GC cell-derived exosomes to assess the angiogenesis mediated by exosomes in vitro. Additionally, PTEN was overexpressed in HUVECs to analyze the mechanism by which miR-23a regulates angiogenesis. miR-23a was highly expressed in GC tissues and cells and GC cell-derived exosomes. Angiogenesis was promoted by the co-culture of HUVECs and GC cells-derived exosomes, as evidenced by the increased expression of VEGF but decreased expression of TSP-1. PTEN was targeted by miR-23a and was lowly expressed in GC tissues. In a co-culture system, miR-23a carried by GC cells-derived exosomes promoted angiogenesis via the repression of PTEN. Collectively, GC cell-derived exosomal miR-23a could promote angiogenesis and provide blood supply for growth of GC cells. This study contributes to advancement of miRNA-targeted therapeutics.

The authors identified an error in the analysis of the DLS measurement of exosome size distribution in Fig. 4A. The original analysis utilized an unreasonable parameter setting during analysis after exosome extraction, resulting in a small error in the curve. Therefore, the authors reanalyzed the data and obtained a more accurate result. The curves are similar, and no changes to the report's conclusions are required.

BACKGROUND:Circular RNAs (circRNAs) represent a class of newly identified transcripts that act as competing endogenous RNAs (ceRNAs) to modulate gene expression by competing for the shared microRNAs (miRNAs) in humans. In this study, we set out to investigate the role of the circRNA-miRNA-mRNA ceRNA network in gastric cancer (GC).METHODS:A differential analysis on GC-related circRNAs, miRNAs and mRNAs was performed utilizing the R language "limma" package, followed by GO and KEGG enrichment analyses. The Cytoscape visualization software was used to construct the circRNA-miRNA-mRNA ceRNA network. RT-qPCR, Western blot assay, immunohistochemistry, RNA pull down, RIP and dual luciferase gene reporter assay were conducted to verify the expression of the related circRNA, miRNA and mRNA and their interaction in GC tissues and cells.RESULTS:The bioinformatics analysis screened 13 circRNAs, 241 miRNAs and 7483 mRNAs related to GC. Ten DEmRNAs (AURKA, BUB1, CCNF, FEN1, FGF2, ITPKB, CDKN1A, TRIP13, KNTC1 and KIT) were identified from the constructed PPI network and module analysis, among which AURKA was the most critical. A circ_0061265-miRNA-885-3p-AURKA ceRNA network was constructed. In vitro cell experiment demonstrated significantly upregulated circ_0061265 and AURKA, but downregulated miR-885-3p in GC. Moreover, circ_0061265 promoted the occurrence of GC by competitively binding to miRNA-885-3p to regulate AURKA expression.CONCLUSION:Our work validated that circ_0061265 may increase AURKA expression by competitively binding to miRNA-885-3p, thereby promoting GC development.

Enhancer RNAs (eRNAs) can serve as an independent prognostic factor for poor outcomes of cancer patients. The purpose of this study was to identify a vital eRNA signature that has prognostic value for thyroid cancer based on GTEx and TCGA screening. We downloaded gene expression data and clinical data of thyroid cancer included in the GTEx and TCGA databases and conducted data consolidation. eRNA expression data were extracted, and subjected to differential analysis and cluster analysis. Univariate Cox regression was used to screen the prognostic factors of thyroid cancer. Multivariate Cox regression was applied for prognostic risk assessment model construction, with the efficacy evaluated by receiver operating characteristic (ROC) curve. Downstream regulatory genes of candidate eRNAs were determined using correlation analysis. There were 79 differentially expressed eRNAs associated with thyroid cancer. These differentially expressed eRNAs could assign all thyroid cancer samples into three molecular subtypes, which showed a strong link to lymph node metastasis (N stage) of thyroid cancer patients. Additionally, four key eRNAs AC141930.1, NBDY, MEG3 and AP002358.1 closely related to the prognosis of thyroid cancer patients. The risk model based on the four eRNAs predicted the prognosis of thyroid cancer patients effectively. TPO, MGST2, THBS2 and SLC25A47P1 were potential downstream regulators of the four eRNAs involved in the development of thyroid cancer. Collectively, our data suggest that a four-eRNA signature consisting of AC141930.1, NBDY, MEG3 and AP002358.1 can accurately predict the prognosis of thyroid cancer patients.

OBJECTIVE:To explore the effect of targeted nursing on the quality of sleep and life in lung cancer patients undergoing chemotherapy.METHODS:This study was conducted in 88 lung cancer patients who underwent chemotherapy. According to the random number table, these patients were assigned to the control group (n=44) and the experimental group (n=44). In the control group, patients received routine nursing. Meanwhile, patients in the experimental group received both routine nursing and targeted nursing. The quality of sleep score, quality of life score, psychological state-related score, and visual analogue scale (VAS) score on admission and 1 week after discharge were compared between the two groups.RESULTS:There were no differences in the quality of sleep score, quality of life score, psychological state-related score, and VAS score between the two groups of patients on admission (all P>0.05). Compared with those on admission, the quality of sleep score, quality of life score, psychological state-related score, and VAS score in both groups 1 week after discharge were declined (all P<0.05). Additionally, the changes in the experimental group were much bigger than those in the control group (all P<0.001). Satisfaction in nursing in the experimental group was higher than that in the control group (P<0.05).CONCLUSION:Targeted nursing can improve the quality of sleep, quality of life, psychological state, and satisfaction in nursing in lung cancer patients undergoing chemotherapy.

Objective - This study aims to identify superenhancer (SE)-transcriptional factor (TF) regulatory network related to eight common malignant tumors based on ChIP-seq data modified by histone H3K27ac in the enhancer region of the SRA database. Methods - H3K27ac ChIP-seq data of eight common malignant tumor samples were downloaded from the SRA database and subjected to comparison with the human reference genome hg19. TFs regulated by SEs were screened with HOMER software. Core regulatory circuitry (CRC) in malignant tumor samples was defined through CRCmapper software and validated by RNA-seq data in TCGA. The findings were substantiated in bladder cancer cell experiments. Results - Different malignant tumors could be distinguished through the H3K27ac signal. After SE identification in eight common malignant tumor samples, 35 SE-regulated genes were defined as malignant tumor specific. SE-regulated specific TFs effectively distinguished the types of malignant tumors. Finally, we obtained 60 CRC TFs, and SMAD3 exhibited a strong H3K27ac signal in eight common malignant tumor samples. In vitro experimental data verified the presence of a SE-TF regulatory network in bladder cancer, and SE-TF regulatory network enhanced the malignant phenotype of bladder cancer cells. Conclusion - The SE-TF regulatory network with SMAD3 as the core TF may participate in the carcinogenesis of malignant tumors.

Background Mesenchymal stem cells (MSCs) are pluripotent mesenchymal cells present in various adult tissues. MSCs secrete exosomes as regulators of the tumor niche, with involvement in tumorigenesis and metastasis. The regulatory role of microRNAs (miRs or miRNAs) in MSCs via targeting cyclin E1 (CCNE1) or cyclin E2 (CCNE2) has been extensively reported. Since exosomes are considered as protective and enriched sources of shuttle miRNAs, we hypothesized that exosomal transfer of miR-144 from bone marrow-derived MSCs (BMMSCs) would affect the development of non-small cell lung cancer (NSCLC) cells by targeting CCNE1 and CCNE2. Methods We first quantified the levels of miR-144, CCNE1, and CCNE2 in NSCLC tissues and cell lines and then undertook gain- and loss-of-function studies of miR-144, CCNE1, and CCNE2 to investigate their roles in the biological characteristics of NSCLC in vitro. NSCLC cells (A549) were exposed to exosomes derived from MSCs, and cell proliferation and colony formation rate were determined using in vitro assays. Finally, effects of BMMSC-derived exosomal miR-144 on tumor development were studied in vivo. Results In NSCLC tissues and cell lines, miR-144 was expressed poorly and CCNE1 and CCNE2 were expressed highly. Artificially elevating miR-144 inhibited cell proliferation, colony formation, and the number of S phase-arrested cells in NSCLC by downregulating CCNE1 and CCNE2. Additionally, BMMSC-derived exosomal miR-144 led to restrained NSCLC cell proliferation and colony formation. These inhibitory effects of BMMSC-derived exosomes carrying miR-144 on NSCLC were confirmed by experiments in vivo. Conclusion Collectively, these findings revealed inhibitory effects of BMMSC-derived exosomal miR-144 on NSCLC progression, which were mediated by downregulation of CCNE1 and CCNE2.

The relationship between Lamin B2 and tumor proliferation and migration is unclear. We explored the impact of Lamin B2 on non-small cell lung cancer (NSCLC) cells. Tissue microarray and immunohistochemistry were combined to evaluate Lamin B2 expression and its relationship with the clinicopathological factors found in NSCLC. Western blotting, immunofluorescence analysis, and bioinformatics were used to investigate the effects of Lamin B2 on various regulatory pathways in cancer. Cytological experiments were conducted to evaluate Lamin B2 expression in tumor cells. We conducted co-immunoprecipitation and chromatin immunoprecipitation to explore the molecular mechanisms underlying the relationship between Lamin B2 and NSCLC and evaluate the results of rescue experiments. Lamin B2 was highly expressed in NSCLC and positively correlated with lymph node metastasis. In NSCLC, Lamin B2 interacted with Cyclin D1, upregulating G9α expression, thus increasing H3K9me2 levels. H3K9me2 binds to the promoter region of the E-cadherin gene (CDH1) to induce CDH1 silencing and promotes cancer cell migration. Thus, we found that Lamin B2 was highly expressed in NSCLC cells and promoted their migration by increasing H3K9me2 levels, which induced E-cadherin gene silencing.

BACKGROUND:Emerging evidence indicates a regulatory role of long non-coding RNAs (lncRNAs) in the development of gastric cancer (GC), but the mechanisms underlying their function have remained largely unknown. Recent microarray-based expression profiling has led to the identification of a novel differentially expressed lncRNA, LINC00858, in GC. Subsequently, LINC00858 was found to be highly expressed in GC tissues and cells. This study was designed to clarify the functional role of LINC00858 in GC, including its effect on methylation of the WNK2 gene promoter and its downstream MAPK signaling pathway. METHODS:After exogenous over-expression and knockdown of LINC00858 and the addition of a MAPK pathway inhibitor in GC cells, we explored the effects of LINC00858 and the MAPK signaling pathway on GC cell behavior using various in vitro and in vivo assays. RESULTS:LINC00858 was found to negatively regulate WNK2 expression by enhancing its promoter methylation and to activate the MAPK signaling pathway. Moreover, we found that knockdown of LINC00858 or inhibition of the MAPK signaling pathway resulted in decreased GC cell growth, migration and invasion, as well as decreased cell cycle progression, along with increased apoptosis and decreased tumorigenicity. CONCLUSIONS:Together, these findings indicate that silencing of LINC00858 increases WNK2 expression and inhibits the MAPK signaling pathway, thereby inhibiting GC growth and development. Our data highlight LINC00858 as a potential target in GC therapy.

Gastric cancer (GC) is a highly prevalent malignancy featured by dismal oncological outcomes. Accumulating pieces of evidence have consensus over the therapeutic significance of extracellular vesicles (EVs) and its role in carcinogenesis. Here, we planned to uncover EVs' role in GC by shuttling microRNA-1290 (miR-1290) and to identify the possible molecular mechanism associated with Grhl2, PD-L1, and ZEB1. Grhl2 was under-expressed in GC tissues, exhibiting a negative correlation with PD-L1 expression. In addition, Grhl2 promoted T cell proliferation by down-regulating PD-L1 via inhibiting ZEB1, while miR-1290 was found to negatively regulate Grhl2. EVs were also isolated from GC cells or normal gastric epithelial cells and identified with the presence of EV markers. miR-1290 expression was determined to be enriched in the EVs derived from GC cells and observed to promote the suppressive action of GC cells on T cell activation by up-regulating PD-L1 via the Grhl2/ZEB1 pathway in the co-culture system of GC cells with or without treatment of EVs with T cells. Moreover, we also developed a mouse model of GC and injected the EVs derived from miR-1290-inhibitor-treated GC cells into the tumor-bearing mice for further validation of mechanism in vivo. Intriguingly, the pivotal role of EVs-shuttled miR-1290 as an oncomiR was demonstrated in vivo. Collectively, we found that miR-1290 in EVs secreted from GC cells contributed to immune escape through the Grhl2/ZEB1/PD-L1 axis.

Objective: To identify the risk factors of adverse reactions in patients with advanced non-small cell lung cancer (NSCLC) treated with icotinib hydrochloride targeted therapy, and to observe the effect of targeted nursing. Methods: In total, 170 patients with advanced NSCLC receiving targeted treatment with icotinib hydrochloride from February 2017 to May 2018 and were selected for a retrospective study. According to the occurrence of adverse reactions, they were divided into group A (with adverse reactions) and group B (without adverse reactions), respectively as the observation group and the control group. Self-designed questionnaires were applied to investigate the clinical data, psychological level, cognition level of patients on disease knowledge, treatment compliance and professional level of staff. The independent risk factors influencing the occurrence of adverse reactions of patients were analyzed with a multivariate regression model. Then, 200 patients of the same type of disease who were admitted from February 2018 to May 2019 were randomly divided into the study group (group C) and the conventional group (group D), with 100 patients in each group. In view of the risk factors in the retrospective study, targeted nursing measures were designed, and the research group implemented targeted nursing to observe the impact of targeted nursing on patients’ quality of life, mental health level, professional level of responsible nurses, treatment compliance, incidence of complications and other indicators. Results: Psychological level, self-cognition of disease knowledge, age, nutritional status, smoking history, gender, treatment compliance and professional level of nursing staff were all influencing factors of adverse reactions. After targeted nursing in group C, patients’ quality of life, SDS, SAS scores and treatment compliance improved significantly (P<0.05). Group C presented markedly higher overall satisfaction of nursing service (P<0.05), and the notably lower incidence of adverse reactions than that in group D (P<0.05). The incidence of adverse reactions in group C was significantly lower than that in group D. Conclusion: Targeted nursing programs can improve the quality of life, reduce the incidence of adverse reactions and enhance the mental health of patients with NSCLC treated with icotinib hydrochloride.

Lung adenocarcinoma is the most common subtype of non-small-cell lung cancer affecting people all over the globe. Recent studies have indicated that long non-coding RNAs (lncRNAs) possess the ability to regulate gene expression. Initially, we uncovered increased LINC00355 expressions in lung adenocarcinoma tissues and cells. Functionally, our findings demonstrated that LINC00355 silencing suppressed the proliferation in vitro and in vivo. In addition, we found that LINC00355 negatively regulated miR-195 in lung adenocarcinoma cells. Simultaneously, silencing LINC00355 by shRNA resulted in suppressed proliferation, colony formation and promoted cell cycle arrest and apoptosis via miR-195. Moreover, silencing LINC00355 by shRNA inhibited the cyclin E1 (CCNE1) gene expression via miR-195 in lung adenocarcinoma cells. Collectively, this study demonstrates the novel lncRNA LINC00355 in regulatory network of CCNE1 via miR-195 in lung adenocarcinoma, highlighting LINC00355 as a new target for the treatment of lung adenocarcinoma.

Introduction: The molecular mechanism underlying the induction of resistance to tyrosine kinase inhibitors (TKIs) via the membranous/cytoplasmic/nuclear translocation of EGFR has not yet been reported. Methods: We performed immunohistochemistry to detect the distribution of EGFR in lung adenocarcinoma specimens after TKI treatment and analyzed the relationship between different EGFR locations and patient survival duration. Mass spectrometry analysis and immunoprecipitation were performed to show the interaction of cytosolic EGFR with YY1 associated protein 1 (YAP) and salt inducible kinase 2 (SIK2). Dual-luciferase assays, immunoblotting, real-time polymerase chain reaction, and functional experiments were used to elucidate the role of EGFR cytoplasmic/nuclear translocation in Hippo pathway dysregulation. Results: Patients with advanced lung adenocarcinoma with membranous mutant EGFR (19del or 21 L858R) showed significantly longer progression-free survival than those with cytoplasmic mutant EGFR after gefitinib treatment. The concentration that inhibits 50% in PC-9 with cytoplasmic EGFR was higher than that in hunman non-small cell lung cancer 827 with membranous EGFR. During first-generation TKI resistance induction, membrane EGFR translocated to the cytoplasm/nucleus, accompanied by the Hippo pathway inhibition. Cytoplasmic EGFR and SIK2 interaction inhibited large tumor suppressor kinase 1 (LATS1) and macrophage stimulating 1 (MST1) interaction, promoting YAP nuclear translocation. However, cells with osimertinib-induced resistance also showed EGFR translocation and lower phospho-EGF receptor but did not show Hippo pathway inhibition. Moreover, osimertinib and erlotinib could restore sensitivity to each other in resistant cells. Conclusions: Plasma/nuclear translocation of EGFR and inhibition of the Hippo pathway are some of the important mechanisms underlying the resistance induced by first-generation TKIs. Membrane/plasma translocation of EGFR induced by osimertinib may be another resistance phenomenon besides MNNG HOS transforming gene (c-MET) amplification, C797S mutation, and ERK pathway inhibition. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

BACKGROUND:Several single nucleotide polymorphisms (SNPs), rs16892766 in the 8q23.3 region and rs6983267, rs10505477, rs7014346 and rs7837328 in the 8q24.21 region, have been identified by genome-wide association studies (GWAS) and a number of case-control studies to be closely associated with risk of colorectal cancer (CRC). In the present study, a meta-analysis was performed to confirm if these loci are risk factors for susceptibility to CRC, taking heterogeneity of population into consideration.METHODS:The whole literature search was conducted via database of MEDLINE and Embase, through which 33 articles with 49 studies (141,899 cases and 157,536 controls) were finally included in this meta-analysis to evaluate the association between the 5 polymorphisms and risk of CRC under allelic model.RESULTS:A meta-analysis of the pooled data showed that the G allele of rs6983267, the A allele of rs7014346, the T allele of rs10505477, the C allele of rs16892766 and the A allele of rs7837328 were associated with significantly increased risk of CRC under allelic model. Additionally, subgroup analyses of four SNPs (rs7837328 excluded) by ethnicity witnessed a notable association between the G allele of rs6983267 and increased risk of CRC among Caucasians, Asians and Africans. Furthermore, the C allele of rs16892766 was strongly linked with elevated risk of CRC among Caucasians and Africans. However, the A allele of rs7014346 and T allele of rs10505477 only heightened risk for CRC among Caucasians and showed no effects among Asians.CONCLUSION:In summary, rs6983267 is a risk factor for CRC among Caucasians, Asians and Africans; rs7014346 and rs10505477 are risky genetic polymorphisms only among Caucasians; rs16892766 is a hazardous element among populations with Caucasian and African ancestry; and rs7837328 could elevate the susceptibility to CRC in a multinational group. However, more potential factors related with CRC risk should be investigated in further studies.

Aim: There is increasing evidence that ERCC1 and XPD have roles in response to chemotherapy among patients with NSCLC, but the results are conflicting. Therefore, we conducted the present prospective study in a Chinese population. Methods: A total of 632 primary NSCLC patients were included, followed-up from May 2006 to May 2011. Polymorphisms were detected by real time PCR with TaqMan probse, using genomic DNA extracted from peripheral blood samples. The Cox regression model was used to analyze the hazard ratios (HR) for ERCC1 and XPD. Results: The median time of follow-up was 31.6 months. Our results showed the ERCC1 118 T/T(HR=1.65, 95% CI=1.17-2.43) and XPD 751 Gln/Gln genotypes (HR=1.52, 95% CI=1.04-2.08) were associated with an increased risk of death from NSCLC. Moreover, the ERCC118 T allele and XPD 751 Gln allele genotypes had a more higher risk of death from NSCLC among both ex-smokers and current smokers. Conclusion: In summary, ERCC1 and XPD gene polymorphisms might provide better prognostic predictive information for NSCLC patients in Chinese populations, with smoking possibly interacting with the genotypes.