Long non-coding RNAs (lncRNAs) modulate a variety of cancerous biological processes, including the promotion of tumorigenicity in tumor parenchymal cells. However, there is a lack of studies assessing the regulation of lncRNAs in cancer-associated fibroblasts. In the present study, a novel lncRNA, TIRY, was found to act as a miRNA sponge and to downregulate miR-14 expression in oral squamous cell carcinoma (OSCC). Fluorescence in situ hybridization assay was used to evaluate TIRY expression in OSCC tissues. Survival analysis in a prospective cohort revealed a correlation between high TIRY expression and short progression-free survival. Subsequently, TIRY expression in cancer-associated fibroblasts and primary fibroblasts from adjacent normal (para-carcinoma) tissues was assessed using quantitative reverse transcription polymerase chain reaction. TIRY overexpression in cancer-associated fibroblasts isolated from OSCC tissues was induced by overexpressing the TIRY plasmid, and candidate microRNA expressions were assessed using quantitative real-time polymerase chain reaction. Moreover, the expression of proteins related to epithelial-to-mesenchymal transition (EMT) was determined; the proliferation, metastasis, and invasion of cancer cells co-cultured with TIRY-overexpressing cancer-associated fibroblasts were determined. We found significantly decreased miR-14 expression in cancer-associated fibroblast-derived exosomes and increased expression of EMT markers including transcription factors (Snail and FOXC2) and cellular scaffolding proteins (α-SMA, β-catenin, and FSP1). TIRY overexpression in cancer-associated fibroblasts activated the Wnt/β-catenin signaling pathway and promoted the invasion and metastasis of OSCC cells through miR-14 sponging based on cancer-associated exosome secretion. Our findings provide a novel molecular mechanism underlying the role of TIRY in cancer-associated fibroblasts in tumor biology; moreover, TIRY is a potential therapeutic target in OSCC. Impact statement This study demonstrated the novel lncRNA, TIRY, enhances epithelial-to-mesenchymal transition in cancer-associated fibroblasts and promotes the metastasis of tumor via miR-14 sponging in oral squamous cell carcinoma, and thus provide a novel molecular mechanism underlying the role of TIRY in CAFs in tumor biology and a potential target in OSCC. Further, the data showed that TIRY expression was negatively correlated with miR-14 transcription levels and was associated with poor prognosis in OSCC specimens. Therefore, TIRY may be a potential prognostic biomarker of overall survival and progression-free survival in OSCC. Moreover, TIRY adds to the understanding of regulatory mechanisms involved in CAFs and epithelial cancer cells in OSCC and may provide novel insights for further understanding tumor biology.
Circular RNAs (circRNAs) is a novel class of non-coding RNAs that regulate gene expression during cancer progression. Circ_0092314 is a newly discovered circRNA that was upregulated in pancreatic cancer (PAAD) tissues. However, the detailed functions and underlying mechanisms of circ_0092314 in PAAD cells remain unclear.We first determined the expression of circ_0092314 in PAAD and normal tissues and further investigated the functional roles of circ_0092314 in regulating epithelial-mesenchymal transition (EMT) of PAAD cells. We also assessed the regulatory action of circ_0092314 on the microRNA-671 (miR-671) and its target S100P.Circ_0092314 was markedly upregulated in PAAD tissues and cells, and its overexpression was closely correlated with worse prognosis of PAAD patients. Functionally, circ_0092314 promotes proliferation, invasion and EMT in vitro and tumor growth in vivo. Mechanistically, we demonstrated that circ_0092314 directly binds to miR-671 and relieve its suppression of the downstream target S100P, which induces EMT and activates the AKT signaling pathway. The tumor-promoting effects caused by overexpression of circ_0092314 could be revered by re-expression of miR-671 in PAAD cells.Overall, our study demonstrates that circ_0092314 exerts critical roles in promoting the EMT features of PAAD cells, and provides insight into how elevated expression of circ_0092314 might influence PAAD progression.
Background: Proton pump inhibitors (PPIs) are usually prescribed to protect against gastrointestinal bleeding in patients on dual antiplatelet therapy. This meta-analysis reviewed clinical outcomes in patients taking aspirin and clopidogrel, with and without concomitant PPIs to address concerns of adverse reactions. Methods: We searched PubMed, Embase, and the Cochrane Library for articles published between January 1, 2010 and April 11, 2017. The primary end points were major adverse cardiovascular events and gastrointestinal bleeding. Secondary end points were myocardial infarction, stent thrombosis, revascularization, cardiogenic death, and all-cause mortality. Results: The meta-analysis included 33,492 patients in 4 randomized controlled trials and 8 controlled observational studies. Overall, patients taking PPIs had statistical differences in major adverse cardiovascular events [odds ratio (OR) 1.17 (95% confidence interval [CI] 1.07–1.28); P = .001; I2 = 28.3%], gastrointestinal bleeding [OR 0.58 (95% CI 0.36–0.92); P = .022; I2 = 80.6%], stent thrombosis [OR 1.30 (95% CI 1.01–1.68); P = .041; I2 = 0%], and revascularization [OR 1.20 (95% CI 1.04–1.38); P = .011; I2 = 5.1%], compared those not taking PPIs. There were no significant differences in myocardial infarction [OR 1.03 (95% CI 0.87–1.22); P = .742; I2 = 0%], cardiogenic death [OR 1.09 (95% CI 0.83–1.43); P = .526; I2 = 0%], or all-cause mortality [OR 1.08 (95% CI 0.93–1.25); P = .329; I2 = 0%). Conclusions: Among the patients taking aspirin and clopidogrel, the results indicated that the combined use of PPIs increased the rates of major adverse cardiovascular events, stent thrombosis, and revascularization.
e22008 Background: Determining prognosis in advanced cancer is of key importance. Various prognostic scores have been developed. However, they are often very complex, and physicians still do not accurately estimate survival time according to these tools. In this study, we dynamically evaluated the feasibility of clinical routine examination including blood cells and biochemistry as indices to estimate survival in end-stage cancer patients. Methods: From January 2016 to December 2017, the clinical data of 556 patients with advanced cancer in Xinfeng County People's Hospital and Tongji Hospital were collected. 201 cases among them died, we retrospectively analyzed clinical data of these 201 patients within 6 months before death, The clinical symptoms and blood biochemical changes in 1 week, 1 month, 3 months and 6 months before the death were observed. Results: 201 cases of death among the 556 cases included 72 cases of liver cancer, 53 cases of lung cancer, 42 cases of digestive system tumor (excluding liver cancer), 18 cases of head and neck squamous cell carcinoma, 11 cases of urogenital tumors, and 5 cases of others. The incidence of symptoms was fatigue (94.5%), pain (90.0%), constipation (89.1%), dysphagia (27.9%) and dyspnea (20.9%) in 1 week prior to death. Multivariate Logistic regression analysis showed that white blood cell count (P= 0.012) and neutrophil count (P= 0.008), alanine aminotransferase (P= 0.003), albumin (P= 0.000), urea nitrogen (P= 0.035), serum sodium (P= 0.002), lactate dehydrogenase (P= 0.038) and C reactive protein (P= 0.000) were independent prognostic factors of end-stage tumor death. The hematological indices of 201 patients in 6 months before death were dynamically analyzed, the results of 1 week before death were compared with those of 1 month, 3 months and 6 months before death (P< 0.03). The trends of these independent prognostic factors were more obvious between 1 week and 6 months before death. Conclusions: Dynamic changes in clinical routine hematological indices of end-stage cancer patients within 6 months prior to death can obviously predict the prognosis, which is helpful for the accurate judgement of patients' survival and palliative care.
Summary Background Recent evidence found probiotics could inhibit Helicobacter pylori colonization from both in vitro and in vivo studies. Aim To systematically evaluate whether adding probiotics to anti‐ H. pylori regimens could improve eradication rates and reduce side effects during anti‐ H. pylori treatment. Methods Eligible articles were identified by searches of electronic databases. We included all randomized trials comparing probiotics supplementation to placebo or no treatment during anti‐ H. pylori regimens. Statistical analysis was performed with Review Manager 4.2.8. Subanalysis/Sensitivity analysis was also performed. Results We identified 14 randomized trials ( n = 1671). Pooled H. pylori eradication rates were 83.6% (95% CI = 80.5–86.7%) and 74.8% (95% CI = 71.1–78.5%) for patients with or without probiotics by intention‐to‐treat analysis, respectively, the odds ratio (OR) was 1.84 (95% CI = 1.34–2.54); the occurrence of total side effects were 24.7% (95% CI = 20.0–29.4%) and 38.5% (95% CI = 33.0–44.1%) for groups with or without probiotics, especially for diarrhoea, the summary OR was 0.44 (95% CI = 0.30–0.66). Conclusions Our review suggests that supplementation with probiotics could be effective in increasing eradication rates of anti‐ H. pylori therapy, and could be considered helpful for patients with eradication failure. Furthermore, probiotics show a positive impact on H. pylori therapy‐related side effects.
Erlotinib, a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, demonstrated therapeutic efficacy against pancreatic cancer. However, acquired resistance to erlotinib in pancreatic cancer is widely observed, and the exact mechanisms have not been fully explored until now. We examined the role of circular RNA circ_0013587 in the acquired resistance to erlotinib in pancreatic cancer cells and explored the underlying mechanisms.We selected erlotinib-resistant pancreatic cancer cells from the AsPC-1 cell line. The expression of circ_0013587 was examined by qRT-PCR assays. The effects of circ_0013587 on pancreatic cancer cell proliferation, invasion, and erlotinib resistance were assessed by cell functional assays. Bioinformatic analysis and dual-luciferase reporter assays identified circ_0013587 and E-cadherin as direct targets of miR-1227. Mouse xenograft models were employed to investigate the function of circ_0013587 in erlotinib resistance of tumors in vivo.Circ_0013587 expression was significantly reduced in erlotinib-resistant AsPC-1 cells. We found that increasing circ_0013587 levels in erlotinib-resistant AsPC-1 cells re-sensitized them, whereas reducing circ_0013587 levels in erlotinib-sensitive AsPC-1 cells made them resistant. Mechanically, circ_0013587 released E-cadherin from the suppression of miR-1227, leading to E-cadherin up-regulation. Rescue assays highlighted that circ_0013587 reversed erlotinib resistance in pancreatic cancer cells by increasing E-cadherin levels through reducing the expression of miR-1227. Furthermore, circ_0013587 overexpression sensitized erlotinib-resistant AsPC-1 cells to erlotinib in xenograft models.Our results demonstrated that down-regulation of circ_0013587 contributes to acquired resistance to erlotinib in pancreatic cancer cells through mediating the miR-1227/E-cadherin pathway and that circ_0013587 is a potential target molecular to overcome erlotinib resistance.
Long non‑coding RNAs (lncRNAs) are involved in colorectal cancer (CRC) progression, however the mechanisms remain largely unknown. The present study aimed to reveal the role and possible molecular mechanisms of a new LNCRNA, LINC00858, in CRC. LINC00858 was increased in CRC tumor tissues, and patients with high LINC00858 expression had a shorter survival time. Knockdown of LINC00858 expression suppressed cell proliferation and induced G0/G1 cell cycle arrest and apoptosis in TP53‑wild‑type CRC cells. Subsequently, using Starbase v2.0 database, miR‑25‑3p was confirmed to interact with LINC00858 and was downregulated by LINC00858. Reduction of miR‑25‑3p expression with an inhibitor significantly attenuated the biological effects of LINC00858 knockdown in CRC cells. Furthermore, using TargetScan, SMAD7 was validated to interact with miR‑25‑3p and was downregulated by miR‑25‑3p. Lastly, the ectopic overexpression of SMAD7 rescued the suppressive effects of LINC00858 knockdown in CRC cells. Collectively, the results from the present study, to the best of our knowledge, firstly demonstrated a novel LINC00858/miR‑25‑3p/SMAD7 regulatory axis that promoted CRC progression, indicating LINC00858 as a promising therapeutic target for CRC.
BACKGROUND:Several lines of evidence indicate that the process of atherosclerosis and lurninal narrowing after PTCA of atherosclerotic lesions is largely due to endothelial injury and smooth muscle cells hyperplasia Calcitoning gene-related peptide(CGRP)was reported to stimulate the proliferation of human umbilical vein endothelial cells(HUVECs) and inhibit the growth of vascular smooth muscle cells.This study was to define the potential for gene transfer to facilitate endothelial cell regeneration and promote recovery of endothelial dysfunction. METHODS AND RESULTS:Recombinant retrovirus comtaining human α-CGRP cDNA(termed pRCGRP)was constructed and used to infect HUVECs in culture.The level of CGRP gene expression and the mitogenic effects of CGRP on cultured HUVECs were determined by RT-PCR,radioimmunoassay(RIA)and cell proliferative activity. CGRP gere expression was observed only when cultured HUVECs were transduced with vectors containing the CGRP cDNA.No evidence of aimilar gene expression was observed in nontransfected or empty vector transfected HUVECs.Twelve days after transduction,CGRP level in the supernatant of CGRP vectors tranduced cells was detected at 12.4±0.5pM,whereas that of normal and control group were undectable Transduction of HUVECs with vectors bearing CGRP cDNA construct showed a marked increase in the number of viable cells observed at 24～120 hours after transduction compared with transduced cultures containing the empty(control)vector CGRP vectors enhanced cell cycle progression,as determined by the MTT metabolic assay and Flow Cytometry. CONCLUSIONS:These primary results represent the first demonstration of the proliferative effects of CGRP retroviral vector on HUVEC.The CGRP gene cam be effectively transfered into HUVEC and stably expressed with retroviral vector.CGRP vectors containing the leading sequence enabled mature CGRP to be secreted from the cells.Taken together,these data indicate the potential utility of CGRP constructs in the development of a novel gene therapy spproach to vascular restenosis and atherosclerosis and may lay solid foundations for in vivo gene transfer next.
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