Platelet glycoprotein IIb/IIIa antagonists in ischemic stroke patients without endovascular therapy: A meta-analysis.

Platelet glycoprotein (GP) IIb/IIIa antagonists have been employed in selective patients after endovascular therapy (EVT) for acute ischemic stroke (AIS), yet application in patients without EVT is debated. This meta-analysis of randomized controlled studies on AIS patients without EVT assessed the effectiveness and safety of platelet GP IIb/IIIa antagonists compared with traditional antiplatelet or thrombolysis therapy. Articles were retrieved from databases, including PubMed, Web of Science, EMBASE, and Cochrane. The risk of bias and certainty level of evidence were assessed. Fifteen studies were included. GP IIb/IIIa antagonists increased the proportion of patients with modified Rankin Scale (mRS) 0-1 (odd ratio [OR] 1.37, 95% confidence interval [CI] 1.04-1.81, p = 0.03), mRS 0-2 (OR 1.27, 95% CI 1.12-1.46, p = 0.0004), and Barthel Index (BI) 95-100 (OR 1.25, p = 0.005); decreased the proportion of stroke progression within 5 days (OR 0.66, p = 0.006); and lowered the mean mRS score at 90 days (mean difference [MD] -0.43, p = 0.002) and the National Institute of Health stroke scale score at 7 days (MD -1.64, p < 0.00001) compared with conventional treatment. Proportions of stroke recurrence within 90 days (OR 1.20, p = 0.60), any intracranial hemorrhage (aICH) (OR 1.20, p = 0.12), symptomatic intracranial hemorrhage (sICH) (OR 0.91, p = 0.88), and death (OR 0.87, p = 0.25) had no statistical difference between both groups. This meta-analysis finds that compared with traditional antiplatelet or thrombolysis therapy, GP IIb/IIIa antagonists administered within 24-96 h of ischemic stroke onset significantly improve functional prognosis of patients with AIS not receiving EVT, as indicated by mRS and BI at 90 days, and do not increase the incidence of aICH, sICH, and death.

Prognostic nomogram in patients with right-sided colon cancer after colectomy: a surveillance, epidemiology, and end results-based study.

Objective: This study aimed to develop and validate a nomogram for predicting overall survival (OS) in patients undergoing surgery for right-sided colon cancer (RCC). Methods: We collected 25,203 patients with RCC from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided them into 7:3 training and internal validation set. Utilizing the Cox proportional hazards regression model, we constructed a nomogram based on prognostic risk factors. Furthermore, for external validation, we retrospectively followed up with 228 patients from Jiaxing First Hospital and assessed and calibrated the nomogram using the C-index and calibration curves. Results: After identifying independent prognostic factors through univariate and multivariate analyses, a nomogram was developed. The c-index values of this nomogram differed as follows: 0.851 (95% CI: 0.845-0.857) in the training set, 0.860 (95% CI: 0.850-0.870) in the internal validation set, and 0.834 (95% CI: 0.780-0.888) in the external validation set, indicating the model's strong discriminative ability. Calibration curves for 1-year, 3-year, and 5-year overall survival (OS) probabilities exhibited a high level of consistency between predicted and actual survival rates. Furthermore, Decision Curve Analysis (DCA) demonstrated that the new model consistently outperformed the TNM staging system in terms of net benefit. Conclusion: We developed and validated a survival prediction model for patients with RCC. This novel nomogram outperforms the traditional TNM staging system and can guide clinical practitioners in making optimal clinical decisions.

Multivariate analysis of prognostic factors in patients with lip squamous cell carcinoma after surgery.

BACKGROUND: Lip squamous cell carcinoma (LSCC) was one of the most common cancer types of head and neck tumors. This study aimed to find more predictors of the prognosis in postoperative LSCC patients. METHODS: A total of 147 LSCC patients between June 2012 and June 2018 were collected from two tertiary care institutions. There were 21 clinicopathological factors included and analyzed in our study. The univariate and multivariate Cox regression analyses were performed to find the independent prognostic factors for predicting progression-free survival (PFS) and overall survival (OS) in postoperative LSCC patients. The role of adjuvant radiotherapy in various subgroups was displayed by Kaplan-Meier plots. RESULTS: The 1-, 3-, and 5-year PFS of postoperative LSCC patients were 88.4%, 70.1%, and 57.8%, respectively. Similarly, the 1-, 3-, and 5-year OS of postoperative LSCC patients were 94.6%, 76.9%, and 69.4%, respectively. The results suggested that postoperative LSCC patients with age at diagnosis ≥ 70 years, grade with moderate or poor differentiate, the American Joint Committee on Cancer (AJCC) stage IV, higher systemic immune-inflammation index (SII), surgical margin < 5, and age-adjusted Charlson Comorbidity Index (ACCI) ≥ 5 tend to have a poorer PFS (all P < 0.05). Besides, postoperative LSCC patients with age at diagnosis ≥ 70 years, AJCC stage IV, higher GPS, higher SII, and ACCI ≥ 5 tend to have a worse OS (all P < 0.05). Additionally, postoperative patients with LSCC in the subgroup of ACCI < 5 and AJCC III-IV stage was more likely to benefit from adjuvant radiotherapy, but not for the other subgroups. CONCLUSION: We identified a series of significant immune-inflammation-related and comorbidity-related clinicopathological factors associated with the prognosis of postoperative LSCC patients by local data from two tertiary care institutions in China, which can be helpful for patients and surgeons to pay more attention to nutrition, inflammation, and complications and finally obtained a better prognosis.

High expression of CDKN2A is associated with poor prognosis in colorectal cancer and may guide PD-1-mediated immunotherapy.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies worldwide. Immunotherapy targeting the programmed death protein 1(PD-1) and its ligand (PD-L1), is a promising treatment option for many cancers, but has exhibited poor therapeutic efficacy in CRC. This study aimed to identify and validate the prognostic value of immune-related genes and PD-1-associated genes for immunotherapy treatment of CRC. METHODS: An extensive analysis of prognostic immune-related DEGs and PD-1-related genes has highlighted CDKN2A as a vital overlapping gene. To further explore its expression in CRC and its prognostic value, we conducted qRT-PCR, Western blot experiments, and consulted various databases. Subsequently, we conducted gene expression analysis, survival and prognostic analysis, enrichment analysis, immune infiltration assessment, and TIDE analysis to assess the significance of CDKN2A. RESULTS: In CRC, CDKN2A was highly expressed compared to normal tissue. It was found that CDKN2A expression was related to clinicopathological features such as inflammation and tumor stage. Furthermore, a significant correlation was identified between CDKN2A and immune infiltration, specifically involving CD4 T cells, CD8 T cells, and macrophages. The analysis of the GSEA of CRC samples with high CDKN2A expression identified enrichment of genes involved in MYC target-v2 and metabolism pathways. Furthermore, UBE2I, CDK4, CDK6, TP53, and CCND1 were found to be significantly coexpressed with CDKN2A, suggesting a potential role that these gene play in CRC and immunotherapy. CONCLUSIONS: Our study revealed that high CDKN2A expression in CRC is a potentially valuable prognostic biomarker, which may guide PD-1-mediated immunotherapy.

L-arginine homeostasis governs adult neural stem cell activation by modulating energy metabolism in vivo.

Neurogenesis in the developing and adult brain is intimately linked to remodeling of cellular metabolism. However, it is still unclear how distinct metabolic programs and energy sources govern neural stem cell (NSC) behavior and subsequent neuronal differentiation. Here, we found that adult mice lacking the mitochondrial urea metabolism enzyme, Arginase-II (Arg-II), exhibited NSC overactivation, thereby leading to accelerated NSC pool depletion and decreased hippocampal neurogenesis over time. Mechanistically, Arg-II deficiency resulted in elevated L-arginine levels and induction of a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) caused by impaired attachment of hexokinase-I to mitochondria. Notably, selective inhibition of OXPHOS ameliorated NSC overactivation and restored abnormal neurogenesis in Arg-II deficient mice. Therefore, Arg-II-mediated intracellular L-arginine homeostasis directly influences the metabolic fitness of neural stem cells that is essential to maintain neurogenesis with age.

Construction and validation of a novel algorithm based on oncosis-related lncRNAs comprising the immune landscape and prediction of colorectal cancer prognosis.

Colorectal cancer (CRC) has high morbidity and mortality, particularly if diagnosed at an advanced stage. Although there have been several studies on CRC, few have investigated the relationship between oncosis and CRC. Thus, the purpose of the present study was to identify oncosis-related long noncoding RNAs (lncRNAs) and to establish a clinical prognostic model. Original data were acquired from The Cancer Genome Atlas database and PubMed. Differentially expressed oncosis-related lncRNAs (DEorlncRNAs) were identified and were subsequently formed into pairs. Next, a series of tests and analyses, including both univariate and multivariate analyses, as well as Lasso and Cox regression analyses, were performed to establish a receiver operating characteristic curve. A cut-off point was subsequently used to divide the samples into groups labelled as high- or low-risk. Thus, a model was established and evaluated in several dimensions. Six pairs of DEorlncRNAs associated with prognosis according to the algorithm were screened out and the CRC cases were divided into high- and low-risk groups. Significant differences between patients in the different risk groups were observed for several traits, including survival outcomes, clinical pathology characteristics, immune cell infiltration status and drug sensitivity. In addition, PCR and flow cytometry were performed to further verify the model. In summary, a new risk model algorithm based on six pairs of DEorlncRNAs in CRC, which does not require specific data regarding the level of gene expression, was established and validated. This algorithm may be used to predict patient prognosis, immune cell infiltration and drug sensitivity.

Loss of RNA-Binding Protein HuR Leads to Defective Ependymal Cells and Hydrocephalus.

Multiciliated ependymal cells line the ventricle wall and generate CSF flow through ciliary beating. Defects in ependymal cells cause hydrocephalus; however, there are still significant gaps in our understanding the molecular, cellular and developmental mechanisms involved in the pathogenesis of hydrocephalus. Here, we demonstrate that specific deletion of RNA-binding protein (RBP) Hu antigen R (HuR) in the mouse brain results in hydrocephalus and causes postnatal death. HuR deficiency leads to impaired ependymal cell development with defective motile ciliogenesis in both female and male mice. Transcriptome-wide analysis reveals that HuR binds to mRNA transcripts related to ciliogenesis, including cilia and flagella associated protein 52 (Cfap52), the effector gene of Foxj-1 and Rfx transcriptional factors. HuR deficiency accelerates the degradation of Cfap52 mRNA, while overexpression of Cfap52 is able to promote the development of HuR-deficient ependymal cells. Taken together, our results unravel the important role of HuR in posttranscriptional regulation of ependymal cell development by stabilizing Cfap52 mRNA.SIGNIFICANCE STATEMENT This study identifies Hu antigen R (HuR) as a genetic factor involved in the pathogenesis of hydrocephalus. Mechanistically, HuR regulates ependymal cell differentiation and ciliogenesis through stabilizing Cfap52 mRNA, the effector gene of Foxj-1 and Rfx transcriptional factors.

[Corrigendum] LYPD8 regulates the proliferation and migration of colorectal cancer cells through inhibiting the secretion of IL­6 and TNF­α.

Following the publication of the above paper, the authors realized that, in their follow­up experiments, the STAT3 and p65 antibodies they used had already expired prior to the results being published. This affected the confidence that the authors could place in the results published in Figs. 1 and 3E. In addition, the findings were also inconsistent with Fig. 4A and B, potentially causing confusion for the readers. The authors therefore repeated some of these experiments with newly purchased antibodies; they also changed the RT-qPCR results. In the published manuscript, the authors investigated the expression of LYPD8 mRNA expression in tissues from stages I, II, and III whereas in the revised manuscript they have investigated stages II and IV. In addition, the authors have supplemented the manuscript with new transwell assays. The revised figures are presented on the next two pages (Figs 1-4). Repeating these particular experiments has resulted in the following changes being necessary to the text of the published paper (changes are highlighted in bold): i) The fourth sentence in the Abstract, on p. 2389, should read as follows: "The results revealed that the expression of LYPD8 was significantly reduced in the CRC tissue compared with that in precancerous tissue and normal tissue, particularly in stage IV tissue." ('III' has been changed to 'IV'). ii) In the Materials and methods section, "Histological analysis" subsection on p. 2390, the last three sentences should be replaced with the following text: "The histological sections were then stained with the DAB Kit (cat. no. PV­9000; ZSGB­BIO, Beijing, China). All sections were observed under a bright­field microscope (Nikon Corporation, Tokyo, Japan)." iii) In the "Cell culture" subsection in the right­hand column, the first four sentences should be revised to the following: "Four CRC cell lines (SW480, SW620, HCT116 and RKO) were used. SW480 (ATCC® CCL­228™, organism, human; tissue, colon; disease, colorectal adenocarcinoma), SW620 (ATCC® CCL­227™, organism, human; tissue, colon; derived from metastatic site, lymph node; disease, colorectal adenocarcinoma), HCT116 (ATCC® CCL­247™, organism, human; tissue, colon; disease, colorectal carcinoma) and RKO (ATCC® CRL­2577™, organism, human; tissue, colon; disease, carcinoma) cells were purchased from the American Type Culture Collection (Manassas, VA, USA). The four cell lines within passages 10 were used in all experiments, and the cell lines were maintained at 37˚C in a humidified incubator containing 5% CO2". Also, in line 8 of p. 2391, the cell lines here should be changed to "SW480, SW620 and HCT116 cells", and on line 11, "HT29 cells" should be changed to "RKO cells". iv) In the Results section, the following changes to the text are necessary: In the "Correlation of the expression of LYPD8 with STAT3/P65 phosphorylation and IL­6/TNF­α secretion in patients with CRC" subsection, in the second sentence, "immunofluorescence" should have been written as "immunohistochemistry", and the fourth sentence should have read as follows: "The results of the western blotting showed that the levels of p­P65/P65 and p­STAT3/STAT3 gradually increased between stage II and IV (Fig. 1B and C)." Then, the three sentences starting on line 7 on p. 2391 should now read as follows: "Following this, the gene expression levels of LYWPD8 in stage II and IV CRC tissue, precancerous tissue, and normal tissue were assessed using RT­qPCR analysis (Fig. 2C). Compared with the precancerous tissue and normal tissue, the gene expression of LYPD8 was significantly reduced in stage II and IV tissues. Furthermore, the expression of LYPD8 was reduced in stage IV tissue compared with that in stage II tissue." v) In the subsequent subsection, "Construction and overexpression of LYPD8 in CRC cells", the first sentence should have read as follows: "The plasmid DNA for overexpressing LYPD8 was constructed using the eukaryotic expression vector (pIRES2), as shown in Fig. 3A and B, and the relative expression levels of LYPD8 in the RTO, SW480 HCT116 and SW620 cells were examined by RT-qPCR analysis. vi) In the "Overexpression of LYPD8 inhibits CRC cell proliferation and migration" subsection, the penultimate sentence as it appears towards the foot of p. 2392 should now read as follows: "As shown in Fig. 4C and D, a more marked inhibitory effect on cell migration was observed in the LYPD8 OE group compared with that in the control, LYPD8 OE + IL­6 and LYPD8 OE + TNF­α groups." vi) In the Discussion, the sentence starting on p. 2394, right­hand column, line 10 should read as follows: "By contrast, the expression of LYPD8 was significantly reduced in stage II and IV CRC tissues." vii) Finally, some revisions were necessary to the descriptions in the figure legends for Figs. 1, 2 and 4, as follows (only the affected text is included, and the changes are indicated in bold): Figure 1. STAT3 and P65 are activated in colonic tumor tissues from patients. (A) Representative immunohistochemistry images revealing activated STAT3 and P65 in colonic cancer tissue and precancerous tissue. Scale bar, 100 µm. (B) Representative western blotting revealing the expression of p­P65, P65, p­STAT3 and STAT3 in stages II and IV colonic tumor tissues. GAPDH was used as a control. (C) Band intensities of western blotting for p­P65/P65 and p­STAT3/STAT3 in stage II and IV tissues were analyzed. The data are reported as the mean ± standard deviation of experiments (n=4). **P<0.05, phosphorylation levels of STAT3 in stage II tissues vs. in stage IV tissues. Figure 2. Association between IL­6/TNF­α and the expression of LYPD8 in colonic tumor tissue, precancerous tissue and normal tissue at different stages. (A) IL­6 and (B) TNF­α secretion were analyzed by ELISA in stage II and IV colonic tumor tissue and precancerous tissue. (C) Gene expression of LYPD8 in stage II and IV colonic tumor tissue and precancerous tissue. ß­actin was used as a control. The data are reported as the mean ± standard deviation of experiments (n=6). **P<0.01, LYPD8 mRNA expression of normal tissue, precancerous tissue vs. colonic tumor tissue in stage II and IV tissues. Figure 4. Effects of the overexpression of LYPD8 on SW480 cell proliferation and migration. (A) Cell viability of the Control, LYPD, LYPD8 OE + IL­6 and LYPD8 OE + TNF­α groups of SW480 cells. (B) SW480 cells were treated with different concentrations (0.5, 1 and 2 µM) of niclosamide and different concentrations (5, 15 and 30 µM) of JSH­23, respectively. (C) Numbers of migratory SW480 cells from the Control, LYPD8, LYPD8 OE + IL­6 and LYPD8 OE + TNF­α groups. (D) Transwell assay of SW480 cells from the (a) Control, (b) LYPD8 OE, (c) LYPD8 OE + IL­6 and (d) LYPD8 OE + TNF­α groups (magnification, ×200).  Note that the replacement of the original figures and these revisions made to the text do not drastically alter the overall conclusions reported in the study. The authors are very grateful to the Editor of Oncology Reports for allowing them the opportunity to publish this Corrigendum; furthermore, they apologize for any inconvenience caused to the readership of the Journal. [the original articles was published in Oncology Reports 41: 2389­2395, 2019; DOI: 10.3892/or.2019.7034].

The SELS rs34713741 Polymorphism Is Associated with Susceptibility to Colorectal Cancer and Gastric Cancer: A Meta-Analysis.

Aims: The selenoprotein S (SELS) gene has been suggested to be an important factor in the development of multiple diseases, including gastric cancer (GC) and colorectal cancer (CRC). However, the association between the SELS gene rs34713741 polymorphism and risk of GC and CRC is inconclusive. Thus, we aimed to investigate the relationship between this polymorphism and the susceptibility to GC and CRC through a meta-analysis. Materials and Methods: Literature was retrieved through the following electronic databases: PubMed, Embase, Web of Science, and Chinese National Knowledge Infrastructure. The pooled odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of the associations of the alleles of rs4713741 locus with the risk of CRC and GC. Results: Seven studies that collectively included 2331 cases and 2233 controls were utilized for this meta-analysis. Under the allelic and dominant models, the T allele of the SELS rs34713741 polymorphism was significantly associated with CRC risk (allelic model: OR = 1.20, 95% CI = 1.08-1.33, p = 0.0004; dominant model: OR = 1.25, 95% CI = 1.10-1.43, p = 0.001). In addition, all of the genetic models (allelic, dominant, and recessive models) identified the rs34713741 T allele as being significantly associated with GC risk (allelic model: OR = 1.67, 95% CI = 1.30-2.15, p < 0.001; dominant model: OR = 1.70, 95% CI = 1.25-2.30, p = 0.0006; recessive model: OR = 2.39, 95% CI = 1.26-4.50, p = 0.007). Conclusions: The SELS gene rs34713741 T-allele is a highly probable risk factor for both CRC and GC. The results of this study will provide support for using this single nucleotide polymorphism in the diagnosis of GC and CRC.

Polymorphism rs6478109 in the TNFSF15 gene contributes to the susceptibility to Crohn's disease but not ulcerative colitis: a meta-analysis.

OBJECTIVE: Polymorphisms in the tumor necrosis factor superfamily 15 (TNFSF15) gene contribute to susceptibility to inflammatory bowel disease (IBD). However, associations between TNFSF15 rs6478109, rs7869487, and rs7865494 polymorphisms and IBD remain unclear. METHODS: Eligible articles were retrieved from the PubMed, EMBASE, Web of Science, and CNKI databases through 20 March 2020. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the relationships of TNFSF15 polymorphisms with IBD susceptibility. RESULTS: Under the recessive model, TNFSF15 rs6478109 was associated with IBD risk (OR = 0.56; 95% CI: 0.35, 0.92). Stratification analyses based on the type of disease-Crohn's disease (CD) or ulcerative colitis (UC)-revealed a significant association under the allelic and recessive models between TNFSF15 rs6478109 and CD (allelic model: OR = 0.84, 95% CI: 0.71, 0.99; recessive model: OR = 0.44, 95% CI: 0.22, 0.87) but not UC. Stratification by ethnicity indicated a significantly decreased risk of IBD in Asian populations with TNFSF15 rs6478109 under the recessive model (OR = 0.56, 95% CI: 0.35, 0.92). CONCLUSIONS: Our meta-analysis suggested that under the allelic and recessive models, the TNFSF15 rs6478109 polymorphism was likely protective for CD but not UC in the Asian population.

CircRNA_0005075 suppresses carcinogenesis via regulating miR-431/p53/epithelial-mesenchymal transition axis in gastric cancer.

This study was aimed to explore the expression and biological function of circRNA_0005075 in gastric cancer (GC) progression and its underlying mechanism. First, the expression level of circRNA_0005075 and microRNA-431 (miR-431) in GC tissues were detected with the quantitative real-time polymerase chain reaction. In addition, after down-regulated the circRNA_0005075 expression by plasmid transfection in GC cells, the Cell Counting Kit-8 (CCK-8), EDU, transwell assay were conducted to evaluate the function of circRNA_0005075 or miR-431 on cell proliferation, metastasis in vitro. Moreover, p53 and Epithelial-mesenchymal transition (EMT) pathway related proteins were also measured with western blotting. Then, our data revealed that CircRNA_0005075 was found to be significantly up-regulated in GC tissues as well as GC cell lines, and the GC patients with higher CircRNA_0005075 expression were more likely to have poor outcomes. Down-regulation of CircRNA_0005075 could significantly suppress the GC cell proliferation and cell metastasis ability, while the addition of miR-431 inhibitors could counteract this effect. Importantly, we discovered that the silencing of circRNA_0005075 could weaken the micro-RNA sponge function for miR-431, and then upregulate the expression of p53 and forbid the EMT signalling pathway, and finally suppress the tumourigenesis of GC. To sum up, CircRNA_0005075 could inhibit cell growth and metastasis of GC through regulating the miR-431/p53/EMT axis. SIGNIFICANCE OF THE STUDY: The research clearly elucidated the potential role and relative regulatory mechanism of circRNA_0005075 in gastric cancer (GC) progression. Briefly, circRNA_0005075 could directly inhibit the expression level of miR-431, then regulate the p53/Epithelial-mesenchymal transition axis, and finally inhibit cell growth and metastasis in GC. Consequently, circRNA_0005075 might act as an oncogene in the GC procession, which provides a promising way for the treatment of GC.

The long noncoding RNA TUG1 is required for TGF-ß/TWIST1/EMT-mediated metastasis in colorectal cancer cells.

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide, and metastasis is the major cause of CRC-related mortality. Transforming growth factor-beta (TGF-ß) has a central role not only in the regulation of the normal colon but also in the development and metastasis of CRC. However, TGF-ß is not considered an ideal therapeutic target because it shows both pro-tumorigenic and anti-tumorigenic activity, depending on the tumor stage. Therefore, it is important to find a downstream signaling component of TGF-ß that can be targeted to impair CRC metastasis. Here, we show that TGF-ß promotes CRC migration and upregulates the expression of long-noncoding RNA Taurine Upregulated Gene 1 (TUG1). TUG1 knockdown inhibited migration, invasion, and epithelial-mesenchymal transition (EMT) of CRC cells in vitro, and reduced CRC lung metastasis in vivo. TGF-ß induced metastasis, and TUG1 knockdown inhibited these effects. In addition, TGF-ß could not reverse the anti-metastasis effects of TUG1 knockdown. These data demonstrate that TUG1 is a downstream molecular of TGF-ß. Moreover, TWIST1 expression was increased with TGF-ß treatment, and TUG1 knockdown decreased TWIST1 expression in CRC cells. TWIST1 knockdown inhibited invasion and EMT in CRC cells; these effects were not changed by simultaneous TUG1 knockdown, indicating that TWIST1 is a downstream mediator of TUG1. Moreover, TUG1 was significantly overexpressed in CRC patients. In conclusion, TGF-ß promotes metastasis of CRC via a TUG1/TWIST1/EMT signaling pathway. TUG1 may be a promising drug target to inhibit TGF-ß pathway activation in the treatment of CRC.

Genetic association between IL23R rs11209026 and rs10889677 polymorphisms and risk of Crohn's disease and ulcerative colitis: evidence from 41 studies.

OBJECTIVE: IL23R plays an important role in the pathogenesis of inflammatory bowel disease (IBD). The IL23R rs11209026 and rs10889677 polymorphisms have been shown to be associated with the development of Crohn's disease (CD) and ulcerative colitis (UC). But the results were inconsistent and inconclusive. So, we aim to investigate the genetic association between rs11209026 and rs10889677 polymorphisms and UC and CD risk by a meta-analysis. METHODS: Literature search was conducted through PubMed, CNKI, and web of science databases. Pooled OR and 95% CI was used to assess the association between the allelic, dominant and recessive models of IL23R rs11209026 and rs10889677 polymorphisms and UC and CD risk. RESULTS: 41 publications with 13,803 patients with CD and 17,446 controls, as well as 5876 patients with UC and 10,053 controls were included in the present study. All the genetic models of rs11209026 polymorphism significantly decrease CD and UC risk (except for the recessive model in UC) (p < 0.05). A subgroup analysis based on ethnicity showed that the allelic (p < 0.00001, OR = 0.65) and dominant models (p < 0.00001, OR = 0.61) of rs11209026 polymorphism were significantly associated with UC risk in Caucasians, but not in Asians (p > 0.05). In addition, the allelic (CD: p < 0.00001, OR = 1.34; UC: p < 0.00001, OR = 1.22) and dominant models (CD: p = 0.002, OR = 1.39; UC: p = 0.01, OR = 1.29), but not the recessive model of rs10889677 polymorphism significantly increase the risk of CD and UC (p > 0.05). A subgroup analysis showed that the genetic models of rs10889677 polymorphism were associated with CD risk in Caucasians (p < 0.05), but not in Asians (p > 0.05). The dominant model of rs10889677 polymorphism was associated with UC risk in Asians (p = 0.04, OR = 1.54), but not in Caucasians (p > 0.05). CONCLUSIONS: Our meta-analysis demonstrated that the rs11209026 polymorphism might be a protective factor against developing IBD, while the rs10889677 polymorphism might be a risk factor for IBD.

MicroRNA-145 Inhibits Cell Migration and Invasion in Colorectal Cancer by Targeting TWIST.

INTRODUCTION: MicroRNAs function as oncogenes or tumor suppressors in the development of various human cancers. We investigated the effect of microRNA-145 (miR-145) on colorectal cancer (CRC) cell invasion and migration. METHODS: The levels of miR-145 in CRC cells were examined by quantitative PCR; Western blotting was used to detect TWIST1 (twist family bHLH transcription factor 1) protein and the epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, vimentin). Then, we transfected miR-145 mimics or inhibitor into CRC cells and used the wound healing and Transwell invasion assays to investigate their migration and invasive capability, respectively. RESULTS: The miR-145 mimics suppressed CRC cell invasion and migration significantly; in contrast, miR-145 downregulation had the opposite effect. Furthermore, miR-145 regulated TWIST1 levels negatively at transcriptional level. TWIST1 knockdown significantly inhibited the CRC cell migration ability and the number of CRC cells that crossed the Transwell membrane. There was no significant difference in terms of migration and invasive capability after the cells had been transfected with miR-145 mimics or inhibitor plus TWIST1 small interfering RNA (siRNA) as compared to the TWIST1 siRNA-only group. Furthermore, we demonstrate that the inhibition of miR-145 could enhance the capability for lung metastasis in vivo. CONCLUSION: Taken together, these findings indicate that miR-145 acts as a new tumor suppressor by regulating TWIST1 and plays a vital role in the invasive and migration ability of CRC cells.

LYPD8 regulates the proliferation and migration of colorectal cancer cells through inhibiting the secretion of IL­6 and TNF­α.

Ly6/Plaur domain­containing 8 (LYPD8) contributes to the segregation of intestinal microbiota and intestinal epithelia and is critical for the prevention of intestinal inflammation. However, its relevance in cancer biology remains to be fully elucidated. The present study aimed to clarify the biological effects of LYPD8 on colon cancer tissue from patients and colorectal cancer (CRC) cells. The results revealed that the expression of LYPD8 was significantly reduced in the CRC tissue compared with that in precancerous tissue and normal tissue, particularly in stage III tissue. The results also revealed increased levels of P65 and signal transducer and activator of transcription 3 (STAT3) phosphorylation and increased secretion of interleukin­6 (IL­6) and tumor necrosis factor­α (TNF­α) in CRC tissue compared with levels in precancerous tissue. Supporting these findings, the levels of secreted TNF­α and IL­6 were significantly reduced when LYPD8 was overexpressed in human CRC cells, and the secretion of TNF­α and IL­6 were positively associated with the phosphorylation of STAT3 and P65. However, this trend was restored upon supplementation with TNF­α and IL­6 in CRC cells. Furthermore, the overexpression of LYPD8 in CRC cells significantly inhibited CRC cell proliferation and migration. Overall, the LYPD8­mediated tumor­inhibiting role involves a direct effect on the secretion of IL­6/TNF­α in CRC cells by reducing the phosphorylation of STAT3 and P65.

The genetic association between iNOS and eNOS polymorphisms and gastric cancer risk: a meta-analysis.

OBJECTIVE: There are a number of susceptible factors for an increased risk of gastric cancer. Nitric oxide (NO) is considered to be associated with the development of a range of cancers. In particular, inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) are known to play a central role in the production of NO. Published studies relating to the association between eNOS rs1799983, rs2070744, and iNOS rs2297518 polymorphisms and the risk of gastric cancer risk are conflicting and inconclusive and require further analysis. MATERIALS AND METHODS: This study involved a meta-analysis of case-control studies relating to eNOS rs1799983, rs2070744, and iNOS rs2297518 polymorphisms published prior to January 2018. Literature searches were carried out in PubMed, Embase, Web of Science, the Cochrane Library databases, and the Chinese National Knowledge Infrastructure. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of association based on genotype data. RESULTS: A total of 1,356 cases and 1,791 controls were included from nine case-control studies involving eNOS rs1799983 (G894T), rs2070744 (T-786C), and iNOS rs2297518 (C150T) polymorphisms. Data analysis indicated that iNOS rs2297518 was a risk factor for Helicobacter pylorus-positive gastric cancer when compared with H. pylorus-negative gastric cancer (p=0.003, OR [95% CI] =2.19 [1.31-3.66]). In addition, the allelic, dominant, and recessive models of eNOS rs2070744 were significantly associated with a risk of gastric cancer (allelic model: p<0.00001, OR [95% CI] =0.23 [0.16-0.34]; dominant model: p<0.00001, OR [95% CI] =0.25 [0.15-0.42]; recessive model: p<0.00001, OR [95% CI] =0.16 [0.08-0.30]). No association was identified between eNOS rs1799983 and the risk of gastric cancer (p>0.05). CONCLUSION: iNOS rs2297518 and eNOS rs2070744 polymorphisms may represent susceptible factors for gastric cancer.

miR-188-5p Suppresses Gastric Cancer Cell Proliferation and Invasion via Targeting ZFP91.

MicroRNAs (miRNAs) have been demonstrated to be essential regulators in the development and progression of various cancers. The role of miR-188-5p in gastric cancer (GC) has not been determined. In this study, we found that the expression of miR-188-5p was downregulated in GC tissues compared with adjacent normal tissues. The lowly expressed miR-188-5p was significantly associated with lymph node metastasis and advanced TNM stage. Moreover, overexpression of miR-188-5p significantly inhibited GC cell proliferation, migration, and invasion but promoted cellular apoptosis. Mechanistically, we identified transcription factor ZFP91 as a target gene of miR-188-5p in GC. We found that miR-188-5p overexpression significantly inhibited the expression of ZFP91 in GC cell lines. There was an inverse correlation between the expression of miR-188-5p and ZFP91 in GC tissues. We found that restoration of ZFP91 in miR-188-5p-overexpressed MGC-803 and SGC-7901 cells promoted cell proliferation, migration, and invasion. Finally, we also showed that overexpression of miR-188-5p inhibited tumor growth in vivo. Taken together, our findings indicated that miR-188-5p serves as a tumor suppressor in human GC by targeting ZFP91, suggesting that miR-188-5p might be a promising therapeutic target for GC treatment.

miR-145 suppresses breast cancer cell migration by targeting FSCN-1 and inhibiting epithelial-mesenchymal transition.

MicroRNAs (miRNAs), small non-coding RNAs, regulate fundamental cellular and developmental processes such as cell growth, apoptosis, migration, and invasion. In our present study, we investigated the inhibitory role of miR-145 on breast cancer cell migration as well as its underlying mechanism. Wound healing assay and transwell migration assay showed that ectopic expression of miR-145 significantly inhibited breast cancer cell migration. Bioinformatics analysis revealed that FSCN-1 was a putative target of miR-145. The expression of FSCN-1 varied among four different breast cancer cells, and inversely correlated with miR-145 levels. Moreover, miR-145 mimic transfection enhanced the expression of FSCN-1 in Bcap-37 and HCC-1937 cells. We also found that siRNA- mediated down-regulation of FSCN-1 inhibited cell motility in breast cancer cells. In addition, we found that up-regulation of miR-145 blocked EMT and decreased the expression of MMP-2/9 in breast cancer cells. These results reveal a new link between miR-145, FSCN-1 and EMT in the regulation of breast cancer migration.

Macrophage-induced tumor angiogenesis is regulated by the TSC2-mTOR pathway.

Tumor-associated macrophages (TAM) have multifaceted roles in tumor development but they have been associated particularly closely with tumor angiogenesis. However, although the accumulation of TAM (M2 phenotype) promotes tumor angiogenesis, the mechanism through which monocytes differentiate to generate TAM is unclear. Here, we report that the mTOR pathway is a critical element in the regulation of monocyte differentiation to TAM. In human peripheral monocytes stimulated by lipopolysaccharide, mTOR was inhibited by rapamycin or activated by RNA interference-mediated knockdown of the mTOR repressor tuberous sclerosis complex 2 (TSC2). Rapamycin caused the monocytes to differentiate into M1 macrophages releasing more interleukin (IL)-12 and less IL-10, whereas TSC2 knockdown caused the monocytes to differentiate into M2 macrophages releasing less IL-12 and more IL-10. In parallel fashion, angiogenic properties were promoted or reduced in human umbilical vein endothelial cells cocultured with TSC2-deficient monocytes or rapamycin-treated monocytes, respectively. Furthermore, tumor angiogenesis and growth in murine xenografts were promoted or reduced by infusion of hosts with TSC2-deficient or TSC2-overexpressing monocytes, respectively. Finally, in vivo depletion of macrophages was sufficient to block the antiangiogenic effects of rapamycin on tumors. Our results define the TSC2-mTOR pathway as a key determinant in the differentiation of monocytes into M2 phenotype TAM that promote angiogenesis.

NSC 74859-mediated inhibition of STAT3 enhances the anti-proliferative activity of cetuximab in hepatocellular carcinoma.

BACKGROUND: Cetuximab [an epidermal growth factor receptor (EGFR) inhibitor], which was shown to be effective in rectal and non-small cell lung cancers (NSCLCs), was only modestly effective in clinical trials of hepatocellular carcinoma (HCC). STAT3, which is thought to be a determinant of HCC sensitivity to antitumour drugs, may be involved. AIMS: To evaluate the efficacy of combination therapy using cetuximab and NSC 74859 (a novel STAT3 inhibitor) in EGFR and STAT3 overexpressing hepatoma cells. METHODS: Hepatoma cell lines were treated with cetuximab, NSC 74859 or a combination of both drugs. Efficacy of treatment was evaluated by determining cell viability using MTT assays and proliferation by cell counting. Expression and activation of STAT3 were determined using Western blot analysis. We evaluated the role of STAT3 in single and combination therapy using siRNA-mediated knock-down of STAT3 or STAT3 overexpression strategies. RESULTS: HepG2 and Huh-7 cells, which had lower levels of pSTAT3 than SK-HEP1 cells, were more sensitive to cetuximab treatment when compared with SK-HEP1 cells. Although none of these cell lines was sensitive to NSC 74859 alone, NSC 74859 potentiated the antiproliferative effect of cetuximab in all three cell lines. siRNA knock-down of STAT3 increased the sensitivity of these cell lines to cetuximab, whereas STAT3 overexpression antagonized these effects. CONCLUSIONS: Enhanced growth inhibition in hepatoma cells treated with both NSC 74859 and cetuximab suggests that cetuximab resistance is probably mediated via STAT3. Combination therapy using both inhibitors of EGFR and STAT3 signalling warrants further investigation under in vivo condition.