Hypoxia induced exosomal Circ-ZNF609 promotes pre-metastatic niche formation and cancer progression via miR-150-5p/VEGFA and HuR/ZO-1 axes in esophageal squamous cell carcinoma.

Exosomes derived from cancer are regarded as significant mediators of cancer-host crosstalk. Hypoxia, on the other hand, is one of the essential characteristics of solid tumors. This research set out to discover how circulating exosomes from hypoxic esophageal squamous cell carcinoma (ESCC) contribute to the formation of metastatic niches and distant metastasis. First, we noticed that human umbilical vein endothelial cells (HUVECs) had their tight connections disrupted and the expression of proteins involved in angiogenesis boosted by ESCC hypoxic exosomes. Hypoxia significantly induced Circ-ZNF609 expression in exosomes from ESCC, which was then internalized by HUVECs, as determined by circular RNA screening. High Circ-ZNF609 expression in HUVECs facilitated angiogenesis and vascular permeability, thereby promoting pre-metastatic niche formation, and enhancing distant metastasis in vitro and in vivo. Exosomal Circ-ZNF609 activated vascular endothelial growth factor A (VEGFA) mechanistically by sponging miR-150-5p. Exosomal Circ-ZNF609 also interacted with HuR and inhibited HuR binding to ZO-1, Claudin-1, and Occludin mRNAs, thereby reducing their translation. Collectively, our findings identified an essential function for exosomal Circ-ZNF609 from ESCC cells, suggesting the potential therapeutic value of exosomes for ESCC patients.

Mechanism of surface oxygen-containing species promoted electrocatalytic CO2 reduction.

Oxygen-containing species have been demonstrated to play a key role in facilitating electrocatalytic CO2 reduction (CO2RR), particularly in enhancing the selectivity towards multi-carbon (C2+) products. However, the underlying promotion mechanism is still under debate, which greatly limits the rational optimization of the catalytic performance of CO2RR. Herein, taking CO2 and O2 co-electrolysis over Cu as the prototype, we successfully clarified how O2 boosts CO2RR from a new perspective by employing comprehensive theoretical simulations. Our results demonstrated that O2 in feed gas can be rapidly reduced into *OH, leading to the partial oxidation of Cu surface under reduction conditions. Surface *OH accelerates the formation of quasi-specifically adsorbed K+ due to the electrostatic interaction between *OH and K+ ions, which significantly increases the concentration of K+ near the Cu surface. These quasi-specifically adsorbed K+ ions can not only lower the C-C coupling barriers but also promote the hydrogenation of CO2 to improve the CO yield rate, which are responsible for the remarkably enhanced efficiency of C2+ products. During the whole process, O2 co-electrolysis plays an indispensable role in stabilizing surface *OH. This mechanism can be also adopted to understand the effect of high pH of electrolyte and residual O in oxide-derived Cu (OD-Cu) on the catalytic efficiency towards C2+ products. Therefore, our work provides new insights into strategies for improving C2+ products on the Cu-based catalysts, i.e., maintaining partial oxidation of surface under reduction conditions.

A simple descriptor for the nitrogen reduction reaction over single atom catalysts.

The performance of supported catalysts is largely decided by metal-support interactions, which is of great significance for the rational design of catalysts. However, how to quantify the structure-activity relationship of supported catalysts remains a great challenge. In this work, taking MoS2 and WS2 supported single atom catalysts (SACs) as prototypes, a simple descriptor, namely, effective d electron number (labeled as Φ), is constructed to quantitatively describe the effect of metal-support interaction on the nitrogen reduction reaction (NRR) activity. This descriptor merely consists of intrinsic properties of the catalyst (including the number of d electrons, electronegativity of the metal atoms and generalized electronegativity of the substrate atoms) and can accurately predict the limiting potential (UL) for the NRR, with no need for any density functional theory calculations. Moreover, this descriptor possesses superb expansibility that can be applied to other materials, including other metal dichalcogenide (MoSe2, MoTe2, WSe2, WTe2 and NbS2) and even MXene (V2CO2, Ti2CO2 and Nb2CO2)-supported SACs. On this basis, a fast screening of excellent NRR catalysts among these systems is performed and three promising NRR catalysts (i.e. Mo@WTe2, Mo@V2CO2 and Re@NbS2) are successfully selected with UL as low as -0.32, -0.24 and -0.31 V, respectively. This work offers new opportunities for advancing the rapid discovery of high-efficiency NRR catalysts, and the design principle is expected to be widely applicable to other catalytic systems and beyond.

Safety and effectiveness of apatinib in elderly patients with metastatic gastric cancer: a sub-analysis from the large-scale, prospective observational study of apatinib for gastric cancer treatment in a real-world clinical setting (AHEAD-G202).

Background: Apatinib was shown to improve the survival of Chinese patients with refractory metastatic gastric cancer (mGC). As an orally administered drug, it has been widely used in elderly patients because the dosing schedule can be adjusted flexibly. However, data on the efficacy and safety of apatinib in elderly patients is scarce. The aim of this study was to evaluate the toxicity and effectiveness of apatinib for elderly patients with mGC in a real-world setting. Methods: Data from the sub-population of patients who were ≥65 years enrolled in the AHEAD-G202 trial were analyzed. Patients with mGC were prospectively registered and initially received ≤850 mg oral apatinib daily combined or not combined with chemotherapy, at the investigator's discretion. The primary endpoint was safety. The secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results: A total of 117 patients were included. There were 51 (43.59%) patients in the low-dose (250 mg) group, 60 (51.28%) patients in the mid-dose (425 to 500 mg) group, and 6 (5.13%) patients in the high-dose (850 mg) group according to the initial daily doses. Hypertension (6.84%) was the only grade 3-4 adverse event (AE) with a prevalence of more than 5% and across the low-dose (11.76%), mid-dose (3.33%) and high-dose group (0%). The median OS and PFS were 7.13 months (95% CI: 5.04 to 9.22 months) and 4.27 months (95% CI: 3.24 to 5.29 months), respectively. The OS and PFS were similar among the 65-74 and ≥75 years groups (χ2=1.406, P=0.306; χ2=0.378, P=0.066, respectively). The OS and PFS were also comparable among the 3 dose groups. Conclusions: Elderly patients with mGC can tolerate and benefit from apatinib therapy. A lower initial daily dosing strategy may be a suitable choice for elderly patients in clinical practice.

Rs7853346 Polymorphism in lncRNA-PTENP1 and rs1799864 Polymorphism in CCR2 are Associated with Radiotherapy-Induced Cognitive Impairment in Subjects with Glioma Via Regulating PTENP1/miR-19b/CCR2 Signaling Pathway.

LncRNA-PTENP1 was reported to promote multiple myeloma cancer stem cell proliferation, and the G allele of rs7853346 polymorphism in lncRNA-PTENP1 was demonstrated to enhance the effect of lncRNA-PTENP1. In this study, we aimed to study the potential effect of lncRNA-PTENP1 and CCR2 mRNA polymorphisms on cognitive impairment in glioma patients. In this study, 279 glioma patients were recruited and grouped according to their genotypes of rs7853346 in PTENP1 and rs1799864 in CCR1. Pathogenic parameters were collected from patients before radiotherapy (month 0) or at month 1 and month 3 after radiotherapy to study the effect of rs7853346 and rs1799864 on cognitive impairment. Sequence analysis, luciferase assay, real-time PCR, and Western blot were performed to study the regulatory relationships between lncRNA-PTENP1, miR-18b, and CCR2. The glioma patient groups exhibited no significant differences concerning basic characteristics. However, the CG&GG/GG genotype alleviated radiotherapy-induced cognitive impairment by exhibiting the highest MMSE among the four groups. On the contrary, parameters including the severity of depression, bladder control, global health status, itchy skin, and weakness of legs all showed no difference among different patient groups at month 0, month 1, and month 3. Also, a long-term positive effect of CG&GG/GG genotype on role functioning and social functioning was also observed after radiotherapy. Compared with patients carrying the CC genotype of rs7853346, the expression of lncRNA-PTENP1 was reduced while the miR-19b level was elevated in patients carrying the CG&GG genotypes of rs7853346. Moreover, the expression of CCR2 mRNA was the highest in the CC/GA&AA group and the lowest in the CG&GG/GG group. Subsequent sequence analysis and luciferase assay indicated that miR-19b could bind to lncRNA-PTENP1 and 3'UTR of CCR2 mRNA, and the knockdown of lncRNA-PTENP1 led to evident up-regulation of miR-19b and down-regulation of CCR2 mRNA/protein in a cellular model, thus verifying the presence of the lncRNA-PTENP1/miR-19b/CCR2 mRNA signaling pathway. In conclusion, by studying the changes in the key parameters of glioma patients who were subjected to radiotherapy, we concluded that the rs7853346 polymorphism in lncRNA-PTENP1 and the rs1799864 polymorphism in CCR2 could independently affect cognitive impairment, while a more significant combined effect on cognitive impairment was exerted in glioma patients via the signaling pathway of PTENP1/miR-19b/CCR2.

The G to A transformation of rs4702 polymorphism in 3'UTR of FURIN reduced the risk of radiotherapy-induced cognitive impairment in glioma patients.

The G allele of rs4702 polymorphism has been reported to reduce the production of mature BDNF and FURIN, both of which were closely associated with cognitive functions. Real-time PCR, ELISA and luciferase assay were performed to explore the interactions between miR-338-3p, FURIN and BDNF. T-RFLP was used to assess the intestinal flora in the stool samples of glioma patients after radiotherapy. We grouped the 106 glioma patients recruited according to the rs4702 polymorphism. The results showed no obvious correlation between rs4702 polymorphism and the expression of miR-338-3p. However, rs4702-A was associated with increased expression of FURIN and BDNF in the serum and PBMC of glioma patients after radiotherapy. Besides, the study found that rs4702-A was remarkably associated with increased enterotype I and decreased enterotype III in the stool of glioma patients after radiotherapy. Rs4702-A was also proved to be closely associated with increased MMSE, role functioning and social functioning at three months after radiotherapy. Furthermore, miR-338-3p repressed the expression of FURIN-G. Compared with G allele, the presence of A allele of rs4702 polymorphism in FURIN could obstruct the suppressive effect of miR-338-3p upon the expression of FURIN and BDNF in intestinal flora. Therefore, the carriers of A allele will be challenged with less risk of radiotherapy-induced cognitive impairment.

Promoting the conversion of CO2 to CH4via synergistic dual active sites.

Carbon-based single-atom catalysts (SACs) have shown promising applications in the conversion of CO2 into CO. However, the deep reduction process for the production of high-value hydrocarbons is largely limited due to the weak activation of CO. Herein, on the basis of first-principles calculations, a simple coordination regulation method of the active site is proposed to improve the conversion of CO2. Taking NiN4 as an example, by introducing heteroatoms (B, C, O, P, and S atoms), we reveal that NiN3B can effectively capture *CO and further convert to CH4 with an ultralow limiting potential of -0.42 V. The excellent catalytic performance is probably attributed to the formed synergistic dual active sites between non-metal B and metal Ni atoms. Moreover, NiN3B can maintain good stability and the catalytic performance can be further enhanced by increasing the B-doping concentration. This work demonstrates that coordination regulation is an effective strategy to improve the performance of single-atom catalysts and paves a possible way to advance the development of non-Cu-based CO2RR electrocatalysts for high-value hydrocarbon products.

Efficacy and safety of apatinib for the treatment of AFP-producing gastric cancer.

BACKGROUND: Alpha-fetoprotein-producing gastric cancer (AFPGC) poses a therapeutic challenge worldwide because of its poor prognosis. This study aimed to evaluate the efficacy and safety of antiangiogenic drug apatinib in advanced AFPGC in a real-world setting. METHODS: From September 2015 to December 2017, twenty-one patients identified with AFPGC from the clinical trial AHEAD-G202, an open-label, prospective, multicenter, non-interventional study of apatinib for advanced metastatic gastric cancer, were enrolled to perform this analysis. Patients received oral apatinib as monotherapy or combination therapy. A treatment cycle was defined as 28 days. The primary outcome was progression-free survival (PFS) and overall survival (OS), and the secondary outcomes included safety, objective response rate (ORR), and disease control rate (DCR). RESULTS: Twenty patients were evaluated for the apatinib efficacy analysis. The ORR of apatinib was 10%, whereas the DCR was 70%. The median PFS was 3.5 months [95%confidence interval (CI): 2.34-4.66]. The median OS was 4.5 months (95%CI: 3.49-5.51). Median OS of AFPGC patients without carcinoembryonic antigen (CEA) elevation achieved 30.8 months. CEA elevation was considered to be a potential independent predictive factor for OS (P = 0.030) and PFS (P = 0.047) by the analysis of multivariate analysis. The most common grade 3 to 4 adverse events (AEs) were hypertension (4.8%), hand-foot syndrome (4.8%), anorexia (4.8%), and vomiting and nausea (4.8%). CONCLUSION: Apatinib showed promising efficacy and an acceptable safety profile in patients with advanced AFPGC. Antiangiogenic therapy may be a good strategy for the treatment of AFPGC as a rare sub-type of gastric cancer. TRIAL REGISTRATION: AHEAD-G202 (NCT02668380).

Safety and effectiveness of apatinib in patients with previously treated metastatic gastric cancer: a sub-analysis from the real-world study of apatinib for gastric cancer treatment (AHEAD-G202).

Apatinib, a VEGFR2 receptor tyrosine kinase inhibitor, showed survival benefits in Asian patients with heavily pretreated advanced gastric cancer. However, the adverse event (AEs) profile of apatinib has limited its use. Dosing schedules are used to alleviate toxicities despite no supportive evidence. This study aimed to analyze the toxicity and effectiveness of apatinib alone, especially with different dosing strategies in advanced gastric cancer patients under a real-world setting. Data from the subpopulation of patients who failed ≥2 chemotherapy regimens enrolled in the AHEAD-G202 trial were analyzed. The primary endpoint was safety. The secondary endpoints were overall survival (OS) and progression-free survival (PFS). Totally 120 patients were included into three groups by the initial daily doses: 43 (35.8%) patients in the low-dose (250 mg) group, 67 (55.8%) patients in the mid-dose (425 mg to 500 mg) group, and 10 (8.3%) patients in the high-dose (675 to 850 mg) group. Grade 3/4 treatment-emergent AEs were infrequent (<5%), with the most commonly reported grade 3/4 AEs being hand-foot syndrome (4.2%), hypertension (4.2%,), fatigue (4.2%), and difficulty in swallowing (4.2%) which gradually decreased among the high-, mid-, and low-dose groups. The median OS and PFS were 6.33 months (95% CI, 4.57-7.73) and 3.83 months (95% CI: 1.40-4.20), respectively and were comparable among the three doses groups. We found heavily pretreated advanced gastric cancer patients can tolerate and benefit from lower-doses of apatinib therapy. The lower initial daily dosing strategy represents an alternative approach for optimizing apatinib dosing in clinical practice.

An open label, multicenter, noninterventional study of apatinib in advanced gastric cancer patients (AHEAD-G202).

BACKGROUND: Apatinib has been proved to be effective and well tolerated among patients in phase II and III studies. Here, we evaluated the safety and effectiveness of apatinib in advanced gastric cancer patients in a real-world setting. METHODS: This study enrolled advanced gastric cancer patients who had progressed or relapsed despite systemic chemotherapy. The primary outcome was safety and the secondary outcomes included overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 337 patients were included. In total, 62 (18.4%), 102 (30.3%), and 173 (51.3%) patients received first, second, and third or higher line apatinib therapy, respectively. Grade 3/4 treatment-emergent adverse events (AEs) were infrequent (<5%), with hypertension (6.8%) being the only grade 3/4 AE occurring in more than 5% of the patients and across the low-dose (250 mg, 7.3%), mid-dose (425-500 mg, 6.1%), and high-dose group (675-850 mg, 2/15, 13.3%). The median OS and PFS were 7.13 months (95% CI, 6.17-7.93) and 4.20 months (95% CI, 4.60-4.77), respectively, and were comparable among the low-, mid-, and high-dose groups. CONCLUSION: Lower daily doses of apatinib achieved comparable OS and PFS versus higher daily doses of apatinib while maintaining a more benign safety profile in advanced gastric cancer patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02668380.

Hypoxia-induced microRNA-10b-3p promotes esophageal squamous cell carcinoma growth and metastasis by targeting TSGA10.

Evidence has shown that hypoxia promotes esophageal squamous cell carcinoma (ESCC) growth and metastasis, but the molecular mechanisms underlying that response remain poorly understood. MicroRNAs (miRNAs) are post-transcriptional regulators that participate in various cancer-related processes. Here, we demonstrated that hypoxia along with hypoxia-inducible factor 1α significantly increased expression of miR-10b-3p. Inhibition of miR-10b-3p weakened the effects of hypoxia on ESCC cell proliferation, migration and invasion, while miR-10b-3p overexpression had the opposite effects. Mechanistically, miR-10b-3p acted as cancer-promoting gene by targeting testis specific 10. Using a xenograft model, we observed that administration of miR-10b-3p agomir to tumors enhanced their growth and metastasis in vivo. These findings verified the potent regulatory role played by hypoxia-induced miR-10b-3p expression in ESCC progression. These results suggest that miR-10b-3p may be a useful therapeutic target for treating ESCC.

Hypoxic exosomes facilitate angiogenesis and metastasis in esophageal squamous cell carcinoma through altering the phenotype and transcriptome of endothelial cells.

BACKGROUND: In cancer progression, hypoxia, or low oxygen tension, is a major regulator of tumor aggressiveness and metastasis. However, how cancer cells adapt to the hypoxia and communicate with other mesenchymal cells in microenvironment during tumor development remains to be elucidated. Here, we investigated the involvement of exosomes in modulating angiogenesis and enhancing metastasis in esophageal squamous cell carcinoma (ESCC). METHODS: Differential centrifugation, transmission electron microscopy and nanoparticle tracking analysis were used to isolate and characterize exosomes. Colony formation and transwell assay were performed to assess the proliferation, migration and invasion of human umbilical vein endothelial cells (HUVECs). The tube formation assay and matrigel plug assay were used to evaluate the vascular formation ability of HUVECs in vitro and in vivo respectively. An in vivo nude mice model was established to detect the regulatory role of exosomes in ESCC progression. Microarray analysis was performed to analyze the transcriptome profiles in HUVECs. RESULTS: Exosomes derived from ESCC cells cultured under hypoxia played a better role in promoting proliferation, migration, invasion and tube formation of HUVECs in vitro and in vivo than exosomes from ESCC cells cultured under normoxia. Moreover, hypoxic exosomes significantly enhanced the tumor growth and lung metastasis compared with normoxic exosomes in nude mice models. Interestingly, endothelial cells were programmed by hypoxic and normoxic exosomes from ESCC cells which altered the transcriptome profile of HUVECs. CONCLUSIONS: Taken together, our data identified an angiogenic role of exosomes from ESCC cells which shed light on the further application of exosomes as valuable therapeutic target for ESCC.

Circulating exosomes from esophageal squamous cell carcinoma mediate the generation of B10 and PD-1high Breg cells.

As one of the most frequently diagnosed cancers, esophageal squamous cell carcinoma (ESCC) remains the leading cause of malignancy-related death worldwide. Many studies have focused on the potential role of cancer cells in educating B cells during cancer progression. Here, we aim to explore the role of circulating exosomes from ESCC in the generation of two main regulatory B (Breg) subsets, including interleukin-10+ Bregs (B10) and programmed cell death (PD)-1high Bregs. Firstly, we observed an elevated percentage of B10 cells in peripheral blood of ESCC patients compared with healthy controls. Then we isolated and characterized exosomes from the peripheral blood of ESCC patients and an ESCC cell line. Exosomes from ESCC patients and the ESCC cell line suppressed the proliferation of B cells and induced the augmentation of B10 and PD-1high Breg cells. By comparing the long non-coding RNA and mRNA expression profiles in exosomes from ESCC patients or healthy controls, we identified a series of differentially expressed genes. Finally, we undertook gene annotation and pathway enrichment analyses on differentially expressed genes to explore the potential mechanism underlying the modulatory role of cancer exosomes in B cells. Our findings contribute to the study on B cell-mediated ESCC immunosuppression and shed light on the possible application of exosomes in anticancer therapies.

The Dosimetric Comparisons of CRT, IMRT, ARC, CRT+IMRT, and CRT+ARC of Postoperative Radiotherapy in IIIA-N2 Stage Non-Small-Cell Lung Cancer Patients.

Currently, studies about PORT in stage IIIA-N2 NSCLC patients in recent years have mostly adopted the conformal radiation therapy (CRT) technique, while other modern techniques such as intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT, hereinafter referred to as ARC), helical tomotherapy (HT), and so forth are also developing quickly. In this paper, we intended to compare the dosimetric characteristics of CRT, IMRT, ARC, CRT+IMRT, and CRT+ARC of PORT in stage IIIA-N2 NSCLC patients. Ten patients with stage IIIA-N2 completely resected NSCLC, whom were treated by PORT in the radiotherapy department of our hospital from January 1, 2017, to January 1, 2018, were randomly selected in this study. For each patient, the CRT plan, IMRT plan, ARC plan, CRT+IMRT plan, and CRT+ARC plan were designed separately on the same set of CT images. The isodose distribution and dose-volume histogram (DVH) of the five plans were compared to determine the dosimetric parameters of the targets, OAR (organs at risk), and the normal tissue (defined as body subtracted to PTV (planning target volume), B-P). No plan had absolute dosimetry advantages than any other plans. In clinical practice, the plans could be chosen according to their dosimetry characteristics.

Identification of a 26-lncRNAs Risk Model for Predicting Overall Survival of Cervical Squamous Cell Carcinoma Based on Integrated Bioinformatics Analysis.

As a common malignancy in women, cervical squamous cell carcinoma is a major cause of cancer-related mortality globally. Recent studies have demonstrated that long non-coding RNA (lncRNA) can function as potential biomarkers in cancer prognosis; however, little is known about its role in cervical cancer. In this study, we downloaded the gene expression profiles along with the clinical data of patients with cervical squamous cell carcinoma from The Cancer Genome Atlas. By applying bioinformatics analysis including random forest selection and Least Absolute Shrinkage and Selection Operator (LASSO) cox regression model along with 10-fold cross-validation, we constructed a 26-lncRNAs risk model that can be used to predict the overall survival of cervical squamous cell carcinoma. After that, Kaplan-Meier analysis combined with log-rank p test was applied to assess the predictive accuracy of the 26-lncRNAs risk model. Further analysis showed that the prognostic value of 26-lncRNAs risk model was independent of other clinicopathological factors. At last, lncRNAs in the model were put into gene ontology biological process enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways analysis, which suggested that these lncRNAs might contribute to cancer-associated processes such as cell cycle and apoptosis. This study indicated that lncRNAs signature could be a useful marker to predict the prognosis of cervical squamous cell carcinoma.

Roles of Fibroblast Activation Protein and Hepatocyte Growth Factor Expressions in Angiogenesis and Metastasis of Gastric Cancer.

This study aims to explore the roles of fibroblast activation protein (FAP) and hepatocyte growth factor (HGF) expressions in the angiogenesis and metastasis of gastric cancer (GC). From May 2012 to December 2015, 110 GC patients who received surgical treatment in the First Hospital of Qinhuangdao were selected. The HGF and FAP expressions in 110 cases of GC, 130 cases of normal gastric mucosa and 115 cases of gastric ulcer were detected by streptavidin-perosidase (SP) method. Venous blood HGF level of GC patients was tested by enzyme-linked immunosorbent assay (ELISA). The micro-vessel number of the patients in the three groups were calculated and analyzed. In GC group, positive expression rates of FAP and HGF protein were 61.8% and 67.3% respectively, which were both higher than those in normal gastric mucosa and gastric ulcer groups. The micro-vessel numbers in patients of the normal gastric mucosa and gastric ulcer groups are far less than that in GC group. FAP, HGF and micro-vessel density (MVD) were significantly correlated with infiltration depth, tumor-node-metastasis (TNM) staging, lymph node metastasis (LNM) and distant metastasis. The results of ELISA showed that serum HGF level was related to tumor size, infiltration degree, TNM staging, LNM and distant metastasis. FAP and HGF expressions in GC were positively correlated with MVD, and the expressions of FAP and HGF in GC were in positive correlation. Our study provided evidence that high FAP and HGF expressions may be positively correlated with the angiogenesis and metastasis of GC.

A six-microRNA risk score model predicts prognosis in esophageal squamous cell carcinoma.

Esophageal cancer ranks the eighth most common cancer and the sixth most common cause of cancer death worldwide. MicroRNAs (miRNAs) are small noncoding RNAs that regulate a wide variety of cancer-related cellular processes. In the current study, a series of previously published gene expression microarray data from Gene Expression Ominus and The Cancer Genome Atlas were downloaded and further divided into training, internal, and external validation sets. Least absolute shrinkage and selectionator operator Cox regression model along with 10-fold cross-validation was performed to select the miRNAs associated with the prognosis of esophageal squamous cell carcinoma (ESCC) and constructed a six-miRNA signature. Then the prediction accuracy of this signature was assessed in validation and test set using Kaplan-Meier analysis, time-dependent receiver operating characteristic (ROC) curves and dynamic area under the ROC curve. According to the result, the prediction accuracy of miRNA signature was much better than that of tumor-node-metastasis (TNM) stage in all the three sets. Stratified analysis also demonstrated that the predict ability of this signature was independent of TNM stage. Finally, function experiments including apoptosis and colony formation assay were performed to further reveal the regulatory role of miRNAs in ESCC. Our study demonstrated the promising potential application of this novel six-miRNA signature as an independent biomarker for survival prediction of ESCC patients.

DANCR-mediated microRNA-665 regulates proliferation and metastasis of cervical cancer through the ERK/SMAD pathway.

Emerging evidence has indicated that microRNAs (miRNAs) play an important role in cervical cancer (CC). However, the role of miRNA (miR)-665 in cervical cancer remains unclear. The aim of the present study was to investigate the potential functions of miR-665 in CC and to identify the underlying mechanisms of action. Herein, we show that miR-665 was downregulated in CC tissues and cell lines, which is negatively correlated with tumor size, distant metastasis, advanced TNM stage and poor prognosis. Functionally, miR-665 inhibited cell proliferation, migration and invasion and resistance of cisplatin for CC cells, as well as tumor growth. We validated that transforming growth factor beta receptor 1 (TGFBR1) was a direct target of miR-665 and mediated the ERK/SMAD pathway. In addition, we identified miR-665 as the competing endogenous RNA for long noncoding (lnc)-DANCR. These observations suggested that lnc-DANCR-mediated miR-665 downregulation regulates the malignant phenotype of CC cells by targeting TGFBR1 through the ERK/SMAD pathway, which may present a pathway for novel therapeutic stratagems for CC therapy.

A seven-lncRNA signature predicts overall survival in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common types of cancer and the leading causes of cancer-related mortality worldwide, especially in Eastern Asia. Here, we downloaded the microarray data of lncRNA expression profiles of ESCC patients from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data sets and divided into training, validation and test set. The random survival forest (RSF) algorithm and Cox regression analysis were applied to identify a seven-lncRNA signature. Then the predictive ability of the seven-lncRNA signature was evaluated in the validation and test set using Kaplan-Meier test, time-dependent receiver operating characteristic (ROC) curves and dynamic area under curve (AUC). Stratified analysis and multivariate Cox regression also demonstrated the independence of the signature in prognosis prediction from other clinical factors. Besides, the predict accuracy of lncRNA signature was much better than that of tumor-node-metastasis (TNM) stage in all the three sets. LncRNA combined with TNM displayed better prognostic predict ability than either alone. The role of LINC00173 from the signature in modulating the proliferation and cell cycle of ESCC cells was also observed. These results indicated that this seven-lncRNA signature could be used as an independent prognostic biomarker for prognosis prediction of patients with ESCC.