BackgroundThe long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) has been reported to be overexpressed in colorectal cancer (CRC). However, its underlying mechanisms in the progression of CRC have not been well studied.MethodsTo investigate the clinical significance of NEAT1, we analyzed its expression levels in a publicly available dataset and in 71 CRC samples from Fudan University Shanghai Cancer Center. Functional assays, including the CCK8, EdU, colony formation, wound healing, and Transwell assays, were used to determine the oncogenic role of NEAT1 in human CRC progression. Furthermore, RNA pull-down, mass spectrometry, RNA immunoprecipitation, and Dual-Luciferase Reporter Assays were used to determine the mechanism of NEAT1 in CRC progression. Animal experiments were used to determine the role of NEAT1 in CRC tumorigenicity and metastasis in vivo.ResultsNEAT1 expression was significantly upregulated in CRC tissues compared with its expression in normal tissues. Altered NEAT1 expression led to marked changes in proliferation, migration, and invasion of CRC cells both in vitro and in vivo. Mechanistically, we found that NEAT1 directly bound to the DDX5 protein, regulated its stability, and sequentially activated Wnt signaling. Our study showed that NEAT1 indirectly activated the Wnt/β-catenin signaling pathway via DDX5 and fulfilled its oncogenic functions in a DDX5-mediated manner. Clinically, concomitant NEAT1 and DDX5 protein levels negatively correlated with the overall survival and disease-free survival of CRC patients.ConclusionsOur findings indicated that NEAT1 activated Wnt signaling to promote colorectal cancer progression and metastasis. The NEAT1/DDX5/Wnt/β-catenin axis could be a potential therapeutic target of pharmacological strategies.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0656-7) contains supplementary material, which is available to authorized users.

Serum biomarkers have not been fully incorporated into clinical use for the diagnosis of renal cell carcinoma (RCC). The recent discovery of long noncoding RNAs (lncRNAs), which have been reported in a variety of cancer types, suggested a promising new class of biomarkers for tumour diagnosis. The aim of our study was to evaluate whether the levels of circulating lncRNAs could be used as a tumour marker to discriminate between clear cell RCC (ccRCC) patients and healthy controls. Serum samples were collected from 71 ccRCC patients including 62 age- and sex-matched healthy controls and 8 patients with benign renal tumours. Eighty-two cancer-associated lncRNAs were assessed by reverse transcription and quantitative polymerase chain reaction in paired tissues and serum. A 5-lncRNA signature, including lncRNA-LET, PVT1, PANDAR, PTENP1 and linc00963, were identified and validated in the training set and testing set, respectively. The receiver operating characteristic curves for this serum 5-lncRNA signature were 0.900 and 0.823 for the two sets of serum samples. Moreover, five-minus-one lncRNA signatures demonstrated that none of the lncRNAs had a higher area under the curve than the others in either set. A risk model for the serum 5-lncRNA signature also determined that benign renal tumours can be distinguished from ccRCC samples. This work may facilitate the detection of ccRCC and serve as the basis for further studies of the clinical value of serum lncRNAs in maintaining surveillance and forecasting prognosis.

The aberrant expression of long noncoding RNAs (lncRNAs) has been reported frequently in specific cancers, including high-grade serous ovarian cancer (HGSOC). The purpose of the present study was to explore the clinical significance and underlying mechanisms of a significantly dysregulated lncRNA (NEAT1) in HGSOC. Our results showed that elevated NEAT1 expression in human HGSOC specimens correlated with a poor prognosis. Functional experiments demonstrated that knockdown of NEAT1 significantly prohibited ovarian cancer cell proliferation and invasion in vitro and restrained tumor growth in vivo. LIN28B was identified by bioinformatics analysis along with experimental evidence as a direct actor that enhanced NEAT1 stability. A rescue functional assay confirmed that the LIN28B/NEAT1 axis contributed to oncogenic functions in ovarian cancer cells. Moreover, gene expression profile data and dual luciferase reporter assay results demonstrated that NEAT1 functioned as a competing endogenous RNA (ceRNA) for miR-506 to promote cell proliferation and migration. Taken together, our results showed that NEAT1, stabilized by LIN28B, promoted HGSOC progression by sponging miR-506. Thus, NEAT1 can be regarded as a vital diagnostic biomarker for HGSOC and a therapeutic target.

Although PD-L1 has been shown to play a well-characterized role in inhibiting antitumor immunity via engagement of its receptor PD-1 in T lymphocytes, little is known about the tumor cell-intrinsic function of PD-L1 and its association with prognosis. Here, we investigate this issue and dissect the molecular mechanisms underlying the role of PD-L1 in glucose metabolism, proliferation, migration, and invasion in human cervical cancer cells. As a result, we found that PD-L1 overexpression in cervical cancer cells increases glucose metabolism and metastasis-related behaviors. Mechanistically, PD-L1 bound directly to integrin β4 (ITGB4), activating the AKT/GSK3β signaling pathway and consequently inducing the expression of the transcriptional repressor SNAI1. SNAIL in turn influenced the expression of genes involved in the epithelial-to-mesenchymal transition and regulated glucose metabolism by inhibiting SIRT3 promoter activity. High expression of PD-L1 and ITGB4 in human cervical carcinomas was significantly associated with lymph node metastasis and poor prognosis. Finally, F-fluorodeoxyglucose microPET/CT and bioluminescence imaging analyses of cervical xenograft tumors in mice revealed that PD-L1 overexpression markedly increases tumor glucose uptake and promotes lymph node metastasis. Together, these results demonstrate that PD-L1 can promote the growth and metastasis of cervical cancer by activating the ITGB4/SNAI1/SIRT3 signaling pathway, and also suggest the possibility of targeting PD-L1 and its downstream effectors as a potential approach for interfering with cervical cancer growth and metastasis.

ObjectiveProgrammed death-ligand 1 (PD-L1) was expressed in various tumors and antibodies targeting its receptor programmed cell death-1 (PD-1) are emerging cancer therapeutics. This study was designed to evaluate the expression of PD-L1 and its correlation with clinicopathologic features and clinical outcomes in ovarian clear cell carcinoma (OCCC).MethodsThe PD-L1 expression was measured by tissue-microarray-based immunohistochemistry from 122 eligible patients diagnosed with OCCC. The associations of clinicopathologic features with progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier method and multivariate analysis was further performed by Cox regression model.ResultsOverall, high PD-L1 expression (PD-L1high) was observed in 44.7% (55/123) of OCCC patients, and was strongly associated with advanced stages (p=0.020), positive ascitic fluid (p=0.016), platinum-resistant (PR) disease (p=0.045), and recurrence (p=0.038). Moreover, patients with PD-L1high were associated with poorer OS (hazard ratio [HR]=2.877; p=0.001) and PFS (HR=1.843; p=0.021) than those with low PD-L1 expression (PD-L1low). In subgroup analysis, PD-L1high patients experienced a poorer PFS (HR=1.926; p=0.044) and OS (HR=2.492; p=0.021) than PD-L1low cases among advanced stages (III–IV), but this difference was not observed in stage I–II patients. Meanwhile, PD-L1high was associated with poorer prognosis than PD-L1low in PR patients (OS, HR=2.253; p=0.037; PFS, HR=1.448; p=0.233). Multivariate analysis revealed that PD-L1high and advanced stages (III–IV) were adverse independent prognosticators for both PFS (HRPD-L1=2.0; pPD-L1=0.038; HRstage=10.2; pstage<0.001) and OS (HRPD-L1=3.0; pPD-L1=0.011; HRstage=14.3; pstage<0.001).ConclusionPD-L1high might serve as a risk factor for PFS and OS in patients with OCCC. It is possible that immunotherapy targeting PD-L1 pathway could be used in OCCC.

Background: The long non-coding RNA Linc00152 stimulates tumor progression in cancer. However, its clinical significance and biological functions in lung adenocarcinoma remains unknown. We evaluate the expression of Linc00152 in lung adenocarcinoma and its possible correlation with clinicopathologic features and patient survival to reveal its biological effects in cancer progression and prognosis. Methods: Total RNA extraction was performed on 110 pairs of lung adenocarcinoma and adjacent normal tissue samples, and then RT-qPCR was conducted. Chi-square test analysis was used to calculate the correlation between pathological parameters and the Linc00152 mRNA levels. Kaplan-Meier and Cox proportional hazards analyses were used to analyze the overall survival (OS) and disease-free survival (DFS) rates. We also detected the potential functional effects of overexpression and knockdown of Linc00152 in vitro cell proliferation, tumor cell invasion and migration, as well as in vivo nude mouse xenograft and metastasis models. Results: The Linc00152 expression levels were higher in lung adenocarcinoma samples than in the adjacent normal tissues. Linc00152 expression levels tightly correlated with lymph node metastasis station, remote metastasis and TNM staging. The Kaplan-Meier analysis suggested that high Linc00152 expression caused significantly poorer OS and DFS rates, and a multivariate analysis revealed that Linc00152 was an independent risk factor for both DFS and OS. Overexpression of Linc00152 in lung cancer cells stimulated proliferation, tumor cell invasion and migration. Knockdown of Linc00152 inhibited cell growth and cell invasion and migration. Finally, Linc00152 knockdown inhibited lung tumor growth and tumor metastasis in nude mice models. Conclusions: Our study suggests that Linc00152 independently predicts poor prognosis and promotes tumor progression in lung adenocarcinoma. Linc00152 needs to be considered as a potential molecular target in future cancer pharmacology.

Myocardial infarction (MI) is one of cardiovascular diseases that pose a serious threat to human health. The pathophysiology of MI is complex and contains several sequential phases including blockage of a coronary artery, necrosis of myocardial cells, inflammation, and myocardial fibrosis. Aiming at the treatment of different stages of MI, in this work, an injectable alginate based composite hydrogel is developed to load vascular endothelial active factor (VEGF) and silk fibroin (SF) microspheres containing bone morphogenetic protein 9 (BMP9) for releasing VEGF and BMP9 to realize their respective functions. The results of in vitro experiments indicate a rapid initial release of VEGF during the first few days and a relatively slow and sustained release of BMP9 for days, facilitating the formation of blood vessels in the early stage and inhibiting myocardial fibrosis in the long-term stage, respectively. Intramyocardial injection of such composite hydrogel into the infarct border zone of mice MI model via multiple points promotes angiogenesis and reduces the infarction size. Taken together, these results indicate that the dual-release of VEGF and BMP9 from the composite hydrogel results in a collaborative effect on the treatment of MI and improvement of heart function, showing a promising potential for cardiac clinical application.

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