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BACKGROUND: Esophageal cancer (ESCA) constitutes one of the most common cancers worldwide. The identification of potential biomarkers is important to improving the diagnostic accuracy and treatment efficiency for patients with ESCA. In this study, we aimed to identify biomarkers related to ESCA progression through a comprehensive analysis of long non-coding RNAs (lncRNAs), microRNA (miRNAs), and mRNA expression profiles in ESCA. METHODS: Differentially expressed lncRNAs, miRNAs, and mRNAs (DElncRNAs, DEmiRNAs, and DEmRNAs, respectively) in ESCA samples compared with normal controls were obtained. A competing endogenous RNA (ceRNA) network consisting of interacting DElncRNAs, DEmiRNAs, and DEmRNAs was constructed using a combination of the miRCode and TargetScan databases. Relationships between RNAs in the ceRNA network and overall survival in patients with EC were explored through another independent ESCA dataset from The Cancer Genome Atlas. RESULTS: A total of 1,014 DElncRNAs, 3,677 DEmRNAs, and 35 DEmiRNAs were identified in ESCA samples compared with normal samples. Functional enrichment analysis indicated that the DEmRNAs were involved in cell activity, inflammatory response, and oxygen metabolism-related biological processes. A ceRNA network containing 5 DEmiRNAs, 582 DEmRNAs and 764 DElncRNAs was obtained. In the survival analysis, 39 genes were found to be significantly associated with overall survival in patients with EC, including GOLGA7, NFYB, TOP1, and TMTC3. CONCLUSIONS: Our study constructed a ceRNA network for ESCA for the first time, which will be helpful for the disease’s diagnosis and treatment.

Long non-coding RNAs (lncRNAs) have been suggested as important regulators of cancer development and progression in hepatocellular carcinoma (HCC). Nevertheless, the clinical value and biological roles of LINC00978 in HCC remain unclear. In this study, we detected the expression of LINC00978 in tumor tissues and serum of HCC patients, examined the roles of LINC00978 in HCC progression and elucidated the underlying molecular mechanisms. We found that LINC00978 expression was upregulated in tumor tissues and serum of HCC patients. Higher serum levels of LINC00978 could distinguish HCC patients from hepatitis and liver cirrhosis patients and healthy controls. LINC00978 knockdown inhibited HCC cell proliferation, migration and invasion while promoted cell cycle arrest and apoptosis. Overexpression of LINC00978 led to the opposite effects. LINC00978 knockdown also inhibited HCC growth and metastasis in mouse tumor models. Mechanistically, LINC00978 bound to EZH2 and mediated its accumulation at the promoter region of p21 and E-cadherin genes, leading to the trimethylation of H27K3 and the inhibition of p21 and E-cadherin expression. Moreover, the simultaneous depletion of p21 and E-cadherin expression reversed the inhibitory effects of LINC00978 knockdown on HCC cell proliferation, migration, and invasion. Taken together, these findings suggest that LINC00978 promotes HCC progression by inhibiting p21 and E-cadherin expression via EZH2-mediated epigenetic silencing. LINC00978 may represent a novel biomarker for HCC diagnosis, prognosis, and therapy.

Lanfang Guo,1,* Jianmei Gu,2,* Sinan Hou,3 Dabiao Liu,1 Mengjie Zhou,1 Tengjiang Hua,1 Jinye Zhang,2 Zhijun Ge,4 Jing Xu5 1Department of Clinical Laboratory Medicine, The Fourth People’s Hospital of Zhenjiang, Zhenjiang, Jiangsu 212013, China; 2Departmemt of Clinical Laboratory Medicine, Nantong Tumor Hospital, Nantong, Jiangsu 226361, China; 3Departmemt of Clinical Laboratory Medicine, Lianyungang Traditional Chinese Medicine Hospital, Lianyungang, Jiangsu 222002, China; 4Department of Critical Care Medicine, The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu 214200, China; 5Departmemt of Clinical Laboratory Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212013, China *These authors contributed equally to this work Background: Long non-coding RNAs (lncRNAs) play important roles in human cancers. However, the functional roles of lncRNAs in non-small-cell lung cancer (NSCLC) and the underlying mechanisms are not well understood. Methods: We examined the expression of lncRNA DANCR in NSCLC by qRT-PCR and explored its biological roles in NSCLC progression by cell and molecular biology studies. Results: DANCR expression level was increased in human NSCLC. The knockdown of DANCR inhibited NSCLC cell proliferation by inducing cell apoptosis and cell cycle arrest. In addition, DANCR knockdown suppressed NSCLC cell migration and invasion via inhibition of epithelial–mesenchymal transition (EMT). On the contrary, DANCR overexpression had the opposite effects. DANCR knockdown inhibited EZH-2-mediated epigenetic silencing of p21 promoter and increased p21 expression. Moreover, DANCR knockdown inhibited NSCLC cell proliferation, migration, and invasion in a p21-dependent manner. Conclusion: DANCR plays oncogenic roles in NSCLC and may provide a novel biomarker for NSCLC diagnosis and prognosis. Keywords: DANCR, NSCLC, progression, biomarker

Long non-coding RNAs (LncRNAs) have been suggested as important regulators of cancer development and progression in non-small cell lung cancer (NSCLC). Nevertheless, the biological roles and clinical significance of lncRNA UFC1 in NSCLC remain unclear. We detected the expression of UFC1 in tumor tissues, serum, and serum exosomes of NSCLC patients by qRT-PCR. Gene overexpression or silencing were used to examine the biological roles of UFC1 in NSCLC. RNA immunoprecipitation and ChIP assays were performed to evaluate the interaction between UFC1 and enhancer of zeste homolog 2 (EZH2) and the binding of EZH2 to PTEN gene promoter. Rescue study was used to access the importance of PTEN regulation by UFC1 in NSCLC progression. UFC1 expression was upregulated in tumor tissues, serum, and serum exosomes of NSCLC patients and high level of UFC1 was associated with tumor infiltration. UFC1 knockdown inhibited NSCLC cell proliferation, migration and invasion while promoted cell cycle arrest and apoptosis. UFC1 overexpression led to the opposite effects. Mechanistically, UFC1 bound to EZH2 and mediated its accumulation at the promoter region of PTEN gene, resulting in the trimethylation of H3K27 and the inhibition of PTEN expression. UFC1 knockdown inhibited NSCLC growth in mouse xenograft tumor models while the simultaneous depletion of PTEN reversed this effect. NSCLC cells derived exosomes could promote NSCLC cell proliferation, migration and invasion through the transfer of UFC1. Moreover, Exosome-transmitted UFC1 promotes NSCLC progression by inhibiting PTEN expression via EZH2-mediated epigenetic silencing. Exosome-mediated transmit of UFC1 may represent a new mechanism for NSCLC progression and provide a potential marker for NSCLC diagnosis.

Background Long non-coding RNAs (lncRNAs) have emerged as important regulators of human cancers. However, the functional roles of lncRNAs and the mechanisms responsible for their aberrant expression in gastric cancer (GC) have not been well characterized. Methods In this study, we examined the expression of lncRNA UFC1 in GC by qRT-PCR and explored its correlation with clinicopathological parameters. In vitro cell functional assays and in vivo animal studies were performed to determine the roles of UFC1 in GC progression. Results UFC1 was elevated and predicted poorer prognosis in GC. UFC1 knockdown inhibited while UFC1 overexpression promoted GC cell proliferation, migration, and invasion. UFC1 bound to miR-498 to antagonize its tumor suppressive effect on Lin28b. Suppression of Lin28b by miR-498 could be rescued by UFC1 overexpression, whereas Lin28b overexpression partially rescued UFC1 knockdown-mediated inhibition of GC cell function. Lin28b expression was increased in GC and suggested a co-expression pattern with UFC1. Conclusions UFC1 has a promoting role in GC progression, at least in part, by acting as a miR-498 sponge and derepressing Lin28b expression, which would provide a novel biomarker for GC diagnosis and prognosis and offer a potential target for GC therapy. Electronic supplementary material The online version of this article (10.1186/s13046-018-0803-6) contains supplementary material, which is available to authorized users.

Long noncoding RNAs (LncRNAs) play important roles in tumor development and progression. The expression of lncRNAs is frequently dysregulated in human cancer. DANCR (anti-differentiation noncoding RNA) is a newly identified lncRNA in human cancer, however, its functional roles and clinical value in gastric cancer (GC) remains unknown. In this study, we investigated the expression of DANCR in the tumor tissues and serum of GC patients and analyzed the correlation between DANCR expression levels and the clinicopathological characteristics. Our results showed that the expression of DANCR was higher in the tumor tissues than that in the adjacent non-cancerous tissues. The expression level of DANCR was also elevated in the serum of GC patients compared to that of healthy controls. The expression levels of DANCR were significantly associated with tumor size, TNM stage, lymphatic metastasis and invasion depth. DANCR knockdown inhibited the proliferation of GC cells by inducing cell cycle arrest and cell apoptosis. In addition, DANCR knockdown suppressed gastric cancer growth in vivo. Moreover, DANCR knockdown inhibited the migration and invasion of GC cells via the suppression of epithelial-mesenchymal transition (EMT). However, DANCR overexpression had the opposite effect. DANCR is activated by SALL4 in gastric cancer cells and exerted its oncogenic activities through the activation of β-catenin pathway. Taken together, our findings suggest that DANCR promotes the progression of gastric cancer and have the potential to serve as a novel diagnostic biomarker.

Emerging evidence has revealed that neutrophils have phenotypic and functional plasticity. Neutrophils could be polarized towards a pro-tumor phenotype by tumor-derived factors. In the present study, we investigated the role of the interaction with neutrophils on the functions of gastric cancer cells in vitro. Human promyelocytic leukemia HL-60 cells were induced to differentiate into neutrophil-like cells (HL-60N) using dimethyl sulfoxide (DMSO). Human gastric cancer cells were co-cultured with HL-60N cells or treated with the conditioned medium (CM) of cancer-activated HL-60N cells. The migration and invasion of gastric cancer cells were significantly enhanced while their proliferation was minimally altered. The expression of pro-inflammatory factors including IL-6, IL-8, IL-1β, and TNFα was significantly increased in cancer-activated HL-60N cells, which induced the activation of the ERK pathway and epithelial-mesenchymal transition (EMT) in gastric cancer cells. Blocking the ERK pathway activation reversed the promoting effects of cancer-activated HL-60N cells on gastric cancer cell migration and invasion. In addition, mouse gastric cancer cell derived CM could also increase the expression of pro-inflammatory factors in mouse bone marrow neutrophils, which in turn enhanced the migration and invasion of mouse gastric cancer cells. Collectively, our findings revealed that the interaction with neutrophils promoted gastric cancer cell migration and invasion through the activation of the ERK pathway and the induction of EMT, indicating that neutrophils may play an important role in gastric cancer metastasis. Therefore, targeting neutrophil-cancer cell interaction may provide a new strategy for the treatment of gastric cancer.

Mesenchymal stem cells (MSCs) can promote tumor growth in a mouse xenograft model, but the exact mechanism remains unclear. In this study, we investigated the effects of bone marrow MSC-derived exosomes (MSC-exosomes) on tumor growth in vitro and in vivo. Our results showed that MSC-exosomes promoted tumor growth in vivo. MSC-exosomes enhanced vascular endothelial growth factor (VEGF) expression in tumor cells by activating extracellular signal-regulated kinase1/2 (ERK1/2) pathway. Inhibition of ERK1/2 activation reserved the increase of VEGF level by MSC-exosomes. Our findings demonstrate a new mechanism through which MSC-exosome-mediated cell-cell interactions may contribute to tumor progression.

The majority of human skeleton develops through the endochondral pathway, in which cartilage-forming chondrocytes proliferate and enlarge into hypertrophic chondrocytes that eventually undergo apoptosis and are replaced by bone. Although at a terminal differentiation stage, hypertrophic chondrocytes have been implicated as the principal engine of bone growth. Abnormal chondrocyte hypertrophy has been seen in many skeletal dysplasia and osteoarthritis. Meanwhile, as a specific marker of hypertrophic chondrocytes, the type X collagen gene (COL10A1) is also critical for endochondral bone formation, as mutation and altered COL10A1 expression are often accompanied by abnormal chondrocyte hypertrophy in many skeletal diseases. However, how the type X collagen gene is regulated during chondrocyte hypertrophy has not been fully elucidated. We have recently demonstrated that Runx2 interaction with a 150-bp mouse Col10a1 cis-enhancer is required but not sufficient for its hypertrophic chondrocyte-specific reporter expression in transgenic mice, suggesting requirement of additional Col10a1 regulators. In this study, we report in silico sequence analysis of this 150-bp enhancer and identification of its multiple binding factors, including AP1, MEF2, NFAT, Runx1 and TBX5. Using this enhancer as bait, we performed yeast one-hybrid assay and identified multiple candidate Col10a1-interacting genes, including cyclooxygenase 1 (Cox-1) and Cox-2. We have also performed mass spectrometry analysis and detected EF1-alpha, Fus, GdF7 and Runx3 as components of the specific complex formed by the cis-enhancer and nuclear extracts from hypertrophic MCT (mouse chondrocytes immortalized with large T antigen) cells that express Col10a1 abundantly. Notably, some of the candidate genes are differentially expressed in hypertrophic MCT cells and have been associated with chondrocyte hypertrophy and Runx2, an indispensible Col10a1 regulator. Intriguingly, we detected high-level Cox-2 expression in hypertrophic MCT cells. Electrophoretic mobility shift assay and chromatin immunoprecipitation assays confirmed the interaction between Cox-2 and Col10a1 cis-enhancer, supporting its role as a candidate Col10a1 regulator. Together, our data support a Cox-2-containing, Runx2-centered Col10a1 regulatory mechanism, during chondrocyte hypertrophic differentiation.

Background Mesenchymal stem cells (MSCs) promote tumor growth by differentiating into carcinoma-associated fibroblasts (CAFs) and composing the tumor microenvironment. However, the mechanisms responsible for the transition of MSCs to CAFs are not well understood. Exosomes regulate cellular activities by mediating cell-cell communication. In this study, we aimed to investigate whether cancer cell-derived exosomes were involved in regulating the differentiation of human umbilical cord-derived MSCs (hucMSCs) to CAFs. Methodology/Principal Findings We first showed that gastric cancer cell-derived exosomes induced the expression of CAF markers in hucMSCs. We then demonstrated that gastric cancer cell-derived exosomes stimulated the phosphorylation of Smad-2 in hucMSCs. We further confirmed that TGF-β receptor 1 kinase inhibitor attenuated Smad-2 phosphorylation and CAF marker expression in hucMSCs after exposure to gastric cancer cell-derived exosomes. Conclusion/Significance Our results suggest that gastric cancer cells triggered the differentiation of hucMSCs to CAFs by exosomes-mediated TGF-β transfer and TGF-β/Smad pathway activation, which may represent a novel mechanism for MSCs to CAFs transition in cancer.