Pei Ma

Long non-coding RNA TUG1 is up-regulated in hepatocellular carcinoma and promotes cell growth and apoptosis by epigenetically silencing of KLF2

BackgroundHepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and the biology of this cancer remains poorly understood. Recent evidence indicates that long non-coding RNAs (lncRNAs) are found to be dysregulated in a variety of cancers, including HCC. Taurine Up-regulated Gene 1 (TUG1), a 7.1-kb lncRNA, recruiting and binding to polycomb repressive complex 2 (PRC2), is found to be disregulated in non-small cell lung carcinoma (NSCLC) and esophageal squamous cell carcinoma (ESCC). However, its clinical significance and potential role in HCC remain unclear.Methods and resultsIn this study, expression of TUG1 was analyzed in 77 HCC tissues and matched normal tissues by using quantitative polymerase chain reaction (qPCR). TUG1 expression was up-regulated in HCC tissues and the higher expression of TUG1 was significantly correlated with tumor size and Barcelona Clinic Liver Cancer (BCLC) stage. Moreover, silencing of TUG1 expression inhibited HCC cell proliferation, colony formation, tumorigenicity and induced apoptosis in HCC cell lines. We also found that TUG1 overexpression was induced by nuclear transcription factor SP1 and TUG1 could epigeneticly repress Kruppel-like factor 2 (KLF2) transcription in HCC cells by binding with PRC2 and recruiting it to KLF2 promoter region.ConclusionOur results suggest that lncRNA TUG1, as a growth regulator, may serve as a new diagnostic biomarker and therapy target for HCC.

Upregulated long non-coding RNA AGAP2-AS1 represses LATS2 and KLF2 expression through interacting with EZH2 and LSD1 in non-small-cell lung cancer cells

Recently, long non-coding RNAs (lncRNAs) are identified as new crucial regulators of diverse cellular processes, including cell proliferation, differentiation and cancer cells metastasis. Accumulating evidence has revealed that aberrant lncRNA expression plays important roles in carcinogenesis and tumor progression. However, the expression pattern and biological function of lncRNAs in non-small-cell lung cancer (NSCLC) remain largely unknown. In this study, we performed comprehensive analysis of lncRNA expression in human NSCLC samples by using microarray data from Gene Expression Omnibus. After validation in a cohort of 80 pairs of NSCLC tissues, we identified a differentially expressed novel oncogenic lncRNA termed as AGAP2-AS1. The AGAP2-AS1 expression level was significantly upregulated in NSCLC tissues and negatively correlated with poor prognostic outcomes in patients. In vitro loss- and gain-of-function assays revealed that AGAP2-AS1 knockdown inhibited cell proliferation, migration and invasion, and induced cell apoptosis. In vivo assays also confirmed the ability of AGAP2-AS1 to promote tumor growth. Furthermore, mechanistic investigation showed that AGAP2-AS1 could bind with enhancer of zeste homolog 2 and lysine (K)-specific demethylase 1A, and recruit them to KLF2 and LATS2 promoter regions to repress their transcription. Taken together, our findings indicate that AGAP2-AS1 may act as an oncogene by repressing tumor-suppressor LATS2 and KLF2 transcription. By clarifying the AGAP2-AS1 mechanisms underlying NSCLC development and progression, these findings might promote the development of novel therapeutic strategies for this disease.

Increased expression of LncRNA PANDAR predicts a poor prognosis in gastric cancer.

Long non-coding RNAs (lncRNAs) are emerging as biomarkers and as important regulators in biological processes and tumorigenesis in cancer. PANDAR (promoter of CDKN1A antisense DNA damage activated RNA) serves as biomarkers and involves in development of multiple cancers. However, its clinical value of PANDAR in gastric cancer is still unknown. Hence, we carried out the present study aiming to identify the clinical significance of PANDAR in gastric cancer patients. We analyzed the expression levels of PANDAR in 100 paired gastric cancer tissues using Quantitative Real-time PCR. Our results showed that the expression of PANDAR was significantly increased in gastric cancer tissues compared with paired adjacent normal tissues. Furthermore, high expression of PANDAR was correlated with depth of invasion, TNM stage and lymphatic metastasis. Importantly, high expression of PANDAR could serve as an independent unfavorable prognostic role in gastric cancer. In conclusion, PANDAR may be a potential novel biomarker that predicts prognosis in gastric cancer.

Extracellular vesicles-mediated noncoding RNAs transfer in cancer

Extracellular vesicles (EVs) are small membranous vesicles secreted from numerous cell types and have been found involved in cell-to-cell communication by transferring noncoding RNAs (ncRNAs) including microRNAs, long noncoding RNAs, and circular RNAs. Emerging evidence shows that EV-associated ncRNAs play important roles in a wide range of diseases, particularly in cancer where they function through regulating protein expression of the pivotal genes that make contributions to tumorigenesis. Given their stability and abundance in serum, EV-associated ncRNAs can act as new diagnostic biomarkers and new therapeutic targets for cancer. Herein, we review the properties of EV-associated ncRNAs, their functions, and potential significance in cancer.

Transcriptome analysis of EGFR tyrosine kinase inhibitors resistance associated long noncoding RNA in non-small cell lung cancer

The non-small cell lung cancer (NSCLC) patients harbor mutations in the epidermal growth factor receptor (EGFR) can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib, and show improved progression-free survival. However, most of the patients who are initially responsive to EGFR TKIs with activating EGFR mutations eventually develop acquired resistance after long-term therapy, and are followed by disease progression. Recently, diverse mechanisms of acquired EGFR TKI resistance have been reported, but little is known about the role of long noncoding RNAs in EGFR TKIs resistance. To gain insight into the expression pattern and potential function of lncRNAs in NSCLC cells EGFR-TKI resistance, we analyzed expression patterns in EGFR-TKIs-resistant cell lines and compared it with their parental sensitive cell line by using gene profiling datasets from Gene Expression Omnibus (GEO). Then, the expression levels of five chose lncRNAs were validated in PC9-gefitinib resistant cells (PC9G) and sensitive cells by using real-time quantitative PCR (qPCR). Among of these five lncRNAs, CASC9 expression was upregulated in PC9G and knockdown of its expression could increase the sensitivity of PC9G cells to gefitinib, while EWAST1 (LINC00227) is downregulated in PC9G cells and overexpressed EWAST1 also lead to increased sensitivity of PC9G cells to gefitinib. As indicated by GO analysis, the CASC9 and EWAST1 co-expressed genes are involved in several important pathways including regulation of cell growth, regulation of cell apoptosis and Chromatin assembly. Taken together, dysregulated lncRNAs play critical roles in EGFR-TKIs resistant NSCLC cells and might be used as novel potential targets to reverse EGFR-TKI resistance for NSCLC patients.

Long noncoding RNA LINC01234 functions as a competing endogenous RNA to regulate CBFB expression by sponging miR-204-5p in gastric cancer

Purpose: Long noncoding RNAs (lncRNAs) have emerged as important regulators in a variety of human diseases, including cancers. However, the overall biological roles and clinical significance of most lncRNAs in gastric carcinogenesis are not fully understood. We investigated the clinical significance, biological function, and mechanism of LINC01234 in gastric cancer. Experimental Design: First, we analyzed LINC01234 alterations in gastric cancerous and noncancerous tissues through an analysis of sequencing data obtained from The Cancer Genome Atlas. Next, we evaluated the effect of LINC01234 on the gastric cancer cell proliferation and apoptosis, and its regulation of miR-204-5p by acting as a competing endogenous RNA (ceRNA). The animal model was used to support the in vitro experimental findings. Results: We found that LINC01234 expression was significantly upregulated in gastric cancer tissues and was associated with larger tumor size, advanced TNM stage, lymph node metastasis, and shorter survival time. Furthermore, knockdown of LINC01234-induced apoptosis and growth arrest in vitro and inhibited tumorigenesis in mouse xenografts. Mechanistic investigations indicated that LINC01234 functioned as a ceRNA for miR-204-5p, thereby leading to the derepression of its endogenous target core-binding factor β (CBFB). Conclusions: LINC01234 is significantly overexpressed in gastric cancer, and LINC01234–miR-204-5p–CBFB axis plays a critical role in gastric cancer tumorigenesis. Our findings may provide a potential new target for gastric cancer diagnosis and therapy. Clin Cancer Res; 24(8); 2002–14. ©2018 AACR.

E2F1 induces TINCR transcriptional activity and accelerates gastric cancer progression via activation of TINCR/ STAU1 / CDKN2B signaling axis

Recent evidence indicates that E2F1 transcription factor have pivotal roles in the regulation of cellular processes, and is found to be dysregulated in a variety of cancers. Long non-coding RNAs (lncRNAs) are also reported to exert important effect on tumorigenesis. E2F1 is aberrantly expressed in gastric cancer (GC), and biology functions of E2F1 in GC are controversial. The biological characteristics of E2F1 and correlation between E2F1 and lncRNAs in GC remain to be found. In this study, integrated analysis revealed that E2F1 expression was significantly increased in GC cases and its expression was positively correlated with the poor pathologic stage, large tumor size and poor prognosis. Forced E2F1 expression promotes proliferation, whereas loss of E2F1 function decreased cell proliferation by blocking of cell cycle in GC cells. Mechanistic analyses indicated that E2F1 accelerates GC growth partly through induces TINCR transcription. TINCR could bind to STAU1 (staufen1) protein, and influence CDKN2B mRNA stability and expression, thereby affecting the proliferation of GC cells. Together, our findings suggest that E2F1/TINCR/STAU1/CDKN2B signaling axis contributes to the oncogenic potential of GC and may constitute a potential therapeutic target in this disease.

Multiple functions of m 6 A RNA methylation in cancer

First identified in 1974, m6A RNA methylation, which serves as a predominant internal modification of RNA in higher eukaryotes, has gained prodigious interest in recent years. Modifications of m6A are dynamic and reversible in mammalian cells, which have been proposed as another layer of epigenetic regulation similar to DNA and histone modifications. m6A RNA methylation is involved in all stages in the life cycle of RNA, ranging from RNA processing, through nuclear export, translation modulation to RNA degradation, which suggests its potential of influencing a plurality of aspects of RNA metabolism. All of the recent studies have pointed to a complicated regulation network of m6A modification in different tissues, cell lines, and space–time models. m6A methylation has been found to have an impact on tumor initiation and progression through various mechanisms. Furthermore, m6A RNA methylation has provided new opportunities for early stage diagnosis and treatment of cancers.Herein, we review the chemical basis of m6A RNA methylation, its multiple functions and potential significance in cancer.

Upregulation of the long noncoding RNA FOXD2-AS1 promotes carcinogenesis by epigenetically silencing EphB3 through EZH2 and LSD1, and predicts poor prognosis in gastric cancer

Accumulating data indicate that long noncoding RNAs (lncRNAs) serve as important modulators in biological processes and are dysregulated in diverse tumors. The function of FOXD2-AS1 in gastric cancer (GC) progression and related biological mechanisms remain undefined. A comprehensive analysis identified that FOXD2-AS1 enrichment was upregulated markedly in GC and positively correlated with a large tumor size, a later pathologic stage, and a poor prognosis. Gene-set enrichment analysis (GSEA) in GEO datasets uncovered that cell cycle and DNA replication associated genes were enriched in patients with high FOXD2-AS1 expression. Loss of FOXD2-AS1 function inhibited cell growth via inhibiting the cell cycle in GC, whereas upregulation of FOXD2-AS1 expression promoted cancer progression. The enhancer of zeste homolog 2 (EZH2) and lysine (K)-specific demethylase 1A (LSD1) proteins were found to serve as binding partners of FOXD2-AS1 and mediators of FOXD2-AS1 function. Mechanically, FOXD2-AS1 promoted GC tumorigenesis partly through EZH2 and LSD1 mediated EphB3 downregulation. The present results revealed that FOXD2-AS1 acted as a tumor inducer in GC partly through EphB3 inhibition by direct interaction with EZH2 and LSD1, and may prove to be a potential biomarker of carcinogenesis.

Taurine‑upregulated gene 1: A vital long non‑coding RNA associated with cancer in humans (Review)

It is widely reported that long non‑coding RNAs (lncRNAs) are involved in regulating cell differentiation, proliferation, apoptosis and other biological processes. Certain lncRNAs have been found to be crucial in various types of tumor. Taurine‑upregulated gene 1 (TUG1) has been shown to be expressed in a tissue‑specific pattern and exert oncogenic or tumor suppressive functions in different types of cancer in humans. According to previous studies, TUG1 is predominantly located in the nucleus and may regulate gene expression at the transcriptional level. It mediates chromosomal remodeling and coordinates with polycomb repressive complex 2 (PRC2) to regulate gene expression. Although the mechanisms of how TUG1 affects the tumor genesis process remain to be fully elucidated, increasing studies have suggested that TUG1 offers potential as a diagnostic and prognostic biomarker, and as a therapeutic target in certain types of tumor. This review aims to summarize current evidence concerning the characteristics, mechanisms and associations with cancer of TUG1.