Epstein-Barr virus (EBV) infection is causatively related to a variety of human cancers, including nasopharyngeal carcinoma (NPC) and gastric cancer (GC). EBV encodes 44 mature miRNAs, a number of which have been proven to promote carcinogenesis by targeting host genes or self-viral genes. However, in this study, we found that an EBV-encoded microRNA, termed EBV-miR-BART6-3p, inhibited EBV-associated cancer cell migration and invasion including NPC and GC by reversing the epithelial–mesenchymal transition (EMT) process. Using microarray analysis, we identified and validated that a novel long non-coding RNA (lncRNA) LOC553103 was downregulated by EBV-miR-BART6-3p, and LOC553103 knockdown by specific siRNAs phenocopied the effect of EBV-miR-BART6-3p, while LOC553103 overexpression promoted cancer cell migration and invasion to facilitate EMT. In conclusion, we determined that EBV-miR-BART6-3p, a microRNA encoded by oncogenic EBV, inhibited EBV-associated cancer cell migration and invasion by targeting and downregulating a novel lncRNA LOC553103. Thus, our study presents an unreported mechanism underlying EBV infection in EBV-associated cancer carcinogenesis, and provides a potential novel diagnosis and treatment biomarker for NPC and other EBV-related cancers.
Epstein-Barr virus (EBV) infection is closely associated with tumorigenesis and development of nasopharyngeal carcinoma (NPC), but the underlying molecular mechanisms remain poorly understood. It has been recently reported that EBV encodes 44 mature miRNAs, some of which were found to promote tumor development by targeting virus-infected host genes or self-viral genes. However, few targets of EBV encoded-miRNAs that are related to NPC development have been identified to date. In this study, we revealed that in NPC cells, EBV-miR-BART10-3p directly targets BTRC gene that encodes βTrCP (beta-transducin repeat containing E3 ubiquitin protein ligase). We found that EBV-miR-BART10-3p expression in clinical samples from a cohort of 106 NPC patients negatively correlated with BTRC expression levels. Over-expression of EBV-miR-BART10-3p and down-regulation of BTRC were associated with poor prognosis in NPC patients. EBV-miR-BART10-3p promoted the invasion and migration cabilities of NPC cells through the targeting of BTRC and regulation of the expression of the downstream substrates β-catenin and Snail. As a result, EBV-miR-BART10-3p facilitated epithelial-mesenchymal transition of NPC. Our study presents an unreported mechanism underlying EBV infection in NPC carcinogenesis, and provides a potential novel biomarker for NPC diagnosis, treatment and prognosis.
Circulating RNAs in serum, plasma or other body liquid have emerged as useful and highly promising biomarkers for noninvasive diagnostic application. Herein, we aimed to establish a serum long non-coding RNAs (lncRNAs) signature for diagnosing nasopharyngeal carcinoma (NPC). In this study, we recruited a cohort of 101 NPC patients, 20 patients with chronic nasopharyngitis (CN), 20 EBV carriers (EC) and 101 healthy controls. qRT-PCR was performed with NPC cells and serum samples to screen a pool of 38 NPC-related lncRNAs obtained from the LncRNADisease database. A profile of three circulating lncRNAs (MALAT1, AFAP1-AS1 and AL359062) was established for NPC diagnosis. By Receiver Operating Characteristic (ROC) curve analysis, this three-lncRNA signature showed high accuracy in discriminating NPC from healthy controls (AUC = 0.918), CN (AUC = 0.893) or EC (AUC = 0.877). Furthermore, high levels of these three lncRNAs were closely related to advanced NPC tumor node metastasis stages and EBV infection. Serum levels of these three lncRNAs declined significantly in patients after therapy. Our present study indicates that circulating MALAT1, AFAP1-AS1 and AL359062 may represent novel serum biomarkers for NPC diagnosis and prognostic prediction after treatment.
The aim of this study is to explore the differentially expressed lncRNAs, which may have potential biological function and diagnostic value in colorectal cancer (CRC). Through integrated data mining, we finally identified nine differentially expressed lncRNAs and their potential mRNA targets. After a series of bioinformatics analyses, we screened significant pathways and GO terms that are related to the up-regulated and down-regulated transcripts respectively. Meanwhile, the nine lncRNAs were validated in 30 paired tissues and cell lines by qRT-PCR and the results were basically consistent with the microarray data. We also tested the nine lncRNAs in the serum of 30 CRC patients matched with the CRC tissue, 30 non-cancer patients and 30 health controls. Finally, we found that BLACAT1 was significant for the diagnosis of CRC. The area under the curve (AUC), sensitivity and specificity were 0.858 (95% CI: 0.765–0.951), 83.3% and 76.7% respectively between CRC patients and health controls. Moreover, BLACAT1 also had distinct value to discriminate CRC from other non-cancer diseases. The results indicated that the differentially expressed lncRNAs and their potential target transcripts could be considered as potential therapeutic targets for CRC patients. Meanwhile, lncRNA BLACAT1 might represent a new supplementary biomarker for the diagnosis of CRC.
Epstein‐Barr virus (EBV) is a tumorigenic virus that can cause various human malignancies such as nasopharyngeal carcinoma (NPC) and gastric cancer (GC). EBV encodes 44 mature micro (mi)RNAs, mostly exhibiting oncogenic properties and promoting cancer progression. However, we have previously found that one EBV‐encoded miRNA, namely EBV‐miR‐BART6‐3p, acts as a tumor suppressor by inhibiting metastasis and invasion. Here, we report that EBV‐miR‐BART6‐3p inhibits the proliferation of EBV‐associated cancers, NPC, and GC, by targeting and downregulating a long non‐coding RNA (lncRNA), LOC553103. Through proteomics analysis, we determined that stathmin (STMN1) is affected by EBV‐miR‐BART6‐3p and LOC553103. Further, via RNA immunoprecipitation and luciferase reporter assay, we confirmed that LOC553103 directly binds and stabilizes the 3′UTR region of STMN1 mRNA. These results indicate that the EBV‐miR‐BART6‐3p/LOC553103/STMN1 axis regulates the expression of cell cycle‐associated proteins, which then inhibit EBV‐associated tumor cell proliferation. These findings provide potential targets or strategies for novel EBV‐related cancer treatments, as well as contributes new insights into the understanding of EBV infection‐related carcinogenesis.
Cancer stem cells (CSCs) represent a small portion of tumor cells with self-renewal ability in tumor tissues and are a key factor in tumor resistance, recurrence, and metastasis. CSCs produce a large number of exosomes through various mechanisms, such as paracrine and autocrine signaling. Studies have shown that CSC-derived exosomes (CSC-Exos) carry a variety of gene mutations and specific epigenetic modifications indicative of unique cell phenotypes and metabolic pathways, enabling exchange of information in the tumor microenvironment (TME) to promote tumor invasion and metastasis. In addition, CSC-Exos carry a variety of metabolites, especially proteins and miRNAs, which can activate signaling pathways to further promote tumor development. CSC-Exos have dual effects on cancer development. Due to advances in liquid biopsy technology for early cancer detection, CSCs-Exos may become an important tool for early cancer diagnosis and therapeutic drug delivery. In this article, we will review how CSC-Exos exert the above effects based on the above two aspects and explore their mechanism of action.
Background Metabolic reprogramming is a hallmark of cancer. However, the roles of long noncoding RNAs (lncRNAs) in cancer metabolism, especially glucose metabolism remain largely unknown. Results In this study, we identified and functionally characterized a novel metabolism-related lncRNA, LINC00930, which was upregulated and associated with tumorigenesis, lymphatic invasion, metastasis, and poor prognosis in nasopharyngeal carcinoma (NPC). Functionally, LINC00930 was required for increased glycolysis activity and cell proliferation in multiple NPC models in vitro and in vivo. Mechanistically, LINC00930 served as a scaffold to recruit the RBBP5 and GCN5 complex to the PFKFB3 promoter and increased H3K4 trimethylation and H3K9 acetylation levels in the PFKFB3 promoter region, which epigenetically transactivating PFKFB3, and thus promoting glycolytic flux and cell cycle progression. Clinically, targeting LINC00930 and PFKFB3 in combination with radiotherapy induced tumor regression. Conclusions Collectively, LINC00930 is mechanistically, functionally and clinically oncogenic in NPC. Targeting LINC00930 and its pathway may be meaningful for treating patients with NPC.
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