Taurine-upregulated gene 1: A functional long noncoding RNA in tumorigenesis

Taurine-upregulated gene 1 (TUG1) is a 7.1 kb long noncoding RNA (lncRNA) first recognized in 2005 as an important element for retinal development in rodents. Subsequently, this lncRNA has been shown to participate in oncogenic processes through alteration in chromatin structure, sponging microRNAs, and affecting the expression of some cancer-related pathways. While most of the studies have revealed an oncogenic role for this lncRNA, some reports have shown downregulation of TUG1 in lung cancer samples compared with noncancerous samples. In triple negative breast cancer samples, the expression of this lncRNA has been decreased. Besides, its expression has been higher in HER2-enriched and basal-like subtypes compared with luminal A. In the current review, we discuss the latest literature about the expression pattern and functional roles of TUG1 in diverse cancer types. In addition, its role in epithelial−mesenchymal transition and activation of Wnt/β-catenin pathway in human malignancies will be explored.     

长非编码RNA的作用机制及在肿瘤发生发展中的意义

功能基因组学的飞速发展将越来越多的目光引向了对非编码转录产物功能的研究。在人的转录组中,存在着一类长度大于200nt,但并不具备编码蛋白质功能的基因转录产物,即长非编码RNA(long noncoding RNA,lncRNA)。相比于小分子RNA,它们仍是目前基因组转录产物中较为陌生的部分。在整个基因组转录产物中,lncRNA所占的比例远远超过编码RNA所占的比例。不同于编码RNA,lncRNA的保守性要差得多,然而在其分子内部,却含有较为保守的局部区段,且其表达具有时空特异性,这些现象都提示了lncRNA具有重要的生理生化功能。越来越多的研究表明,lncRNA在基因表达调控方面发挥着十分重要的作用,与物种进化、胚胎发育、物质代谢以及肿瘤发生等都有着紧密的联系,其功能的深入研究将使目前对细胞的结构网络和调控网络的认识带来革命性的变化,具有不可估量的科学和临床价值。该文将着重讨论lncRNA在不同层面上对基因表达的调控机制以及在肿瘤发生发展中的意义。     

Immune-related long noncoding RNA signature for predicting survival and immune checkpoint blockade in hepatocellular carcinoma

Long noncoding RNAs (lncRNAs) show multiple functions, including immune response. Recently, the immune-related lncRNAs have been reported in some cancers. We first investigated the immune-related lncRNA signature as a potential target in hepatocellular carcinoma (HCC) survival. The training set (n = 368) and the independent external validation cohort (n = 115) were used. Immune genes and lncRNAs coexpression were constructed to identify immune-related lncRNAs. Cox regression analyses were perfumed to establish the immune-related lncRNA signature. Regulatory roles of this signature on cancer pathways and the immunologic features were investigated. The correlation between immune checkpoint inhibitors and this signature was examined. In this study, the immune-related lncRNA signature was identified in HCC, which could stratify patients into high- and low-risk groups. This immune-related lncRNA signature was correlated with disease progression and worse survival and was an independent prognostic biomarker. Our immune-related lncRNA signature was still a powerful tool in predicting survival in each stratum of age, gender, and tumor stage. This signature mediated cell cycle, glycolysis, DNA repair, mammalian target of rapamycin signaling, and immunologic characteristics (i.e., natural killer cells vs. Th1 cells down, etc). This signature was associated with immune cell infiltration (i.e., macrophages M0, Tregs, CD4 memory T cells, and macrophages M1, etc.,) and immune checkpoint blockade (ICB) immunotherapy-related molecules (i.e., PD-L1, PD-L2, and IDO1). Our findings suggested that the immune-related lncRNA signature had an important value for survival prediction and may have the potential to measure the response to ICB immunotherapy. This signature may guide the selection of the immunotherapy for HCC.     

ZNF204P is a stemness-associated oncogenic long non-coding RNA in hepatocellular carcinoma

Hepatocellular carcinoma is a major health burden, and though various treatments through much research are available, difficulties in early diagnosis and drug resistance to chemotherapy-based treatments render several ineffective. Cancer stem cell model has been used to explain formation of heterogeneous cell population within tumor mass, which is one of the underlying causes of high recurrence rate and acquired chemoresistance, highlighting the importance of CSC identification and understanding the molecular mechanisms of CSC drivers. Extracellular CSC-markers such as CD133, CD90 and EpCAM have been used successfully in CSC isolation, but studies have indicated that increasingly complex combinations are required for accurate identification. Pseudogene-derived long non-coding RNAs are useful candidates as intracellular CSC markers - factors that regulate pluripotency and self-renewal – given their cancer-specific expression and versatile regulation across several levels. Here, we present the use of microarray data to identify stemness-associated factors in liver cancer, and selection of sole pseudogene-derived lncRNA ZNF204P for experimental validation. ZNF204P knockdown impairs cell proliferation and migration/invasion. As the cytosolic ZNF204P shares miRNA binding sites with OCT4 and SOX2, well-known drivers of pluripotency and self-renewal, we propose that ZNF204P promotes tumorigenesis through the miRNA-145-5p/OCT4, SOX2 axis.     

Dependence of artesunate on long noncoding RNA-RP11 to inhibit epithelial-mesenchymal transition of hepatocellular carcinoma

As a first line medicine for malaria treatment, artesunate (ART) also shows antitumor potential. However, little is known about the effect of ART on the cancer cell epithelial-mesenchymal transition (EMT). In this study, we found that ART inhibited cell growth in SK-HEP1 and SM7721 hepatocellular carcinoma cell lines. A microarray was used to identify differentially expressed protein-coding RNAs (pcRNA) and long noncoding RNAs (lncRNA) between SK-HEP1 cells with and without ART treatment. A differentially expressed lncRNA—RP11, the most related to the EMT of liver cancer cells—RP11 was identified by abioinformatics method Overexpressing and silencing assays were used to verify the role of RP11 in cancer cell EMT. The levels of RP11- and EMT-related genes in liver cancer samples from 75 patients were detected by using qualitative polymerase chain reaction or immunohistochemistry. We identified 1334 pcRNAs and 1670 lncRNA with differential expression induced by ART. ART inhibits EMT, proliferation, migration, invasion, and adhesion of liver cancer cells. RP11 depresses the inhibitory effect of ART on cancer cell EMT. The level of RP11 is associated with cancer cell EMT and metastasis and survival rate of the patient. These data suggest that RP11-linking ART and cancer cell EMT are important for ART-inhibited metastasis of liver cancer.     

Long noncoding RNA FOXD2-AS1 promotes glioma malignancy and tumorigenesis via targeting miR-185-5p/CCND2 axis

Glioma is the most aggressive malignant tumor in the adult central nervous system. Abnormal long noncoding RNA (lncRNA) FOXD2-AS1 expression was associated with tumor development. However, the possible role of FOXD2-AS1 in the progression of glioma is not known. In the present study, we used in vitro and in vivo assays to investigate the effect of abnormal expression of FOXD2-AS1 on glioma progression and to explore the mechanisms. FOXD2-AS1 was upregulated in glioma tissue, cells, and sphere subpopulation. Upregulation of FOXD2-AS1 was correlated with poor prognosis of glioma. Downregulation of FOXD2-AS1 decreased cell proliferation, migration, invasion, stemness, and epithelial-mesenchymal transition (EMT) in glioma cells and inhibited tumor growth in transplanted tumor. We also revealed that FOXD2-AS1 was mainly located in cytoplasm and microRNA (miR)-185-5p both targeted FOXD2-AS1 and CCND2 messenger RNA (mRNA) 3′-untranslated region (3′-UTR). miR-185-5p was downregulated in glioma tissue, cells, and sphere subpopulation. Downregulation of miR-185-5p was closely correlated with poor prognosis of glioma patients. In addition, miR-185-5p mimics decreased cell proliferation, migration, invasion, stemness, and EMT in glioma cells. CCND2 was upregulated in glioma tissue, cells, and sphere subpopulation. Upregulation of CCND2 was closely correlated with poor prognosis of glioma patients. CCND2 knockdown decreased cell proliferation, migration, invasion, and EMT in glioma cells. In glioma tissues, CCND2 expression was negatively associated with miR-185-5p, but positively correlated with FOXD2-AS1. FOXD2-AS1 knockdown and miR-185-5p mimics decreased CCND2 expression. Inhibition of miR-185-5p suppressed FOXD2-AS1 knockdown-induced decrease of CCND2 expression. Overexpression of CCND2 suppressed FOXD2-AS1 knockdown-induced inhibition of glioma malignancy. Taken together, our findings highlight the FOXD2-AS1/miR-185-5p/CCND2 axis in the glioma development.     

Abnormally expressed long noncoding RNA B3GALT5-AS1 may serve as a biomarker for the diagnostic and prognostic of gastric cancer

Early diagnosis of gastric cancer (GC) is an effective method to improve prognosis. Increasing number of long noncoding RNAs (lncRNAs) have been reported as biomarkers for several cancers. We aim to detect the level of lncRNA B3GALT5-AS1 and its association with clinical parameters and to further explore its application value in GC. We measured serum B3GALT5-AS1 expression in 107 patients with GC, 40 polyp patients, and 87 normal controls to explore the significance of serum B3GALT5-AS1 in GC using the quantitative real-time polymerase chain reaction method. The result demonstrated that B3GALT5-AS1 level was markedly richer in GC patients than that in normal people (P < .001). B3GALT5-AS1 may be served as a diagnostic marker for distinguishing GC patients from healthy people, and the proportion under the receiver operating characteristics curve is 0.816 (95% confidence interval, 0.758-0.874; P = .03). Further exploration validated that high serum B3GALT5-AS1 level was related to TNM stage (P = .024), and lymph node metastasis (P = .023). Our study suggested that serum B3GALT5-AS1 may be employed as an ideal biomarker for early screening of GC.     

Long noncoding RNA DLGAP1-AS1 promotes cell proliferation in hepatocellular carcinoma via sequestering miR-486-5p

Hepatocellular carcinoma (HCC) is most prevalent tumor in liver and one of the most fatal cancers in the world. Long noncoding RNAs (lncRNAs) have been accepted as important regulators in carcinomas. But there are still many lncRNAs including DLGAP1-AS1 unannotated in HCC. First of all, GEPIA suggested that DLGAP1-AS1 presented high expression in HCC tissue samples relative to the normal tissues. Besides, overexpression of DLGAP1-AS1 was also proved in HCC cell lines. Moreover, DLGAP1-AS1 knockdown efficiently suppressed cell proliferation in HCC. Interestingly, miR-486-5p was predicted and validated to interact with DLGAP1-AS1, while the level of miR-486-5p was significantly increased In HCC after DLGAP1-AS1 knockdown. Moreover, we uncovered that ectopic expression of miR-486-5p induced suppression on HCC cell proliferation and that miR-486-5p inhibition offset the effect of DLGAP1-AS1 silence on HCC cell proliferation and apoptosis. Furthermore, H3F3B was identified as target of miR-486-5p and was therefore positively regulated by DLGAP1-AS1 in HCC. Of note, H3F3B upregulation partly revived the declined cell proliferative capacity in response to DLGAP1-AS1 knockdown. To conclude, DLGAP1-AS1 exerted its oncogenic role in HCC via miR-486-5p/H3F3B axis. Our new findings provided novel theoretical basis for discovery of therapeutic targets of HCC.     

Silencing of long noncoding RNA LEF1-AS1 prevents the progression of hepatocellular carcinoma via the crosstalk with microRNA-136-5p/WNK1

Long noncoding RNAs (lncRNAs) have been recognized as cancer-associated biological molecules, favoring hepatocellular carcinoma (HCC) progression. This study was conducted to elucidate the effects lncRNA lymphoid enhancer-binding Factor 1 antisense RNA (LEF1-AS1) on the pathological development of HCC, along with the crosstalk involving microRNA-136-5p (miR-136-5p) and with-no-K (lysine) kinase 1 (WNK1). The study recruited primary HCC tissues and their corresponding nonneoplastic liver tissues. The gain- and loss-of-function studies were performed in HCC cells HuH-7 and tumor xenografts in nude mice. The dual luciferase reporter gene assay system, RNA pull-down, and radioimmunoprecipitation assays were applied to detect their interactions among lncRNA LEF1-AS1, miR-136-5p, and WNK1. 5-Ethynyl-2′-deoxyuridine staining, scratch test, Transwell assays, and in vitro tube formation assays were conducted to examine HCC cell proliferation, migration, and invasion and HUVEC angiogenesis. HCC tissues and cells contained high lncRNA LEF1-AS1 expression. LncRNA LEF1-AS1 upregulation triggered markedly increased HCC cell proliferation, migration, and invasion and human umbilical vein endothelial cell angiogenesis. In vivo silencing lncRNA LEF1-AS1 resulted in reduced tumor cell vitality and matrix metalloproteinase-9 and the vascular endothelial growth factor expression. Additionally, the role of lncRNA LEF1-AS1 was found to be largely dependent on WNK1. Association of lncRNA LEF1-AS1 with WNK1 blocked the inhibitory effect of miR-136-5p on WNK1, which was confirmed by in vivo experiments. Altogether, our results revealed an important role of lncRNA LEF1-AS1 in regulating the HCC progression by regulating WNK1, providing a potential biomarker for the therapeutic modalities regarding HCC.     

Knockdown of long noncoding RNA urothelial carcinoma associated 1 inhibits colorectal cancer cell proliferation and promotes apoptosis via modulating autophagy

Long noncoding RNA urothelial carcinoma associated 1 (UCA1) has been implicated in the growth and metastasis of colorectal cancer (CRC), and autophagy contributes to tumorigenesis and cancer cell survival. However, the regulatory role of UCA1 in CRC cell viability by modulating autophagy remains unclear. In the present study, a significant positive correlation was observed between UCA1 and microtubule-associated protein 1 light chain 3 (LC3) levels, and the elevated UCA1 was negatively correlated with the PKB/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway in 293T cells. Downregulation of UCA1 inhibited autophagy activation and cell proliferation, whereas the apoptosis was increased and the cell cycle was arrested in G2 stage. The next results showed that UCA1 was markedly upregulated in Caco-2 cells. Knockdown of UCA1 significantly decreased the LC3-II and autophagy-related gene 5 (ATG5) protein levels and resulted in an increase in p62 expression. Conversely, the autophagy activator rapamycin (RAPA) reversed the effects. Furthermore, downregulated UCA1 decreased Caco-2 cells population in the G1 phase and increased the cells number in G2 phage. The cell proliferation was inhibited, and apoptosis rate was promoted. More important, RAPA could also abrogate the changes induced by knockdown of UCA1. Collectively, these data demonstrated that downregulated UCA1 induced autophagy inhibition, resulting in suppressing cell proliferation and promoting apoptosis, which suggested that UCA1 might serve as a potential new oncogene to regulate CRC cells viability by modulating autophagy.     

Long noncoding RNA SNHG12 indicates the prognosis of prostate cancer and accelerates tumorigenesis via sponging miR-133b

Prostate cancer (PCa) is the second leading cause of death among American men. Increasing evidence has shown that long noncoding RNAs (lncRNAs) play important roles in tumorigenesis of PCa. In this study, we explored the biological functions of small nucleolar RNA host gene 12 (SNHG12) and investigated the interaction between miR-133b and SNHG12 in the progression of PCa. Data was downloaded from The Cancer Genome Atlas and Human Cancer Metastasis Database, and clinicopathological characteristics were analyzed with relapse-free survival rate. We detected SNHG12 expression level in PCa cells and tissues, and then analyzed its clinical significance, which revealed that SNHG12 has the potent to predict prognosis of PCa. Bioinformatic analysis revealed that SNHG12 was closely related to the progression of PCa and could target candidate microRNA (miR-133b). After transfecting SNHG12 silencing plasmid and miR-133b mimic/sponge, biological function assays were conducted and results illustrated that SNHG12 associated with miR-133b exerted biological effects on cancer cell growth, migration, and invasion. Direct interactions between miR-133b and SNHG12 have been found and SNHG12 acts as an oncogene to promote tumorigenesis of PCa by sponging tumor suppressor gene miR-133b.     

Long noncoding RNA SOX21-AS1 promotes cervical cancer progression by competitively sponging miR-7/VDAC1

Growing evidence has shown that long noncoding RNAs (lncRNAs) play crucial roles in cervical cancer. Dy000sregulation of lncRNA SOX21 antisense RNA 1 (SOX21-AS1) has been reported in several tumors. However, its expression pattern and potential biological function in cervical cancer (CC) have not been investigated. In this study, we first reported that SOX21-AS1 expression was significantly upregulated in both CC tissues and cell lines. High expression of SOX21-AS1 was found to be significantly correlated with Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis and depth of cervical invasion. Further clinical assay confirmed that high SOX21-AS1 expression was associated with shorter overall survival and could be used as a potential prognostic biomarker for CC patients. Functional investigation showed that knockdown of SOX21-AS1 suppressed CC cells proliferation, migration, and invasion, as well as epithelial to mesenchymal transition progress. Furthermore, our data showed that microRNA-7 (miR-7) interacted with SOX21-AS1 by directly targeting the miRNA-binding site in the SOX21-AS1 sequence, and quantitative real-time polymerase chain reaction results showed overexpression of SOX21-AS1 decreased the levels of miR-7 in CC cells. Moreover, we confirmed that miR-7 directly targeted the 3′-untranslated region of voltage dependent anion channel 1 (VDAC1). Final in vitro assay suggested that in CC cells with SOX21-AS1, VDAC1 overexpression resulted in an increase of cell proliferation, migration, and invasion. Overall, our findings illuminate how SOX21-AS1 formed a regulatory network to confer an oncogenic function in CC and SOX21-AS1 could be regarded as an efficient therapeutic target and potential biomarker for CC patients.     

Long noncoding RNA ABHD11-AS1 promote cells proliferation and invasion of colorectal cancer via regulating the miR-1254-WNT11 pathway

The purpose of our study was to investigate the effects of the long noncoding RNA (lncRNA) ABHD11-AS1 on colorectal cancer (CRC) progression and further explore its possible underlying mechanisms. In the study, we found that ABHD11-AS1 was highly expressed in CRC tissues and cell lines. High ABHD11-AS1 expression was correlated with poor overall survival of patients with CRC. ABHD11-AS1 knockdown reduced CRC cell proliferation, in vitro invasion, and in vivo tumor growth. Investigation of the underlying mechanism showed that ABHD11-AS1 could act as a molecular sponge of miR-1254, and WNT11 was a downstream target of miR-1254 in CRC. Moreover, there was a negative association between ABHD11-AS1 expression (or WNT11) and miR-1254 in CRC tissues. The rescue assays showed that WNT11 overexpression partially rescued the effects of ABHD11-AS1 inhibition on CRC progression. Thus, we demonstrated that ABHD11-AS1 promotes CRC progression through the miR-1254-WNT11 pathway, which provides a new insight into the therapeutic strategies for CRC.     

Long noncoding RNA PVT1: A highly dysregulated gene in malignancy

Recent studies have verified the contribution of several long noncoding RNAs (lncRNAs) in the carcinogenesis. Among the highly acknowledged lncRNAs is the human homolog of the plasmacytoma variant translocation gene, which is called PVT1. PVT1 resides near Myc oncogene and regulates the oncogenic process through modulation of several signaling pathways, such as TGF-β, Wnt/ β-catenin, PI3K/AKT, and mTOR pathways. This lncRNA has a circular form as well. Expression analyses and functional studies have appraised the oncogenic roles of PVT1 and circPVT1. Experiments in several cancer cell lines have shown that PVT1 silencing suppresses cancer cell proliferation, whereas its overexpression has the opposite effect. Its silencing has led to the accumulation of cells in the G0/G1 phase and diminished the number of cells in the S phase. Moreover, genome-wide association studies have signified the role of single nucleotide polymorphisms of this lncRNA in conferring risk of lymphoma in different populations. In the current study, we have summarized recent data about the role of PVT1 and circPVT1 in the carcinogenesis process.