LncRNA XIST Promotes Pancreatic Cancer Proliferation Through miR-133a/EGFR.
01 Oct 2017-Journal of Cellular Biochemistry (John Wiley & Sons, Ltd)-Vol. 118, Iss: 10, pp 3349-3358
TL;DR: Light is shed on the role and mechanism of XIST/miR‐133a/EGFR in regulating PC cells proliferation and XIST may serve as a potential therapeutic target in PC in the future.
Abstract: According to recent studies, long non-coding RNA X-inactive specific transcript (XIST) is involved in the development and progression of many malignant tumors including pancreatic cancer. We validated the detailed role of XIST in human pancreatic cancer (PC) cell lines and PC tissues so as to determine its exact function and the mechanism by which it affected PC proliferation. In our research, lncRNA-XIST was specifically upregulated in PC tissues and cell lines, and high XIST expression in PC was related to poorer prognosis (larger tumor size, perineural invasion, lymph node micrometastases, and shorter overall survival). XIST augmented PC cell proliferation. Recently, the interaction between lncRNA and miRNA has been frequently reported to play major role in several biological processes. In the present study, XIST and miR-133a reciprocally inhibited each other in PC cells. Exogenous miR-133a expression significantly inhibited PC cell proliferation. Moreover, as exhibited by luciferase reporter gene assays, miR-133a bound to XIST and the 3'UTR of EGFR by direct targeting. In PC tissues, miR-133a expression was down-regulated and EGFR expression was up-regulated; miR-133a was inversely correlated with EGFR and XIST, respectively; XIST was positively correlated with EGFR. Taken together, these findings will shed light on the role and mechanism of XIST/miR-133a/EGFR in regulating PC cells proliferation. XIST may serve as a potential therapeutic target in PC in the future. J. Cell. Biochem. 118: 3349-3358, 2017. © 2017 Wiley Periodicals, Inc.
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TL;DR: Recent integrative analyses have provided evidence that new computational platforms and experimental approaches can be harnessed together to distinguish key ceRNA interactions in specific cancers, which could facilitate the identification of robust biomarkers and therapeutic targets, and hence, more effective cancer therapies and better patient outcome and survival.
Abstract: Noncoding RNAs (ncRNAs) constitute the majority of the human transcribed genome. This largest class of RNA transcripts plays diverse roles in a multitude of cellular processes, and has been implicated in many pathological conditions, especially cancer. The different subclasses of ncRNAs include microRNAs, a class of short ncRNAs; and a variety of long ncRNAs (lncRNAs), such as lincRNAs, antisense RNAs, pseudogenes, and circular RNAs. Many studies have demonstrated the involvement of these ncRNAs in competitive regulatory interactions, known as competing endogenous RNA (ceRNA) networks, whereby lncRNAs can act as microRNA decoys to modulate gene expression. These interactions are often interconnected, thus aberrant expression of any network component could derail the complex regulatory circuitry, culminating in cancer development and progression. Recent integrative analyses have provided evidence that new computational platforms and experimental approaches can be harnessed together to distinguish key ceRNA interactions in specific cancers, which could facilitate the identification of robust biomarkers and therapeutic targets, and hence, more effective cancer therapies and better patient outcome and survival.
755 citations
Cites background from "LncRNA XIST Promotes Pancreatic Can..."
...XIST SMAD7 miR-92b Liver [76] PTEN miR-181a Liver [77] PDK1 miR-139-5p Liver [78] EZH2 miR-101 Gastric [79] AR miR-124 Bladder [80] EGFR miR-133a Pancreas [81]...
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TL;DR: A novel experimental basis for targeted therapy for thyroid cancer from the aspect of lncRNA-miRNA-mRNA interaction is provided, confirming the negative interaction between XIST and miR-34a and modulating thyroid cancer cell proliferation and tumor growth.
Abstract: Thyroid cancer is one of the most prevalent malignancies in endocrine system. Further understanding and revealing the molecular mechanism underlying thyroid cancer are indispensable for the development of effective diagnosis and treatments. In the present study, we attempted to provide novel basis for targeted therapy for thyroid cancer from the aspect of lncRNA-miRNA-mRNA interaction. The expression and cellular function of XIST (X-inactive specific transcript) was determined. miRNAs which may be direct targets of XIST were screened for from online GEO database and miR-34a was selected. Next, the predicted binding between XIST and miR-34a, and the dynamic effect of XIST and miR-34a on downstream MET (hepatocyte growth factor receptor)-PI3K (phosphoinositide 3-kinase)-AKT (α-serine/threonine-protein kinase) signaling was evaluated. XIST was significantly up-regulated in thyroid cancer tissues and cell lines; XIST knockdown suppressed the cell proliferation in vivo and the tumor growth in vitro. Based on online database and online tool prediction results, miR-34a was underexpressed in thyroid cancer and might be a direct target of XIST. Herein, we confirmed the negative interaction between XIST and miR-34a; moreover, XIST knockdown could reduce the protein levels of MET, a downstream target of miR-34a, and the phosphorylation of PI3K and AKT. In thyroid cancer tissues, MET mRNA and protein levels of MET were up-regulated; MET was positively correlated with XIST while negatively correlated with miR-34a, further confirming that XIST serves as a ceRNA for miR-34a through sponging miR-34a, competing with MET for miR-34a binding, and finally modulating thyroid cancer cell proliferation and tumor growth. In the present study, we provided novel experimental basis for targeted therapy for thyroid cancer from the aspect of lncRNA-miRNA-mRNA interaction.
219 citations
TL;DR: This study demonstrated how lncRNA XIST regulates CRC progression and metastasis by competing for miR-200b-3p to modulate the expression of ZEB1 and may be used as a biomarker to predict prognosis in CRC patients.
Abstract: Tumor progression and metastasis is the main cause of death in colorectal cancer (CRC). Long noncoding RNAs (lncRNAs) are critical regulators in various diseases including human cancer. In this study, we found that lncRNA XIST was overexpressed in CRC cell lines and tissues. High expression of lncRNA XIST was associated with adverse overall survival in CRC patients. Knockdown of lncRNA XIST remarkably inhibited CRC cell proliferation, invasion, epithelial-mesenchymal transition (EMT) and CRC stem cell formation in vitro as well as tumor growth and metastasis in vivo. Further study indicated that knockdown of lncRNA XIST markedly increased the expression of microRNA-200b-3p (miR-200b-3p) that has been found to be downregulated in CRC tissues and cell lines, and luciferase activity assay indicated that lncRNA XIST could bind directly with miR-200b-3p. Moreover, knockdown of lncRNA XIST significantly reduced the expression of ZEB1, which was the direct target of miR-200b-3p, and the tumor suppressive effects caused by knockdown of lncRNA XIST could be rescued by re-expression of ZEB1 in CRC cells. Overall, our study demonstrated how lncRNA XIST regulates CRC progression and metastasis by competing for miR-200b-3p to modulate the expression of ZEB1. lncRNA XIST may be used as a biomarker to predict prognosis in CRC patients.
165 citations
Cites result from "LncRNA XIST Promotes Pancreatic Can..."
...lncRNA XIST could promote pancreatic cancer proliferation through miR-133a/EGFR.(19) However, other studies indicated...
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Journal Article•
TL;DR: The current review aims to elucidate the cellular and molecular mechanisms of PNI, which may help to find a strategy for improving the prognosis of malignant tumors.
Abstract: Perineural invasion (PNI) can be found in a variety of malignant tumors. It is a sign of tumor metastasis and invasion and portends the poor prognosis of patients. The pathological description and clinical significance of PNI are clearly understood, but exploration of the underlying molecular mechanism is ongoing. It was previously thought that the low-resistance channel in the anatomic region led to the occurrence of PNI. However, with rapid development of precision medicine and molecular biology, we have gradually realized that the occurrence of PNI is not the result of a single factor. The latest study suggests that PNI of cancer is a continuous and multistep process. A specific peripheral microenvironment, also called the perineural niche, is formed by neural cells, supporting cells, recruited inflammatory cells, altered extracellular matrix, blood vessels, and immune components in the background of carcinoma. Various soluble signaling molecules and their receptors comprise a complex signal network, which achieves the interaction between nerve and tumor. Nerve cells and tumor cells can interact directly or through the opening and closing of the signal transduction pathways and/or the recognition and response of the ligands and receptors. The information is transferred to the targets accurately and effectively, leading to the specific interactions between the nerve cells and the malignant tumor cells. PNI occurs through changes in nerve cells and supporting cells in the background of cancer; change and migration of the perineural matrix; enhancement of the viability, mobility, and invasiveness of the tumor cells; injury and regeneration of nerve cells; interaction, chemotactic movement, contact, and adherence of the nerve cells and the tumor cells; escape from autophagy, apoptosis, and immunological surveillance of tumor cells; and so on. Certainly, exploring the mechanism of PNI clearly has great significance for blocking tumor progression and improving patient survival. The current review aims to elucidate the cellular and molecular mechanisms of PNI, which may help us find a strategy for improving the prognosis of malignant tumors.
112 citations
Cites background from "LncRNA XIST Promotes Pancreatic Can..."
...Studies by Wei W [108] showed that lncRNA-X-inactive specific transcript (XIST) has high expression in pancreatic carcinoma tissues and is negatively correlated with the expression of miR-133a....
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TL;DR: It is demonstrated that lncRNA XIST enhances OS cancer cell proliferation and invasion in part through the miR‐195‐5p/YAP pathway and might be a promising therapeutic target for OS.
Abstract: The lncRNA XIST (X inactive-specific transcript) is an oncogenic lncRNA that is present in various malignant tumors; however, its role and molecular mechanisms in osteosarcoma (OS) progression remain unclear. In the current study, 40 pairs of OS tissues and matched adjacent non-tumor tissues were collected. qRT-PCR was conducted to investigate the differences in XIST expression in tissues and OS cell lines. The proliferation, invasion, and EMT status of OS cells after transfection were assessed with WST-1 assays, Transwell assays, and Western blot analysis, respectively. Whether miR-195-5p was a direct downstream target of XIST was verified by both bioinformatics target gene prediction and dual-luciferase report analysis. A mouse model was established to evaluate tumor proliferation in vivo. Our results demonstrated that XIST expression was significantly upregulated in OS tissues and cell lines and negatively correlated with clinical prognosis. XIST knockdown inhibited cancer cell proliferation and invasion in vitro, inhibited the EMT of OS cells in vitro, and suppressed subcutaneous tumor growth in vivo. Further analysis demonstrated that XIST regulated YAP expression by functioning as a competing endogenous RNA that sponged miR-195-5p in OS cells. XIST directly interacted with miR-195-5p and decreased the binding of miR-195-5p to the YAP 3'UTR, which suppressed the degradation of YAP mRNA by miR-195-5p. In conclusion, this work demonstrates that lncRNA XIST enhances OS cancer cell proliferation and invasion in part through the miR-195-5p/YAP pathway. Therefore, lncRNA XIST might be a promising therapeutic target for OS.
97 citations
Cites background from "LncRNA XIST Promotes Pancreatic Can..."
...X inactive-specific transcript (XIST), derived from the XIST gene, is a newly identified lncRNA and is an oncogenic lncRNA in various malignant tumors, including colorectal cancer,(5) hepatocellular carcinoma,(6) gastric cancer,(7) and pancreatic cancer.(8) Few reports on the expression level of XIST and its function in OS exist....
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...Recent studies have revealed that many lncRNAs are involved in the pathogenesis and progression of multiple cancers, such as colorectal cancer,(5) hepatocellular carcinoma,(6) gastric cancer,(7) and pancreatic cancer.(8) However, the roles of lncRNAs in OS remain largely unknown....
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Cold Spring Harbor Laboratory1, California Institute of Technology2, University of California, Irvine3, Florida State University College of Arts and Sciences4, Yale University5, Wellcome Trust Sanger Institute6, Norwegian University of Science and Technology7, Affymetrix8, University of North Carolina at Chapel Hill9, University of Lausanne10, University of Geneva11, Genome Institute of Singapore12, Stanford University13, Pompeu Fabra University14
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