Upregulation of the long non-coding RNA HOTAIR promotes esophageal squamous cell carcinoma metastasis and poor prognosis.
TL;DR: HOTAIR is a novel molecule involved in both ESCC progression and prognosis and full elucidation of HOTAIR functionality relevant to ESCC may open avenues for the use of lncRNAs in identification of novel drug targets and therapies for ESCC and other prevalent cancers.
Abstract: Recent studies of the individual functionalities of long non-coding RNAs (lncRNAs) in the development and progression of cancer have suggested that HOX transcript antisense RNA (HOTAIR) is capable of reprogramming chromatin organization and promoting cancer cell metastasis. In order to ascertain the expression pattern of the lncRNA HOTAIR and assess its biological role in the development and progression of esophageal squamous cell carcinoma (ESCC), HOTAIR expression in ESCC tissues and adjacent noncancerous tissues were collected from 78 patients and measured by real-time reverse transcription-polymerase chain reaction (RT-PCR). HOTAIR correlation with clinicopathological features and prognosis was also analyzed. Suppression of HOTAIR using siRNA treatment was performed in order to explore its role in tumor progression. Notably elevated HOTAIR expression levels were observed in cancerous tissues compared to adjacent noncancerous tissues (96%, P < 0.01), showing a high correlation with cancer metastasis (P < 0.01), elevated TNM (2009) stage classification (P < 0.01), and lowered overall survival rates (P = 0.003). Multivariate analysis revealed that HOTAIR expression (P = 0.003) is also an independent prognostic factor for comparison of TNM stage (P = 0.024) and lymph node metastasis (P = 0.010). Furthermore, in vitro assays of the ESCC cell line KYSE30 demonstrated that knockdown of HOTAIR reduced cell invasiveness and migration while increasing the response of cells to apoptosis. Thus, HOTAIR is a novel molecule involved in both ESCC progression and prognosis. Full elucidation of HOTAIR functionality relevant to ESCC may open avenues for the use of lncRNAs in identification of novel drug targets and therapies for ESCC and other prevalent cancers.
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01 Jan 2015
TL;DR: The chapter shows that the current understanding of what is a gene should be revised, in order to clearly define the complex relationship between product-coding regions, regulatory sequences, and the organism’s phenotype.
Abstract: Genetic information in most living organisms on Earth is stored in the form of a chemical structure, known as deoxyribonucleic acid (DNA). Researchers discovered that pieces of long DNA molecules, called genes, are recognized by the nuclear multi-subunit complex of ribonucleic acid (RNA) polymerase, which then produces molecules of RNA, complementarily mirroring the original DNA. Some of these RNA molecules carry information that can be used to produce polypeptide chains with pre-defi ned amino acid sequences. These molecules have been named messenger RNAs (mRNAs). Others, such as ribosomal RNAs, transfer RNAs, and small nuclear RNAs, have been found to drive and regulate production of proteins. They are sometimes referred to as housekeeping or structural RNAs. However, sequences of mRNAs together with structural RNAs account for less than 10 % of animal and plant genomes. The rest of the genome was considered silent and non-functional, until on-going research revealed that about 80 % of DNA might be transcribed, producing numerous long noncoding RNA molecules with important functions. This chapter gives an overview of mammalian transcriptome research in recent decades. It discusses the main technology platforms, comparing their strong sides and disadvantages. Some of the most important fi ndings are summarized, with an overview of the future prospectives in long noncoding RNA research. The chapter shows that the current understanding of what is a gene should be revised, in order to clearly defi ne the complex relationship between product-coding regions, regulatory sequences, and the organism’s phenotype.
680 citations
TL;DR: HOTAIR is an lncRNA that plays a role as an oncogenic molecule in different cancer cells, such as breast, gastric, colorectal, and cervical cancer cells and is a potential biomarker for diagnostic and therapeutic purposes in several cancers.
Abstract: Long non-coding RNAs (lncRNAs) refer to a group of RNAs that are usually more than 200 nucleotides and are not involved in protein generation. Instead, lncRNAs are involved in different regulatory processes, such as regulation of gene expression. Different lncRNAs exist throughout the genome. LncRNAs are also known for their roles in different human diseases such as cancer. HOTAIR is an lncRNA that plays a role as an oncogenic molecule in different cancer cells, such as breast, gastric, colorectal, and cervical cancer cells. Therefore, HOTAIR expression level is a potential biomarker for diagnostic and therapeutic purposes in several cancers. This RNA takes part in epigenetic regulation of genes and plays an important role in different cellular pathways by interacting with Polycomb Repressive Complex 2 (PRC2). In this review, we describe the molecular function and regulation of HOTAIR and its role in different types of cancers.
362 citations
TL;DR: The molecular mechanisms underlying HotaIR-mediated aggressive phenotypes of lung cancer are reviewed and HOTAIR’s potential in diagnosis and treatment of lung cancers is discussed, as well as the challenges of exploiting HOTA IR for intervention of Lung cancer.
Abstract: Long non-coding RNAs (lncRNAs) govern fundamental biochemical and cellular processes. lncRNA HOX transcript antisense RNA (HOTAIR) represses gene expression through recruitment of chromatin modifiers. The expression of HOTAIR is elevated in lung cancer and correlates with metastasis and poor prognosis. Moreover, HOTAIR promotes proliferation, survival, invasion, metastasis, and drug resistance in lung cancer cells. Here we review the molecular mechanisms underlying HOTAIR-mediated aggressive phenotypes of lung cancer. We also discuss HOTAIR’s potential in diagnosis and treatment of lung cancer, as well as the challenges of exploiting HOTAIR for intervention of lung cancer.
345 citations
Cites background from "Upregulation of the long non-coding..."
...Since its first link to metastasis in breast cancer, elevated expression of HOTAIR has been reported in at least 16 types of malignancies [19,22-24,49-82]....
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TL;DR: HX antisense intergenic RNA (HOTAIR) is a recently discovered long non-coding RNA that plays critical role in gene regulation and chromatin dynamics, appears to be misregulated in a variety of cancers.
342 citations
Cites background from "Upregulation of the long non-coding..."
...Epigenetic silencing of WIF-1 due to promoter hypermethylation is a frequent mechanism that causes aberrant activation of the WNT⁄β-catenin pathway in several human cancers, as well as in ESCC [104]....
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...Various reports have demonstrated that HOTAIR is a key regulator of chromatin dynamics and is misregulated in various carcinomas such as urothelial carcinoma [92], pancreatic tumors [93], hepatocellular carcinoma [94-97], colorectal carcinomas [98, 99], ovarian cancer tissues [100, 101], sarcomas [102], esophageal squamous cell carcinoma (ESCC) [103-106], renal carcinomas [20], nasopharyngeal carcinoma [107], gastrointestinal stromal tumors [82], Laryngeal squamous cell cancer [108, 109], gall bladder cancers [68], nonfunctional pituitary adenoma [110], prostate cancer [111], cervical tumors [109, 112, 113], melanomas [114], gastric cancers [45, 115, 116], Ta/T1 bladder cancer [72] and endometrial tumors [44, 117], (Table 1)....
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...Cancer patients with higher HOTAIR levels have poor prognosis for overall survival [5, 12, 13, 21, 22, 44, 68, 81, 82, 93, 95, 97-100, 102-106, 110, 111, 117, 119, 129, 130, 134, 135, 137-148]....
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...Exogenously added recombinant human WIF-1 protein in ESCC cells, overexpressing HOTAIR, inhibited the migration and invasion ability, although, no correlations were found between WIF-1 protein level and prognosis of patients with ESCC [104]....
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...AC C EP TE D M AN U SC R IP T Esophageal squamous cell carcinoma (ESCC): ESCC cells and tissues showed inverse correlation between HOTAIR overexpression and decreased WIF-1 (WNT inhibitory factor-1) expression, HOTAIR overexpression also promoted H3K27 tri-methylation in the promoter region of WIF-1 [104]....
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TL;DR: A mixed-modality approach combining ASOs and RNAi reagents improved knockdown efficacy, particularly for those lncRNAs that localize to both nuclear and cytoplasmic compartments.
Abstract: Thousands of long non-coding RNAs (lncRNAs) have been identified in mammalian cells. Some have important functions and their dysregulation can contribute to a variety of disease states. However, most lncRNAs have not been functionally characterized. Complicating their study, lncRNAs have widely varying subcellular distributions: some reside predominantly in the nucleus, the cytoplasm or in both compartments. One method to query function is to suppress expression and examine the resulting phenotype. Methods to suppress expression of mRNAs include antisense oligonucleotides (ASOs) and RNA interference (RNAi). Antisense and RNAi-based gene-knockdown methods vary in efficacy between different cellular compartments. It is not known if this affects their ability to suppress lncRNAs. To address whether localization of the lncRNA influences susceptibility to degradation by either ASOs or RNAi, nuclear lncRNAs (MALAT1 and NEAT1), cytoplasmic lncRNAs (DANCR and OIP5-AS1) and dual-localized lncRNAs (TUG1, CasC7 and HOTAIR) were compared for knockdown efficiency. We found that nuclear lncRNAs were more effectively suppressed using ASOs, cytoplasmic lncRNAs were more effectively suppressed using RNAi and dual-localized lncRNAs were suppressed using both methods. A mixed-modality approach combining ASOs and RNAi reagents improved knockdown efficacy, particularly for those lncRNAs that localize to both nuclear and cytoplasmic compartments.
341 citations
References
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TL;DR: It is shown that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression, indicating that l incRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
Abstract: Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodelling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumours and metastases, and HOTAIR expression level in primary tumours is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb repressive complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings indicate that lincRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
4,605 citations
"Upregulation of the long non-coding..." refers background in this paper
...As a novel molecule in lncRNAs world, HOTAIR initially became well-known for its involvement in primary breast tumors and breast cancer metastases, wherein elevation of HOTAIR promoted invasiveness and metastasis [16]....
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...HOTAIR is primarily associated with polycomb repressive complex 2 (PRC2), where it acts along with trimethylate H3K27 to repress transcription of specific metastasis suppressor genes [15,16]....
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TL;DR: The current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies are discussed.
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4,033 citations
"Upregulation of the long non-coding..." refers background in this paper
...Cancer has been traditionally regarded as a genetic disease, but current research has revealed that cancer development and progression also involves epigenetic abnormalities [6]....
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TL;DR: The transcriptional landscape of the four human HOX loci is characterized at five base pair resolution in 11 anatomic sites and 231 HOX ncRNAs are identified that extend known transcribed regions by more than 30 kilobases, suggesting transcription of ncRNA may demarcate chromosomal domains of gene silencing at a distance.
4,003 citations
TL;DR: This account of epigenetics in cancer reviews the mechanisms and consequences of epigenetic changes in cancer cells and concludes with the implications of these changes for the diagnosis, prognosis, and treatment of cancer.
Abstract: Gene transcription can be activated or inhibited by a reversible modification of the gene; this modification is termed an epigenetic change. This account of epigenetics in cancer reviews the mechan...
3,150 citations
TL;DR: It is demonstrated that linc-MD1 exerts the same control over differentiation timing in human myoblasts, and that its levels are strongly reduced in Duchenne muscle cells, indicating that the ceRNA network plays an important role in muscle differentiation.
2,231 citations