Functional Interaction among lncRNA HOTAIR and MicroRNAs in Cancer and Other Human Diseases.
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ABSTRACT:
SUBMITTER: Cantile M
PROVIDER: S-EPMC7867281 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPancreatic cancer (PC) remains one of the most aggressive cancers worldwide. However, genetic factors underlying PC susceptibility remain largely unclear. Long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) acts as an oncogene and its genetic variation has been linked to many cancers. However, the associations between genetic variants in HOTAIR gene and PC risk has not yet been reported.MethodsA two-stage, case-control study was conducted to investigate the associations between HOTAIR SNPs and the PC risk. Dual luciferase reporter assay and real-time -PCR (RT-PCR) was conducted to evaluate the potential regulatory function of HOTAIR rs4759314 and rs200349340.ResultsWe found the minor alleles of rs4759314 (OR = 1.76; 95 CI 1.37-2.25; P = 0.001) and rs200349340 (OR = 1.32; 95 CI 1.12-1.56; P = 0.001) were significantly associated with PC susceptibility. In functional experiments, we found subjects carrying the minor alleles of rs4759314 and rs200349340 had significantly higher HOTAIR RNA levels (mean ± SD) than those carrying the major alleles in PC tissues. For rs4759314, cells transfected with rs4759314 -G allele construct showed higher relative luciferase activity; while for rs200349340, cells transfected with rs200349340 -G allele construct showed more sensitive change of the relative luciferase activity.ConclusionOur studies revealed that functional SNP rs4759314 and rs200349340 of HOTAIR had strong associations with PC susceptibility. These findings elucidate that functional genetic variants influencing lncRNA expression may explain a portion of PC genetic basis.
| S-EPMC6396528 | biostudies-literature
Project description: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.
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Project description:The role of long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) and its functional single nucleotide polymorphisms (SNPs) in papillary thyroid carcinoma (PTC) is still largely unclear. Therefore, we investigated the involvement of lncRNA HOTAIR and its three haplotype-tagging SNPs (htSNPs) in PTC. There was higher expression of HOTAIR in PTC tissues compared to normal tissues. A series of gain-loss assays demonstrated that HOTAIR acts as a PTC oncogene via promoting tumorigenic properties of PTC cells. Additionally, the functional HOTAIR rs920778 genetic variant was a PTC susceptibility SNP. Subjects with the HOTAIR rs920778 TT genotype had an odds ratio (OR) of 1.88, 1.25 and 1.61 (P = 6.0 × 10(-6), P = 0.028 and P = 3.2 × 10(-5)) for developing PTC in Shandong, Jiangsu and Jilin case-control sets compared with subjects with the CC genotype. This statistically significant associations were only found between the rs920778 genetic polymorphism and PTC risk in females but not in males. The allele-specific regulation on HOTAIR expression by the rs920778 SNP was confirmed both in vitro and in vivo. Our results demonstrate that functional SNPs influencing lncRNA regulation may explain a part of PTC genetic basis.
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Project description:MicroRNAs (miRNAs/miRs) are small non‑coding RNAs (ncRNAs) that regulate gene expression. Emerging knowledge has suggested that miRNAs have a role in the pathogenesis of metabolic disorders, supporting the hypothesis that miRNAs may represent potential biomarkers or targets for this set of diseases. However, the current evidence is often controversial. Therefore, the aim of the present study was to determine the associations between miRNAs‑target genes, miRNA‑long ncRNAs (lncRNAs), and miRNAs‑small molecules in human metabolic diseases, including obesity, type 2 diabetes and non‑alcoholic fatty liver disease. The metabolic disease‑related miRNAs were obtained from the Human MicroRNA Disease Database (HMDD) and miR2Disease database. A search on the databases Matrix Decomposition and Heterogeneous Graph Inference (MDHGI) and DisGeNET were also performed. miRNAs target genes were obtained from three independent sources: Microcosm, TargetScan and miRTarBase. The interactions between miRNAs‑lncRNA and miRNA‑small molecules were performed using the miRNet web tool. The network analyses were performed using Cytoscape software. As a result, a total of 20 miRNAs were revealed to be associated with metabolic disorders in the present study. Notably, 6 miRNAs (miR‑17‑5p, miR‑29c‑3p, miR‑34a‑5p, miR‑103a‑3p, miR‑107 and miR‑132‑3p) were found in the four resources (HMDD, miR2Disease, MDHGI, and DisGeNET) used for these analyses, presenting a stronger association with the diseases. Furthermore, the target genes of these miRNAs participate in several pathways previously associated with metabolic diseases. In addition, interactions between miRNA‑lncRNA and miRNA‑small molecules were also found, suggesting that some molecules can modulate gene expression via such an indirect way. Thus, the results of this data mining and integration analysis provide further information on the possible molecular basis of the metabolic disease pathogenesis as well as provide a path to search for potential biomarkers and therapeutic targets concerning metabolic diseases.
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Project description:Tamoxifen, an estrogen receptor (ER) antagonist, is the mainstay treatment of breast cancer and the development of resistance represents a major obstacle for a cure. Although long non-coding RNAs such as HOTAIR have been implicated in breast tumorigenesis, their roles in chemotherapy resistance remain largely unknown. In this study, we report that HOTAIR (HOX antisense intergenic RNA) is upregulated in tamoxifen-resistant breast cancer tissues compared to their primary counterparts. Mechanistically, HOTAIR is a direct target of ER-mediated transcriptional repression and is thus restored upon the blockade of ER signaling, either by hormone deprivation or by tamoxifen treatment. Interestingly, this elevated HOTAIR increases ER protein level and thus enhances ER occupancy on the chromatin and potentiates its downstream gene regulation. HOTAIR overexpression is sufficient to activate the ER transcriptional program even under hormone-deprived conditions. Functionally, we found that HOTAIR overexpression increases breast cancer cell proliferation, whereas its depletion significantly impairs cell survival and abolishes tamoxifen-resistant cell growth. In conclusion, the long non-coding RNA HOTAIR is directly repressed by ER and its upregulation promotes ligand-independent ER activities and contributes to tamoxifen resistance.
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Project description:Gastric cancer is one of the first malignant cancers in the world and a large number of people die every year due to this disease. Many genetic and epigenetic risk factors have been identified that play a major role in gastric cancer. HOTAIR is an effective epigenetic agent known as long noncoding RNA (lncRNA). HOTAIR has been described to have biological functions in biochemical and cellular processes through interactions with many factors, leading to genomic stability, proliferation, survival, invasion, migration, metastasis, and drug resistance. In the present article, we reviewed the prognostic value of the molecular mechanisms underlying the HOTAIR regulation and its function in the development of Gastric Cancer, whereas elucidation of HOTAIR-protein and HOTAIR-DNA interactions can be helpful in the identification of cancer processes, leading to the development of potential therapeutic strategies.
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Project description:N6-methyladenosine (m6A) modification of RNA regulates normal and cancer biology, but knowledge of its function on long noncoding RNAs (lncRNAs) remains limited. Here, we reveal that m6A regulates the breast cancer-associated human lncRNA HOTAIR. Mapping m6A in breast cancer cell lines, we identify multiple m6A sites on HOTAIR, with 1 single consistently methylated site (A783) that is critical for HOTAIR-driven proliferation and invasion of triple-negative breast cancer (TNBC) cells. Methylated A783 interacts with the m6A "reader" YTHDC1, promoting chromatin association of HOTAIR, proliferation and invasion of TNBC cells, and gene repression. A783U mutant HOTAIR induces a unique antitumor gene expression profile and displays loss-of-function and antimorph behaviors by impairing and, in some cases, causing opposite gene expression changes induced by wild-type (WT) HOTAIR. Our work demonstrates how modification of 1 base in an lncRNA can elicit a distinct gene regulation mechanism and drive cancer-associated phenotypes.
| S-EPMC9731500 | biostudies-literature
Project description:Ovarian cancer is one of the common female malignant tumors globally. However, exactly mechanism of ovarian cancer remained unknown. HOTAIR, a lncRNA in the mammalian HOXC locus, has been fully explored for its genetic variants, expression level and carcinogenesis, development and progression of multiple cancers, except for ovarian cancer. In this study, we hypothesized that abnormal expression of HOTAIR and common variants of HOTAIR are associated with risk of Epithelial ovarian cancer (EOC). We first evaluated the HOTAIR levels in 100 paired tissues of EOC patients and corresponding normal tissues. Results showed that the expression level of HOTAIR in EOC tissues was significantly higher than that in corresponding normal tissues. Then the genotyping analyses of HOTAIR gene was conducted in a Chinese population. The results indicated that rs4759314 and rs7958904 were significantly associated with EOC susceptibility. For rs4759314, the difference between the G allele (as the reference) and the A allele was statistically significant (adjusted OR, 1.34; 95% CI: 1.08-1.65; P = 6.8 × 10-3). For rs7958904, C allele was associated a significantly decreased EOC risk when compared with G allele (OR: 0.77; 95% CI: 0.67-0.89; P = 4.2 × 10-4). The study identified that HOTAIR variants could be a useful biomarker for the predisposition to EOC and for the early diagnosis of the disease.
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Project description:Predicting response to endocrine therapy and survival in oestrogen receptor positive breast cancer is a significant clinical challenge and novel prognostic biomarkers are needed. Long-range regulators of gene expression are emerging as promising biomarkers and therapeutic targets for human diseases, so we have explored the potential of distal enhancer elements of non-coding RNAs in the prognostication of breast cancer survival. HOTAIR is a long non-coding RNA that is overexpressed, promotes metastasis and is predictive of decreased survival. Here, we describe a long-range transcriptional enhancer of the HOTAIR gene that binds several hormone receptors and associated transcription factors, interacts with the HOTAIR promoter and augments transcription. This enhancer is dependent on Forkhead-Box transcription factors and functionally interacts with a novel alternate HOTAIR promoter. HOTAIR expression is negatively regulated by oestrogen, positively regulated by FOXA1 and FOXM1, and is inversely correlated with oestrogen receptor and directly correlated with FOXM1 in breast tumours. The combination of HOTAIR and FOXM1 enables greater discrimination of endocrine therapy responders and non-responders in patients with oestrogen receptor positive breast cancer. Consistent with this, HOTAIR expression is increased in cell-line models of endocrine resistance. Analysis of breast cancer gene expression data indicates that HOTAIR is co-expressed with FOXA1 and FOXM1 in HER2-enriched tumours, and these factors enhance the prognostic power of HOTAIR in aggressive HER2+ breast tumours. Our study elucidates the transcriptional regulation of HOTAIR, identifies HOTAIR and its regulators as novel biomarkers of patient response to endocrine therapy and corroborates the importance of transcriptional enhancers in cancer.
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Project description:MicroRNAs are endogenous small non-coding RNAs that regulate gene expression and cancer development. A rare population of hepatocellular cancer stem cells (HSCs) holds the extensive proliferative and self-renewal potential necessary to form a liver tumour. We postulated that specific transcriptional factors might regulate the expression of microRNAs and subsequently modulate the expression of gene products involved in phenotypic characteristics of HSCs. We evaluated the expression of microRNA in human HSCs by microarray profiling, and defined the target genes and functional effects of two groups of microRNA regulated by IL-6 and transcriptional factor Twist. A subset of highly chemoresistant and invasive HSCs was screened with aberrant expressions of cytokine IL-6 and Twist. We demonstrated that conserved let-7 and miR-181 family members were up-regulated in HSCs by global microarray-based microRNA profiling followed by validation with real-time polymerase chain reaction. Importantly, inhibition of let-7 increases the chemosensitivity of HSCs to sorafenib and doxorubicin whereas silencing of miR-181 led to a reduction in HSCs motility and invasion. Knocking down IL-6 and Twist in HSCs significantly reduced let-7 and miR-181 expression and subsequently inhibited chemoresistance and cell invasion. We showed that let-7 directly targets SOCS-1 and caspase-3, whereas miR-181 directly targets RASSF1A, TIMP3 as well as nemo-like kinase (NLK). In conclusion, alterations of IL-6- and Twist-regulated microRNA expression in HSCs play a part in tumour spreading and responsiveness to chemotherapy. Our results define a novel regulatory mechanism of let-7/miR-181s suggesting that let-7 and miR-181 may be molecular targets for eradication of hepatocellular malignancies.
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