H19

Gene Summary

Gene:H19; H19, imprinted maternally expressed transcript (non-protein coding)
Aliases: ASM, BWS, WT2, ASM1, D11S813E, LINC00008, NCRNA00008
Location:11p15.5
Summary:This gene is located in an imprinted region of chromosome 11 near the insulin-like growth factor 2 (IGF2) gene. This gene is only expressed from the maternally-inherited chromosome, whereas IGF2 is only expressed from the paternally-inherited chromosome. The product of this gene is a long non-coding RNA which functions as a tumor suppressor. Mutations in this gene have been associated with Beckwith-Wiedemann Syndrome and Wilms tumorigenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 09 March, 2017

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 09 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: H19 (cancer-related)

Yang W, Ning N, Jin X
The lncRNA H19 Promotes Cell Proliferation by Competitively Binding to miR-200a and Derepressing β-Catenin Expression in Colorectal Cancer.
Biomed Res Int. 2017; 2017:2767484 [PubMed] Free Access to Full Article Related Publications
H19, a paternally imprinted noncoding RNA, has been found to be overexpressed in various cancers, including colorectal cancer (CRC), and may function as an oncogene. However, the mechanism by which H19 regulates CRC progression remains poorly understood. In this study, we aimed to assess H19 expression levels in CRC tissues, determine the effect of H19 on CRC proliferation, and explore the mechanism by which H19 regulates the proliferation of CRC. We measured H19 expression using qRT-PCR and analysed the effects of H19 on colon cancer cell proliferation via cell growth curve, cell viability assay, and colony formation assays. To elucidate the mechanism underlying these effects, we analysed the interactions between H19 and miRNAs and identified the target gene to which H19 and miRNA competitively bind using a series of molecular biological techniques. H19 expression was upregulated in CRC tissues compared with adjacent noncancerous tissues. H19 overexpression facilitated colon cancer cell proliferation, whereas H19 knockdown inhibited cell proliferation. miR-200a bound to H19 and inhibited its expression, thereby decreasing CRC cell proliferation. β-Catenin was identified as a target gene of miR-200a. H19 regulated β-catenin expression and activity by competitively binding to miR-200a. H19 promotes cell proliferation by competitively binding to miR-200a and derepressing β-catenin in CRC.

Piyamongkol W, Suprasert P
Allelic Characterization of IGF2 and H19 Gene Polymorphisms in Molar Tissues.
Asian Pac J Cancer Prev. 2016; 17(9):4405-4408 [PubMed] Related Publications
BACKGROUND: To investigate the characteristics of allelic distribution of IGF2 and H19 gene polymorphisms in molar tissues compared to normal placentas.
MATERIALS AND METHODS: Forty-nine specimens of molar tissues as well as 100 control normal placental tissues, delivered on the same days, were collected. Polymerase chain reaction (PCR) with restriction fragment length polymorphism (RFLP) on 2% agarose gel electrophoresis was conducted to determine the allelic distribution. The ApaI polymorphism within exon 9 of IGF2 and the RsaI polymorphism within exon 5 of H19 were employed to identify the allelic distribution of the IGF2 and H19 genes, respectively. Then the data for these genes in the molar and normal placenta tissues were compared.
RESULTS: The allelic distribution of IGF2 genes found in molar tissue were 21 (42.9%) aa (undigested), 10 (20.4%) ab (heterozygous) and 18 (36.7%) bb (digested), while in normal placenta tissue the values were 22 (22%) aa, 51 (51%) ab, and 27 (27%) bb. The allelic distribution of H19 in molar tissues was 8 (16.2%) aa (undigested), 8 (16.3%) ab (heterozygous) and 33 (67.4%) bb (digested) and in normal placental tissue was 16 (16%) aa, 36 (36%) ab and 48 (48%) bb in normal placenta tissue. These results were significantly different with P values of 0.001 and 0.037 for the allelic distribution of IGF2 and H19, respectively.
CONCLUSIONS: Molar tissues showed significant differences of allelic distribution of IGF2 and H19 from normal placenta tissues.

Ohtsuka M, Ling H, Ivan C, et al.
H19 Noncoding RNA, an Independent Prognostic Factor, Regulates Essential Rb-E2F and CDK8-β-Catenin Signaling in Colorectal Cancer.
EBioMedicine. 2016; 13:113-124 [PubMed] Free Access to Full Article Related Publications
The clinical significance of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC) remains largely unexplored. Here, we analyzed a large panel of lncRNA candidates with The Cancer Genome Atlas (TCGA) CRC dataset, and identified H19 as the most significant lncRNA associated with CRC patient survival. We further validated such association in two independent CRC cohorts. H19 silencing blocked G1-S transition, reduced cell proliferation, and inhibited cell migration. We profiled gene expression changes to gain mechanism insight of H19 function. Transcriptome data analysis revealed not only previously identified mechanisms such as Let-7 regulation by H19, but also RB1-E2F1 function and β-catenin activity as essential upstream regulators mediating H19 function. Our experimental data showed that H19 affects phosphorylation of RB1 protein by regulating gene expression of CDK4 and CCND1. We further demonstrated that reduced CDK8 expression underlies changes of β-catenin activity, and identified that H19 interacts with macroH2A, an essential regulator of CDK8 gene transcription. However, the relevance of H19-macroH2A interaction in CDK8 regulation remains to be experimentally determined. We further explored the clinical relevance of above mechanisms in clinical samples, and showed that combined analysis of H19 with its targets improved prognostic value of H19 in CRC.

Ma Y, Lu Y, Lu B
MicroRNA and Long Non-Coding RNA in Ovarian Carcinoma: Translational Insights and Potential Clinical Applications.
Cancer Invest. 2016; 34(9):465-476 [PubMed] Related Publications
Reliable biomarkers for the detection of early ovarian carcinoma are currently unavailable. MicroRNA and long non-coding RNA may be important in cancer initiation and progression by regulating gene expression through post-transcriptional mechanisms. MicroRNAs, such as miR-26a and miR-132, have been investigated as novel biomarkers for diagnosis, prognosis, monitoring of therapeutic response, and therapeutic targets in ovarian carcinomas. Some long non-coding RNAs, such as H19 and UCA1, may be involved in the pathogenesis of ovarian carcinomas. MicroRNA and long non-coding RNA have potential clinical utility in the diagnosis of ovarian cancer and predicting prognosis, metastasis, recurrence, and response to therapy.

Lin Y, Xu L, Wei W, et al.
Long Noncoding RNA H19 in Digestive System Cancers: A Meta-Analysis of Its Association with Pathological Features.
Biomed Res Int. 2016; 2016:4863609 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNA (lncRNA) H19 has been reported to be upregulated in malignant digestive tumors, but its clinical relevance is not yet established. The meta-analysis was to investigate the association between H19 expression and pathological features of digestive system cancers. The databases of PubMed, EMBase, Web of Science, CNKI, and WanFang were searched for the related studies. A total of 478 patients from 6 studies were finally included. The meta-analysis showed that the patient group of high H19 expression had a higher risk of poorly differentiated grade, deep tumor invasion (T2 stage or more), lymph node metastasis, and advanced TNM stage than the group of low H19 expression, although there was no difference between them in terms of distant metastasis. Therefore, the high expression of lncRNA H19 might predict poor oncological outcomes of patients with digestive system cancers.

Zhang K, Luo Z, Zhang Y, et al.
Circulating lncRNA H19 in plasma as a novel biomarker for breast cancer.
Cancer Biomark. 2016; 17(2):187-94 [PubMed] Related Publications
BACKGROUND: Long non-coding RNA (lncRNA) H19 has been well studied playing an important role in breast cancer (BC) progress and the expression of H19 may service as a diagnostic target for BC. However, it is unclear if circulating lncRNA H19 could as a potential biomarker for BC diagnosis and monitor.
OBJECTIVE: The objective of our study was to determine whether plasma lncRNA H19 could be used as biomarkers for the screening and early diagnosis of breast cancer.
METHODS: In this study, we carried out a quantitative real-time PCR (qRT-PCR) method to examine the expression levels of lncRNA H19 in 24 pairs of BC tissues and 20 pairs of BC plasma. The differentially expressed of plasma H19 was further validated in another 102 BC patients and 96 healthy controls. The potential correlations between plasma H19 levels and clinicopathological characteristics were analyzed. Receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic values of plasma H19 between 30 early stage BC patients and 30 healthy controls. 24 paired pre- and postoperative plasma samples were detected to assess the tumor monitoring values.
RESULTS: The results revealed that the expression of H19 was significantly increased in BC tissues and plasma compared with healthy controls (P< 0.05), and plasma H19 levels were significantly correlated with estrogen receptor (ER) (P= 0.008), progesterone receptor (PR) (P= 0.025), c-erbB-2 (P= 0.043) and lymph node metastasis (P= 0.006). The area under the ROC curve (AUC) of plasma H19 was 0.81(sensitivity, 56.7%; specificity, 86.7%; P< 0.0001), which was higher than the values of carcinoembryonic antigen (CEA) and carbohydrate antigen 153 (CA153). Furthermore, plasma H19 levels were significantly decreased in postoperative samples than preoperative samples (P= 0.0006).
CONCLUSION: Plasma H19 may serve as a potential biomarker for BC early screening and prognosis monitor.

Soudyab M, Iranpour M, Ghafouri-Fard S
The Role of Long Non-Coding RNAs in Breast Cancer.
Arch Iran Med. 2016; 19(7):508-17 [PubMed] Related Publications
Long non-coding RNA (lncRNA) genes are an important population of non-coding RNAs with defined key roles in normal development as well as tumorigenesis process. Evidences suggest that they can be classified as tumor suppressor genes or oncogenes according to their functions and expression pattern in tumoral tissues. They have been shown to regulate the plasticity of cancer stem cells. Their important roles in the regulation of cancer-related pathways in addition to deregulation of their expression in a number of cancers have suggested that they can be used as markers for cancer detection and prognosis, as well as targets for cancer treatment. Deregulation of a number of lncRNAs, such as HOTAIR, XIST, MALAT, and H19 has been detected in breast cancer samples and cell lines. In addition, the association between lncRNAs signature and breast cancer patients' survival has been assessed in various studies. Here, the expression patterns of lncRNAs in breast cancer, as well as their significance in prognosis and patient treatment are discussed.

Chen T, Yang P, He ZY
Long non-coding RNA H19 can predict a poor prognosis and lymph node metastasis: a meta-analysis in human cancer.
Minerva Med. 2016; 107(4):251-8 [PubMed] Related Publications
INTRODUCTION: A long non-coding RNA (lncRNA) H19 has been reported to be aberrantly regulated in a wide range of cancers. This meta-analysis was performed to explore the potential value of H19 as a biomarker for cancer prognosis.
EVIDENCE ACQUISTION: We searched the electronic databases PubMed and Web of Science (up to April 30, 2016) in attention to collect all relevant researches to identify the association of lncRNA H19 with overall survival (OS), disease free survival (DFS) and lymph node metastasis (LNM).
EVIDENCE SYNTHESIS: Our findings revealed that high levels of H19 expression could predict poor OS (pooled HR: 1.19, 95% CI: 1.08-1.32, P=0.001) and LNM (pooled OR: 1.810, 95% CI: 1.27-2.59, P=0.001) in multiple cancers.
CONCLUSIONS: This meta-analysis showed that overexpression of H19 might potentially serve as a reliable biomarker for poor prognosis in different types of cancers.

Sun W, Yang Y, Xu C, et al.
Roles of long noncoding RNAs in gastric cancer and their clinical applications.
J Cancer Res Clin Oncol. 2016; 142(11):2231-7 [PubMed] Related Publications
PURPOSE: Gastric cancer ranks as the most common cancer in the world. However, the progresses of its diagnosis and treatment are still not satisfactory. The purpose of this study is to summarize the roles of lncRNAs associated with gastric cancer.
METHODS: We searched lncRNAs associated with gastric cancer in PubMed.
RESULTS: Long noncoding RNAs (lncRNAs), transcripts larger than 200 nucleotides, regulate gene expression at various levels. They are playing important roles in the occurrence and development of gastric cancer. They are involved in signaling pathways, crosstalk with microRNAs, and affecting metastasis by regulating epithelial-to-mesenchymal transition. By acting as oncogenes or tumor suppressors, lncRNAs contribute to gastric cancer occurrence and development. Several lncRNAs including HOTAIR, HULC, LINC00152, MALAT2, H19, GHET1, and GACAT3 have been demonstrated having oncogene activities, while other lncRNAs including LEIGC, GAS5, and FER1L4 have been thought as tumor suppressors.
CONCLUSIONS: Several lncRNAs from tissue, blood, and gastric juice have shown potential values in gastric cancer diagnosis or prognosis evaluation.

Hsu CM, Lin PM, Lin HC, et al.
Altered Expression of Imprinted Genes in Squamous Cell Carcinoma of the Head and Neck.
Anticancer Res. 2016; 36(5):2251-8 [PubMed] Related Publications
BACKGROUND: Genomic imprinting is associated with many human diseases, including various types of cancers, however, no studies on gene imprinting are related to squamous cell carcinoma of the head and neck (SCCHN) directly.
MATERIALS AND METHODS: In this study, the expression of a panel of 15 imprinted genes in cancerous and non-cancerous tissues from 73 patients with SCCHN were investigated.
RESULTS: Altered expression of carboxypeptidase A4 (CPA4); protein phosphatase 1 regulatory subunit 9A (PPP1R9A); H19, imprinted maternally expressed transcript (non-protein coding) (H19); paternally expressed gene 3 antisense RNA 1 (PEG3-AS1); retrotransposon-like 1 (RTL1), insulin-like growth factor 2 (IGF2); solute carrier family 22 member 3 (SLC22A3); and gamma-aminobutyric acid type A receptor beta3 subunit (GABRB3) was observed. Down-regulation of PPP1R9A (p<0.05) and GABRB3 (p<0.05) was correlated with more advanced cancer stages. Down-regulation of PEG3-AS1 (p<0.05) and GABRB3 (p<0.01) was correlated with lymph node metastasis. Poor survival was related to higher expression of CPA4 (p<0.01) and lower expression of PEG3-AS1 (p<0.05) and IGF2 (p<0.05). Chemotherapy was also found to have an impact on the expression of imprinted genes.
CONCLUSION: Loss of imprinting is involved in tumorigenesis of SCCHN.

Li M, Chen H, Zhao Y, et al.
H19 Functions as a ceRNA in Promoting Metastasis Through Decreasing miR-200s Activity in Osteosarcoma.
DNA Cell Biol. 2016; 35(5):235-40 [PubMed] Related Publications
Osteosarcoma is the most common primary bone sarcoma around the world. The poor prognosis and high recurrence rate of osteosarcoma are largely due to the high rate of pulmonary metastasis. H19 has been reported to play a potential role in osteosarcoma progression. However, the exact molecular mechanism of metastasis involving H19 remains unclear. In the present study, we performed gain- and loss-of-function assays and found that H19 promotes migration and invasion in osteosarcoma cells. Furthermore, we showed that H19 promotes metastasis through upregulation of ZEB1 and ZEB2 by competitively binding the miR-200 family. Thus, our findings suggest important roles of H19 in osteosarcoma metastasis and indicate its potential application in osteosarcoma therapy.

Li W, Jiang P, Sun X, et al.
Suppressing H19 Modulates Tumorigenicity and Stemness in U251 and U87MG Glioma Cells.
Cell Mol Neurobiol. 2016; 36(8):1219-1227 [PubMed] Free Access to Full Article Related Publications
Glioblastoma multiforme (GBM) is a type of malignant carcinoma found in the brain. Its high frequency of occurrence and poor survival rate have garnered much research attention in recent years. Long non-coding RNAs (lncRNAs) are known to be related to the formation and progression of several cancer types by both promoting and suppressing tumor transformation. H19 is one such lncRNA and has been shown to be upregulated in a few types of cancer. In this study, we discovered that the expression of H19 increased in GBM cell lines. H19 knocked down GBM cells also displayed decreased cellular proliferation and a higher apoptosis rate when induced by temozolomide. Interestingly, the GBM cell lines U87MG and U251 were found to express cancer stem cell markers CD133, NANOG, Oct4 and Sox2. Expression of these markers was downregulated in H19-deficient cells. Collectively, these data suggest a role for H19 in contributing to GBM malignancy and the maintenance of its stem cell properties.

Altinoz MA, Elmaci I, Ince B, et al.
Hemoglobins, Hemorphins, and 11p15.5 Chromosomal Region in Cancer Biology and İmmunity with Special Emphasis for Brain Tumors.
J Neurol Surg A Cent Eur Neurosurg. 2016; 77(3):247-57 [PubMed] Related Publications
In systemic cancers, increased hemolysis leads to extracellular hemoglobin (HB), and experimental studies have shown its provoking role on tumor growth and metastasis. However, investigations have shown that HB chains presented by tumor vascular pericytes or serum protein complexes of HB could also induce antitumor immunity, which may be harnessed to treat refractory cancers and brain tumors. Mounting recent evidence shows that expression of HBs is not restricted to erythrocytes and that HBs exist in the cells of lung and kidney, in macrophages, and in neurons and glia of the central nervous system (CNS). HBs mediate coping with hypoxia and free radical stress in normal and tumor cells, and they are increased in certain tumors including breast, lung, colon, and squamous cell cancers. Recent studies showed HBs in meningioma, in the cyst fluid of craniopharyngioma, in the cerebrospinal fluid (CSF) of pediatric patients with posterior fossa tumors, and in glioblastoma cell lines. Hemorphins, abundant brain peptides formed via HB-chain cleavage, exert opioid activity and antiproliferative and immunomodifier effects. Hence mutations in HBs may modify brain tumorigenesis via influencing hemorphins and perturbing regulations of immune surveillance and cell growth in the neuroectodermal tissues. The β-globin gene cluster resides in the chromosome region 11p15.5, harboring important immunity genes and IGF2, H19, PHLDA2/TSSC3, TRIM3, and SLC22A18 genes associated with cancers and gliomas. 11p15.5 is a prominent region subject to epigenetic regulation. Thus the β-globin loci may exert haplotypal interactions with these. Some clues support this theory. It is well established that iron load induces liver cancer in thalassemia major; however iron load-independent associations also exist. Enhanced rates of hematologic malignancies are associated with HB Lepore, association of hemoglobin E with cholangiocarcinoma, and enhanced gastric cancer rates in the thalassemia trait. In the African Herero population, a mutant form of δ-globin is very prevalent, and this population has higher rates of pediatric brain tumors. Globins are also expressed in healthy endothelia and in tumoral vessels, indicating potential involvement in angiogenesis. Studies on HBs and their cleavage peptides in cancers and brain tumors may lead to innovative treatment strategies.

Li CY, Liang GY, Yao WZ, et al.
Integrated analysis of long non-coding RNA competing interactions reveals the potential role in progression of human gastric cancer.
Int J Oncol. 2016; 48(5):1965-76 [PubMed] Related Publications
Abnormal expression of long non-coding RNAs (lncRNAs) have been shown to play an important role in tumor biology. The Cancer Genome Atlas (TCGA) platform is a large sample sequencing database of lncRNAs, and further analysis of the associations between these data and patients' clinical related information can provide new approaches to find the functions of lncRNA. In the present study, 361 RNA sequencing profiles of gastric cancer (GC) patients were selected from TCGA. Then, we constructed the lncRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) network of GC. There were 25 GC specific lncRNAs (fold change >2, p<0.05) identified, 19 of them were included in ceRNA network. Subsequently, we selected these 19 key lncRNAs and analyzed the correlations with clinical features and overall survival, 14 of them were discriminatively expressed with tumor size, tumor grade, TNM stage and lymphatic metastasis (p<0.05). In addition, eight lncRNAs (RPLP0P2, FOXD2-AS1, H19, TINCR, SLC26A4-AS1, SMIM10L2A, SMIM10L2B and SNORD116-4) were found to be significantly associated with overall survival (log-rank p<0.05). Finally, two key lncRNAs HOTAIR and UCA1 were selected for validation of their expression levels in 82 newly diagnosed GC patients by qRT-PCR. Results showed that the fold changes between TCGA and qRT-PCR were 100% in agreement. In addition, we also found that HOTAIR was significantly correlated with tumor size and lymphatic metastasis (p<0.05), and UCA1 was significantly correlated with tumor size, TNM stage and lymphatic metastasis (p<0.05). The clinical relevance of the two lncRNAs and the bioinformatics analysis results were almost the same. Overall, our study showed the GC specific lncRNAs expression patterns and a ceRNA network in GC. Clinical features related to GC specific lncRNAs also suggested these lncRNAs are worthwhile for further study as novel candidate biomarkers for the clinical diagnosis of GC and potential indicators for prognosis.

Liu G, Xiang T, Wu QF, Wang WX
Long Noncoding RNA H19-Derived miR-675 Enhances Proliferation and Invasion via RUNX1 in Gastric Cancer Cells.
Oncol Res. 2016; 23(3):99-107 [PubMed] Related Publications
The lncRNA H19 and its mature product miR-675 have recently been shown to be upregulated and promote the progression of gastric cancer. However, the detailed function and underlying molecular mechanism of H19/miR-675 in the carcinogenesis of gastric cancer remains unclear. In this study, we found that H19 depended on miR-675 to enhance the proliferation and invasion of gastric cancer AGS cells, and the expression of miR-675 was positively correlated with H19 in patients with gastric cancer. Subsequently, the tumor-suppressor runt domain transcription factor 1 (RUNX1) was confirmed to be a downstream molecule of H19/miR-675 axis, since overexpression of H19 or miR-675 significantly decreased RUNX1 expression in AGS cells, and knockdown of H19 or miR-675 enhanced RUNX1 expression. More importantly, a series of assays further demonstrated that introduction of RUNX1 abrogated H19/miR-675-induced Akt/mTOR pathway activation and the following cellular proliferation and invasion of AGS cells. To our knowledge, this is the time to demonstrate that RUNX1 serves as a link between H19/miR-675 axis and Akt/mTOR signaling and is a pivotal mediator in gastric cancer progression induced by H19/miR-675. Thus, our study provides important clues for understanding the key roles of lncRNA-miRNA functional network and identifying new therapeutic targets for gastric cancer.

Xia Z, Yan R, Duan F, et al.
Genetic Polymorphisms in Long Noncoding RNA H19 Are Associated With Susceptibility to Breast Cancer in Chinese Population.
Medicine (Baltimore). 2016; 95(7):e2771 [PubMed] Free Access to Full Article Related Publications
H19, a maternally expressed imprinted gene transcribing a long noncoding RNA, has previously been reported to be involved in tumorigenesis and cancer progression. However, the association between the H19 polymorphisms and breast cancer (BC) susceptibility has remained elusive. The aim of this study was to evaluate the associations between 2 H19 haplotype tagging SNPs (rs3741219 T>C, rs217727 C>T) and the risk of breast cancer. Our study comprised 464 BC patients and 467 cancer-free controls in China. rs3741219 and rs217727 were genotyped with polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) and created restriction site PCR (CRS-RFLP) assays, respectively. False-positive report probability (FPRP) was calculated to test the false-positive association. On performing univariate analysis, no significant association between H19 polymorphisms (rs3741219 and rs217727) and BC was observed. However, in further stratified analyses, CT+TT genotypes of rs217727 had a significantly lower risk of breast cancer among women with number of pregnancy >2 (OR = 0.79; 95% CI = 0.55-0.97). CT genotype of rs217727 was associated with ER positivity (OR = 2.19; 95 % CI = 1.07-4.45) and HER-2 positivity (OR = 1.34; 95 % CI = 1.05-2.12). It was proved that our results were less likely to be false positives according to false-positive report probability calculation. Our findings extend available data on the association of H19 polymorphisms and BC susceptibility. Further validation in large population or cohort studies is needed.

Wang SH, Wu XC, Zhang MD, et al.
Long noncoding RNA H19 contributes to gallbladder cancer cell proliferation by modulated miR-194-5p targeting AKT2.
Tumour Biol. 2016; 37(7):9721-30 [PubMed] Related Publications
Gallbladder cancer (GBC) is a highly malignant cancer with poor prognosis. Although long noncoding RNA (lncRNA) H19 has been reported to play vital role in many human cancers, whether it is involved in GBC proliferation is still unknown. This study was designed to explore the effect of H19 in GBC cell proliferation. The expression of H19 and AKT2 were significantly elevated in GBC tissues, and the level of miR-194-5p is markedly decreased. Moreover, the RNA levels of H19 and AKT2 were positively correlated, and H19 elevation was significantly associated with tumor size. Cell proliferation decreased significantly after knockdown of H19 in GBC-SD and NOZ cells and after knockdown of AKT2 in NOZ cells. Results from cell cycle studies indicated that the S phase were significantly decreased after knockdown of H19 in NOZ cells but significantly elevated after overexpression of H19 in GBC-SD cells. Furthermore, knockdown of H19 upregulated miR-194-5p levels, yet significantly decreased miR-194-5p targeting AKT2 gene expression in NOZ cells. Inhibitor against miR-194-5p reversed these effects. In addition, overexpression of H19 in GBC-SD cells downregulated miR-194-5p and markedly increased AKT2 expression, and miR-194-5p mimic reversed these effects. Eventually, GBC cells were arrested in G0/G1-phase after H19 knockdown, inhibition of miR-194-5p markedly promoted cells into S-phase and co-transfection of siH19, and miR-194-5p inhibitor exerted mutually counter-regulated effects on cell cycle. These results suggested that H19/miR-194-5p/AKT2 axis regulatory network might modulate cell proliferation in GBC.

Li T, Mo X, Fu L, et al.
Molecular mechanisms of long noncoding RNAs on gastric cancer.
Oncotarget. 2016; 7(8):8601-12 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. Aberrant expression of lncRNAs has been found associated with gastric cancer, one of the most malignant tumors. By complementary base pairing with mRNAs or forming complexes with RNA binding proteins (RBPs), some lncRNAs including GHET1, MALAT1, and TINCR may mediate mRNA stability and splicing. Other lncRNAs, such as BC032469, GAPLINC, and HOTAIR, participate in the competing endogenous RNA (ceRNA) network. Under certain circumstances, ANRIL, GACAT3, H19, MEG3, and TUSC7 exhibit their biological roles by associating with microRNAs (miRNAs). By recruiting histone-modifying complexes, ANRIL, FENDRR, H19, HOTAIR, MALAT1, and PVT1 may inhibit the transcription of target genes in cis or trans. Through these mechanisms, lncRNAs form RNA-dsDNA triplex. CCAT1, GAPLINC, GAS5, H19, MEG3, and TUSC7 play oncogenic or tumor suppressor roles by correlated with tumor suppressor P53 or onco-protein c-Myc, respectively. In conclusion, interaction with DNA, RNA and proteins is involved in lncRNAs' participation in gastric tumorigenesis and development.

Chen J, Yao ZX, Chen JS, et al.
TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome.
J Clin Invest. 2016; 126(2):527-42 [PubMed] Free Access to Full Article Related Publications
Beckwith-Wiedemann syndrome (BWS) is a human stem cell disorder, and individuals with this disease have a substantially increased risk (~800-fold) of developing tumors. Epigenetic silencing of β2-spectrin (β2SP, encoded by SPTBN1), a SMAD adaptor for TGF-β signaling, is causally associated with BWS; however, a role of TGF-β deficiency in BWS-associated neoplastic transformation is unexplored. Here, we have reported that double-heterozygous Sptbn1+/- Smad3+/- mice, which have defective TGF-β signaling, develop multiple tumors that are phenotypically similar to those of BWS patients. Moreover, tumorigenesis-associated genes IGF2 and telomerase reverse transcriptase (TERT) were overexpressed in fibroblasts from BWS patients and TGF-β-defective mice. We further determined that chromatin insulator CCCTC-binding factor (CTCF) is TGF-β inducible and facilitates TGF-β-mediated repression of TERT transcription via interactions with β2SP and SMAD3. This regulation was abrogated in TGF-β-defective mice and BWS, resulting in TERT overexpression. Imprinting of the IGF2/H19 locus and the CDKN1C/KCNQ1 locus on chromosome 11p15.5 is mediated by CTCF, and this regulation is lost in BWS, leading to aberrant overexpression of growth-promoting genes. Therefore, we propose that loss of CTCF-dependent imprinting of tumor-promoting genes, such as IGF2 and TERT, results from a defective TGF-β pathway and is responsible at least in part for BWS-associated tumorigenesis as well as sporadic human cancers that are frequently associated with SPTBN1 and SMAD3 mutations.

Gong WJ, Yin JY, Li XP, et al.
Association of well-characterized lung cancer lncRNA polymorphisms with lung cancer susceptibility and platinum-based chemotherapy response.
Tumour Biol. 2016; 37(6):8349-58 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) play important roles in carcinogenesis and drug efficacy. Platinum-based chemotherapy is first-line treatment for lung cancer chemotherapy. In this study, we aimed to investigate the association of well-characterized lung cancer lncRNA genetic polymorphisms with the lung cancer susceptibility and platinum-based chemotherapy response. A total of 498 lung cancer patients and 213 healthy controls were recruited in the study. Among them, 467 patients received at least two cycles of platinum-based chemotherapy. Thirteen polymorphisms in HOXA distal transcript antisense RNA (HOTTIP), HOX transcript antisense intergenic RNA (HOTAIR), H19, CDKN2B antisense RNA 1 (ANRIL), colon cancer-associated transcript 2 (CCAT2), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and maternally expressed gene 3 (MEG3) genes were genotyped by allele-specific MALDI-TOF mass spectrometry. We found that patients with HOTTIP rs5883064 C allele or rs1859168 A allele had increased lung cancer risk (P = 0.01, P = 0.01, respectively). CCAT2 rs6983267 (P = 0.02, adenocarcinoma) and H19 rs2107425 (P = 0.02, age under 50 years) showed strong relationship with lung cancer susceptibility. CCAT2 rs6983267, H19 rs2839698, MALAT1 rs619586, and HOTAIR rs7958904 were associated with platinum-based chemotherapy response in dominant model ((P = 0.02, P = 0.04, P = 0.04, P = 0.01, respectively). ANRIL rs10120688 (P = 0.02, adenocarcinoma) and rs1333049 (P = 0.04, small-cell lung cancer), H19 rs2107425 (P = 0.02, small-cell lung cancer) and HOTAIR rs1899663 (P = 0.03, male; P = 0.03, smoker) were associated with response to platinum-based chemotherapy. HOTTIP, CCAT2, H19, HOTAIR, MALATI, ANRIL genetic polymorphisms were significantly associated with lung cancer susceptibility or platinum-based chemotherapy response. They may be potential clinical biomarkers to predict lung cancer risk and platinum-based chemotherapy response.

Cui J, Mo J, Luo M, et al.
c-Myc-activated long non-coding RNA H19 downregulates miR-107 and promotes cell cycle progression of non-small cell lung cancer.
Int J Clin Exp Pathol. 2015; 8(10):12400-9 [PubMed] Free Access to Full Article Related Publications
To verify c-Myc can regulate the expression of lncRNA H19 directly in non-small cell lung cancer (NSCLC) and clarify the molecular mechanism on how lncRNA H19 promote the cell cycle progression of NSCLC. The mRNA levels of lncRNA H19 in NSCLC tissues and cells, the adjacent tissues and normal cells were determined by RT-PCR. The expression change of lncRNA H19 in NSCLC cells after transfection with pcDNA3.1-c-Myc or c-Myc-siRNA was determined by RT-PCR, respectively. Targeted role of c-Myc on the promoter of H19 was studied by luciferase reporter assay. Chromosome immune coprecipitation (ChIP) was used to confirm the relationship between c-Myc and H19. MiRNAs that have base-pairing with H19 was predicted by online software. The relationship between H19 and miR-107 was determined by disturbing and overexpressing the expression of H19. The influence of the changes of H19 and miR-107 on cell cycle progression was determined by flow cytometry. The mRNA levels of lncRNA H19 in NSCLC tissues and cells were significantly higher than the adjacent tissues and normal cells, respectively. The expression of H19 increased or decreased accordingly with the overexpression and knockdown of c-Myc. The activity of the promoter of H19 was strengthened by c-Myc. While the expression of miR-107 increased or decreased with the overexpression and knockdown of H19, respectively. The number of cells in G2/M stage decreased significantly with the knockdown of H19 and miR-107 compared with the control group. Our study demonstrates that lncRNA H19, which is induced by c-Myc, is up-regulated in NSCLC. H19 influences the mitotic progression of NSCLC cell lines.

Han L, Ma P, Liu SM, Zhou X
Circulating long noncoding RNA GAS5 as a potential biomarker in breast cancer for assessing the surgical effects.
Tumour Biol. 2016; 37(5):6847-54 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) play a vital role in tumorigenesis. Until now, the value of circulating lncRNAs in the diagnosis of breast cancer (BC) has remained unknown. Here, we have explored the clinical significance of lncRNAs GAS5 and H19 in BC patients. Total RNA in the plasma was extracted from 90 preoperative BC patients, 39 postoperative BC patients, and 76 healthy controls. The expression levels were measured by quantitative real-time PCR. The potential associations between GAS5, H19 levels, and patients' clinical characteristics were analyzed. No significant differences were found between the BC patients and the healthy controls in the expression levels of GAS5 (P = 0.441) and H19 (P = 0.554), normalized by GAPDH. Plasma GAS5 exhibited correlations with the Ki67 proliferation index in 90 preoperative BC patients (P = 0.012). Compared with paired preoperative plasma, the postoperative levels of GAS5 and H19 significantly decreased in 71.8 % of BC patients (28/39) and 82.1 % of BC patients (32/39), respectively. Analysis in the 39 paired preoperative and postoperative plasma samples showed that lower GAS5 levels appeared in the patients with a high Ki67 proliferation index before surgery (P = 0.012) and the patients with a positive lymph node metastasis state after surgery (P = 0.029). Plasma lncRNA GAS5 may have the potential to assess the surgical effects and prognosis for BC patients.

Valent P
Diagnosis and management of mastocytosis: an emerging challenge in applied hematology.
Hematology Am Soc Hematol Educ Program. 2015; 2015:98-105 [PubMed] Related Publications
Mastocytosis is a unique and rare neoplasm defined by abnormal expansion and accumulation of clonal mast cells (MCs) in one or multiple organ systems. Most adult patients are diagnosed to have systemic mastocytosis (SM). Based on histological findings and disease-related organ damage, SM is classified into indolent SM (ISM), smoldering SM (SSM), SM with an associated hematologic non-MC-lineage disease (SM-AHNMD), aggressive SM (ASM), and MC leukemia (MCL). The clinical picture, course, and prognosis vary profoundly among these patients. Nonetheless, independent of the category of SM, neoplastic cells usually exhibit the KIT point-mutation D816V. However, in advanced SM, additional molecular defects are often detected and are considered to contribute to disease progression and drug resistance. These lesions include, among others, somatic mutations in TET2, SRSF2, ASXL1, CBL, RUNX1, and RAS. In SM-AHNMD, such mutations are often found in the "AHNMD component" of the disease. Clinical symptoms in mastocytosis result from (1) the release of proinflammatory and vasoactive mediators from MCs, and (2) SM-induced organ damage. Therapy of SM has to be adjusted to the individual patient and the SM category: in those with ISM and SSM, the goal is to control mediator secretion and/or mediator effects, to keep concomitant allergies under control, and to counteract osteoporosis, whereas in advanced SM (ASM, MCL, and SM-AHNMD) anti-neoplastic drugs are prescribed to suppress MC expansion and/or to keep AHNMD cells under control. Novel drugs directed against mutated KIT and/or other oncogenic kinase targets are tested currently in these patients. In rapidly progressing and drug-resistant cases, high-dose polychemotherapy and stem cell transplantation have to be considered.

Matouk IJ, Halle D, Raveh E, et al.
The role of the oncofetal H19 lncRNA in tumor metastasis: orchestrating the EMT-MET decision.
Oncotarget. 2016; 7(4):3748-65 [PubMed] Free Access to Full Article Related Publications
Long non-coding RNA (lncRNA) genes are emerging as key players in the metastatic cascade. Current evidence indicate that H19 lncRNA and the microRNA(miRNA) miR-675, which is processed from it, play crucial roles in metastasis, through the regulation of critical events specifically the epithelial to mesenchymal (EMT) and the mesenchymal to epithelial transitions (MET). This review summarizes recent mechanistic pathways and tries to put together seemingly conflicting data from different reports under one proposed general scheme underlying the various roles of H19/miR-675 in the metastatic cascade. We propose several approaches to harnessing this knowledge for translational medicine.

Zhu Z, Song L, He J, et al.
Ectopic expressed long non-coding RNA H19 contributes to malignant cell behavior of ovarian cancer.
Int J Clin Exp Pathol. 2015; 8(9):10082-91 [PubMed] Free Access to Full Article Related Publications
Recent studies have highlighted the role of long non-coding RNAs (lncRNAs) in carcinogenesis and have suggested that genes of this class might be used as biomarkers in cancer. However, whether lncRNAs are involved in ovarian cancer (OC) remains largely unknown. In the present study, we focused on lncRNAH19 and investigated the expression and functional role of H19 in OC. H19 expression was measured in 70 pairs of ovarian cancer tissue samples compared with normal controls by real-time quantitative RT-PCR. The effects of H19 on ovarian cancer cells were studied by RNA interference approach. Apoptosis and cell cycle were analyzed by flow cytometry. Cells viability was evaluated using cell counting Kit-8. Our results demonstrated that that H19 silencing inhibited OV90 and SKOV3 OC cell proliferation in vitro. Further investigation into the mechanisms responsible for the growth inhibitory effects by H19 silencing revealed that its knockdown resulted in the induction of cell cycle arrest and apoptosis through certain cell cycle-related and apoptosis-related proteins. Together, our data suggest that LncRNAH19 plays an important role in OC cell proliferation and contributes to a better understanding of the importance of dysregulated lncRNAs in OC progression.

Guo LL, Song CH, Wang P, et al.
Competing endogenous RNA networks and gastric cancer.
World J Gastroenterol. 2015; 21(41):11680-7 [PubMed] Free Access to Full Article Related Publications
Recent studies have showed that RNAs regulate each other with microRNA (miRNA) response elements (MREs) and this mechanism is known as "competing endogenous RNA (ceRNA)" hypothesis. Long non-coding RNAs (lncRNAs) are supposed to play important roles in cancer. Compelling evidence suggests that lncRNAs can interact with miRNAs and regulate the expression of miRNAs as ceRNAs. Several lncRNAs such as H19, HOTAIR and MEG3 have been found to be associated with miRNAs in gastric cancer (GC), generating regulatory crosstalk across the transcriptome. These MRE sharing elements implicated in the ceRNA networks (ceRNETs) are able to regulate mRNA expression. The ceRNA regulatory networks including mRNAs, miRNAs, lncRNAs and circular RNAs may play critical roles in tumorigenesis, and the perturbations of ceRNETs may contribute to the pathogenesis of GC.

Smolle MA, Bullock MD, Ling H, et al.
Long Non-Coding RNAs in Endometrial Carcinoma.
Int J Mol Sci. 2015; 16(11):26463-72 [PubMed] Free Access to Full Article Related Publications
Endometrial carcinoma (EC), the second most common form of gynaecological malignancy, can be divided into two distinct sub-types: Type I tumours arise from hyperplastic endometrium and typically effect women around the time of menopause, whereas type II tumours arise in postmenopausal women from atrophic endometrium. Long non-coding RNAs (lncRNAs) are a novel class of non-protein coding molecules that have recently been implicated in the pathogenesis of many types of cancer including gynaecological tumours. Although they play critical physiological roles in cellular metabolism, their expression and function are deregulated in EC compared with paired normal tissue, indicating that they may also participate in tumour initiation and progression. For instance, the lncRNA MALAT-1 is down-regulated in EC samples compared to normal or hyperplastic endometrium, whereas the lncRNA OVAL is down-regulated in type II disease but up-regulated in type I disease. Other notatble lncRNAs such as HOTAIR, H19 and SRA become up-regulated with increasing EC tumour grade and other features associated with poor prognosis. In the current review, we will examine the growing body of evidence linking deregulated lncRNAs with specific biological functions of tumour cells in EC, we will highlight associations between lncRNAs and the molecular pathways implicated in EC tumourigenesis and we will identify critical knowledge gaps that remain to be addressed.

Pu H, Zheng Q, Li H, et al.
CUDR promotes liver cancer stem cell growth through upregulating TERT and C-Myc.
Oncotarget. 2015; 6(38):40775-98 [PubMed] Free Access to Full Article Related Publications
Cancer up-regulated drug resistant (CUDR) is a novel non-coding RNA gene. Herein, we demonstrate excessive CUDR cooperates with excessive CyclinD1 or PTEN depletion to accelerate liver cancer stem cells growth and liver stem cell malignant transformation in vitro and in vivo. Mechanistically, we reveal the decrease of PTEN in cells may lead to increase binding capacity of CUDR to CyclinD1. Therefore, CUDR-CyclinD1 complex loads onto the long noncoding RNA H19 promoter region that may lead to reduce the DNA methylation on H19 promoter region and then to enhance the H19 expression. Strikingly, the overexpression of H19 increases the binding of TERT to TERC and reduces the interplay between TERT with TERRA, thus enhancing the cell telomerase activity and extending the telomere length. On the other hand, insulator CTCF recruits the CUDR-CyclinD1 complx to form the composite CUDR-CyclinD1-insulator CTCF complex which occupancied on the C-myc gene promoter region, increasing the outcome of oncogene C-myc. Ultimately, excessive TERT and C-myc lead to liver cancer stem cell and hepatocyte-like stem cell malignant proliferation. To understand the novel functions of long noncoding RNA CUDR will help in the development of new liver cancer therapeutic and diagnostic approaches.

Schultz B, Yao X, Deng Y, et al.
A Common Polymorphism within the IGF2 Imprinting Control Region Is Associated with Parent of Origin Specific Effects in Infantile Hemangiomas.
PLoS One. 2015; 10(10):e0113168 [PubMed] Free Access to Full Article Related Publications
Infantile hemangioma (IH) is the most common tumor of the pediatric age group, affecting up to 4% of newborns ranging from inconsequential blemishes, to highly aggressive tumors. Following well defined growth phases (proliferative, plateau involutional) IH usually regress into a fibro-fatty residuum. Despite the high prevalence of IH, little is known regarding the pathogenesis of disease. A reported six fold decrease in IGF2 expression (correlating with transformation of proliferative to involuted lesions) prompted us to study the IGF-2 axis further. We demonstrate that IGF2 expression in IH is strongly related to the expression of a cancer testes and suspected oncogene BORIS (paralog of CTCF), placing IH in the unique category of being the first known benign BORIS positive tumor. IGF2 expression was strongly and positively related to BORIS transcript expression. Furthermore, a stronger association was made when comparing BORIS levels against the expression of CTCF via either a percentage or difference between the two. A common C/T polymorphism at CTCF BS6 appeared to modify the correlation between CTCF/BORIS and IGF2 expression in a parent of origin specific manner. Moreover, these effects may have phenotypic consequences as tumor growth also correlates with the genotype at CTCF BS6. This may provide a framework for explaining the clinical variability seen in IH and suggests new insights regarding CTCF and BORIS related functionality in both normal and malignant states.

Dasgupta S, Dutta J, Annamaneni S, et al.
Association of vitamin D receptor gene polymorphisms with polycystic ovary syndrome among Indian women.
Indian J Med Res. 2015; 142(3):276-85 [PubMed] Free Access to Full Article Related Publications
BACKGROUND & OBJECTIVES: The Vitamin-D receptor (VDR) regulates vitamin D levels and calcium metabolism in the body and these are known to be associated with endocrine dysfunctions, insulin resistance and type-2 diabetes in polycystic ovarian syndrome (PCOS). Studies on VDR polymorphisms among PCOS women are sparse. We undertook this study to investigate the association pattern of VDR polymorphisms (Cdx2, Fok1, Apa1 and Taq1) with PCOS among Indian women.
METHODS: For the present study, 250 women with PCOS and 250 normal healthy control women were selected from Hyderabad city, Telangana, India. The four VDR polymorphisms were genotyped and analysed using ASM-PCR (allele specific multiple PCR) and PCR-RFLP (restriction fragment length polymorphism).
RESULTS: The genotype and allele frequency distributions of only Cdx2 showed significant difference between the PCOS cases and control women, indicating protective role of this SNP against PCOS phenotype. However, significant association was observed between VDR genotypes and some of the PCOS specific clinical/biochemical traits. For example, Fok1 showed a significant genotypic difference for the presence of infertility and Cdx2 genotpes showed association with testosterone levels. Further, the two haplotypes, ACCA and ACTA, were found to be significantly associated with PCOS indicating haplotype specific risk.
INTERPRETATION & CONCLUSIONS: Although VDR polymorphisms have not shown significant association with PCOS, in view of functional significance of the SNPs considered, one cannot yet rule out the possibility of their association with PCOS. Further, specifically designed studies on large cohorts are required to conclusively establish the role of VDR polymorphisms in PCOS, particularly including data on vitamin D levels.

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