Gene Summary

Gene:H19; H19 imprinted maternally expressed transcript
Aliases: ASM, BWS, WT2, ASM1, D11S813E, MIR675HG, LINC00008, NCRNA00008
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: 31 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 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 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

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)

Li Z, Tan H, Zhao W, et al.
Integrative analysis of DNA methylation and gene expression profiles identifies MIR4435-2HG as an oncogenic lncRNA for glioma progression.
Gene. 2019; 715:144012 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) have been shown to play an important role in tumor biogenesis and prognosis. The glioma is a grade classified cancer, however, we still lack the knowledge on their function during glioma progression. While previous studies have shown how lncRNAs regulate protein-coding gene epigenetically, it is still unclear how lncRNAs are regulated epigenetically. In this study, we firstly analyzed the RNA-seq data systematically across grades II, IV, and IV of glioma samples. We identified 60 lncRNAs that are significantly differentially expressed over disease progression (DElncRNA), including well-known PVT1, HOTAIR, H19 and rarely studied CARD8-AS, MIR4435-2HG. Secondly, by integrating HM450K methylation microarray data, we demonstrated that some of the lncRNAs are epigenetically regulated by methylation. Thirdly, we developed a DESeq2-GSEA-ceRNA-survival analysis strategy to investigate their functions. Particularly, MIR4435-2HG is highly expressed in high-grade glioma and may have an impact on EMT and TNFα signaling pathway by functioning as a miRNA sponge of miR-125a-5p and miR-125b-5p to increase the expression of CD44. Our results revealed the dynamic expression of lncRNAs in glioma progression and their epigenetic regulation mechanism.

Zhang H, Yu Y, Zhang K, et al.
Targeted inhibition of long non-coding RNA H19 blocks anaplastic thyroid carcinoma growth and metastasis.
Bioengineered. 2019; 10(1):306-315 [PubMed] Article available free on PMC after 19/07/2020 Related Publications
Long non-coding RNA H19 (H19) is highly expressed in cancers and is considered to highly correlate with the extent of malignant degree. The present study was performed to determine the expression levels of H19 in anaplastic thyroid carcinoma (ATC) tissues and the role of H19 in ATC 8505C cells

Gan L, Lv L, Liao S
Long non‑coding RNA H19 regulates cell growth and metastasis via the miR‑22‑3p/Snail1 axis in gastric cancer.
Int J Oncol. 2019; 54(6):2157-2168 [PubMed] Related Publications
Gastric cancer (GC) is the fifth most prevalent type of malignancy and the third leading cause of cancer‑related mortality worldwide, with the prognosis of patients with late‑stage GC remaining at poor levels. Long non‑coding RNA (lncRNA) H19 (H19) is involved in the growth and metastasis of tumors, and it is upregulated under hypoxic conditions and in certain types of cancer; however, the underlying mechanisms of action of this lncRNA as regards the initiation and development of GC remain unknown. Thus, in the present study, we aimed to determine the role of lncRNA H19 in GC and to elucidate the underlying mechanisms. H19 was found to be upregulated in GC tissues and cells compared with the para‑cancerous tissues, and an elevated expression of H19 was associated with lymph node metastasis and TNM stage. Furthermore, the downregulation of H19 suppressed the proliferation, invasion, migration and epithelial‑mesenchymal transition of GC cells in vitro and suppressed tumor growth in vivo. H19 was also found to be able to bind with miR‑22‑3p, and H19‑induced cell growth and metastasis were shown to be reversed by the upregulation of miR‑22‑3p; the miR‑22‑3p level was found to inversely correlate with H19 expression in GC tissues. Furthermore, the overexpression of miR‑22‑3p notably suppressed the proliferation, migration and invasion of GC cells, and these effects were enhanced by the downregulation of Snail1. In addition, cell growth and metastasis induced by miR‑22‑3p downregulation were partially reversed by the knockdown of Snail1. Furthermore, a negative correlation was observed between the mRNA expression levels of miR‑22‑3p and Snail1 in GC tissues. On the whole, the findings of the present study revealed that H19 was upregulated in GC tissues, which promoted tumor growth and metastasis via the miR‑22‑3p/Snail1 signaling pathway. In summary, these findings provide novel insight into the potential regulatory roles of H19 in GC, and suggest that the H19/miR‑22‑3p/Snail1 axis may prove to be a promising therapeutic target for the treatment of patients with GC.

Safari MR, Mohammad Rezaei F, Dehghan A, et al.
Genomic variants within the long non-coding RNA H19 confer risk of breast cancer in Iranian population.
Gene. 2019; 701:121-124 [PubMed] Related Publications
OBJECTIVE: The long non-coding RNA (lncRNA) H19 is an imprinted lncRNA with acknowledged roles in carcinogenesis.
METHODS: In the current study, we genotyped two single nucleotide polymorphisms (SNPs) within H19 in 111 breast cancer patients and 130 age-matched healthy subjects using tetra primer-ARMS-PCR technique. The T allele of rs2839698 conferred breast cancer risk in the assessed population (OR (95% CI) = 2.52 (1.75-3.64), adjusted P value = 1.3E-6), while and the T allele of rs217727 had a protective effect (OR (95% CI) = 0.42 (0.27-0.66), adjusted P value = 2.8E-4). Both SNPs were associated with breast cancer risk in recessive, dominant and co-dominant models. The T C haplotype (rs2839698 and rs217727) significantly increased risk of breast cancer (OR (95% CI) = 2.4 (1.65-3.45), adjusted P value = 1.2E-5), while the C T haplotype had a protective role (OR (95% CI) = 0.31 (0.18-0.52), adjusted P value = 2.03E-5). The present study highlights the role of H19 SNPs in conferring risk of breast cancer in Iranian population. Future studies with larger sample sizes are required to verify these data.

Mishra S, Verma SS, Rai V, et al.
Long non-coding RNAs are emerging targets of phytochemicals for cancer and other chronic diseases.
Cell Mol Life Sci. 2019; 76(10):1947-1966 [PubMed] Related Publications
The long non-coding RNAs (lncRNAs) are the crucial regulators of human chronic diseases. Therefore, approaches such as antisense oligonucleotides, RNAi technology, and small molecule inhibitors have been used for the therapeutic targeting of lncRNAs. During the last decade, phytochemicals and nutraceuticals have been explored for their potential against lncRNAs. The common lncRNAs known to be modulated by phytochemicals include ROR, PVT1, HOTAIR, MALAT1, H19, MEG3, PCAT29, PANDAR, NEAT1, and GAS5. The phytochemicals such as curcumin, resveratrol, sulforaphane, berberine, EGCG, and gambogic acid have been examined against lncRNAs. In some cases, formulation of phytochemicals has also been used. The disease models where phytochemicals have been demonstrated to modulate lncRNAs expression include cancer, rheumatoid arthritis, osteoarthritis, and nonalcoholic fatty liver disease. The regulation of lncRNAs by phytochemicals can affect multi-steps of tumor development. When administered in combination with the conventional drugs, phytochemicals can also produce synergistic effects on lncRNAs leading to the sensitization of cancer cells. Phytochemicals target lncRNAs either directly or indirectly by affecting a wide variety of upstream molecules. However, the potential of phytochemicals against lncRNAs has been demonstrated mostly by preclinical studies in cancer models. How the modulation of lncRNAs by phytochemicals produce therapeutic effects on cancer and other chronic diseases is discussed in this review.

Mahmoudian-Sani MR, Jalali A, Jamshidi M, et al.
Long Non-Coding RNAs in Thyroid Cancer: Implications for Pathogenesis, Diagnosis, and Therapy.
Oncol Res Treat. 2019; 42(3):136-142 [PubMed] Related Publications
Thyroid cancer is a rare malignancy and accounts for less than 1% of malignant neoplasms in humans; however, it is the most common cancer of the endocrine system and responsible for most deaths from endocrine cancer. Long non-coding (Lnc)RNAs are defined as non-coding transcripts that are more than 200 nucleotides in length. Their expression deregulation plays an important role in the progress of cancer. These molecules are involved in physiologic cellular processes, genomic imprinting, inactivation of chromosome X, maintenance of pluripotency, and the formation of different organs via changes in chromatin, transcription, and translation. LncRNAs can act as a tumor suppressor genes or oncogenes. Several studies have shown that these molecules can interact with microRNAs and prevent their binding to messenger RNAs. Research has shown that these molecules play an important role in tumorigenicity, angiogenesis, proliferation, migration, apoptosis, and differentiation. In thyroid cancer, several lncRNAs (MALAT1, H19, BANCR, HOTAIR) have been identified as contributing factors to cancer development, and can be used as novel biomarkers for early diagnosis or even treatment. In this article, we study the newest lncRNAs and their role in thyroid cancer.

Corrado C, Costa V, Giavaresi G, et al.
Long Non Coding RNA H19: A New Player in Hypoxia-Induced Multiple Myeloma Cell Dissemination.
Int J Mol Sci. 2019; 20(4) [PubMed] Article available free on PMC after 19/07/2020 Related Publications
The long non-coding RNA H19 (lncH19) is broadly transcribed in the first stage of development and silenced in most cells of an adult organism; it appears again in several tumors where, through different molecular mediators, promotes cell proliferation, motility and metastases. LncH19 has been associated with hypoxia-inducible factor 1-alpha (HIF-1α) activation and, in some tumors, it has proved to be necessary and required to sustain hypoxic responses. Here we propose to investigate a putative role for the lncH19 in hypoxia induced multiple myeloma (MM) progression. Transcriptional analysis of MM cell lines (RPMI and MM1.S) exposed to normoxia or hypoxia (1% O₂) was done in order to evaluate lncH19 levels under hypoxic stimulation. Then, to investigate the role of lncH19 in hypoxia mediated MM progression, transcriptional, protein and functional assays have been performed on hypoxia stimulated MM cell lines, silenced or not for lncH19. Our data demonstrated that hypoxic stimulation in MM cell lines induced the overexpression of lncH19, which, in turn, is required for the expression of the hypoxia induced genes involved in MM dissemination, such as C-X-C Motif Chemokine Receptor 4 (CXCR4) and Snail. Moreover, adhesion assays demonstrated that lncH19 silencing abrogates the increased adhesion on stromal cells induced by the hypoxic condition. Finally, Western blot analysis indicated that lncH19 silencing impaired HIF1α nuclear translocation. The LncH19, required for the induction of hypoxic responses in MM cells, could represent a new therapeutic target for MM.

Liu L, Liu L, Lu S
lncRNA H19 promotes viability and epithelial-mesenchymal transition of lung adenocarcinoma cells by targeting miR-29b-3p and modifying STAT3.
Int J Oncol. 2019; 54(3):929-941 [PubMed] Article available free on PMC after 19/07/2020 Related Publications
Considering the joint contribution of long non‑coding RNAs (lncRNAs) and microRNAs (miRNAs/miRs) to tumorigenesis, the aim of the present study was to investigate whether and how lncRNA H19 targets miR‑29b‑3p to affect the progression of lung adenocarcinoma by the modulation of signal transducer and activator of transcription 3 (STAT3). A total of 305 lung adenocarcinoma tissues and four human lung adenocarcinoma cell lines (i.e. Calu‑3, NCI‑H1975, A549 and NCI‑H23) were used. pcDNA3.1‑H19, short interfering RNA (si‑)H19, miR‑29b‑3p mimic, miR‑29b‑3p inhibitor and negative control (NC) were transfected into the cells, and the proliferation, viability and apoptosis of the cells were determined using a Cell Counting Kit‑8 assay, colony formation assay and flow cytometry, respectively. The results indicated that highly expressed H19 and poorly expressed miR‑29b‑3p could serve as predictors for the poor prognosis of lung adenocarcinoma patients. Additionally, si‑H19 and miR‑29b‑3p mimic significantly increased the apoptosis of lung adenocarcinoma cells, and decreased the survival rate and viability of cells. Simultaneously, expression of epithelial‑mesenchymal transition (EMT)‑specific proteins was significantly altered, i.e. increased epithelial cadherin expression, as well as decreased vimentin, Snail and Slug expression. Furthermore, miR‑29b‑3p was verified to be targeted and regulated by H19, and STAT3 was targeted and modified by miR‑29b‑3p. Ultimately, STAT3 was identified to decrease lung adenocarcinoma cell viability, survival, apoptosis and EMT imposed by miR‑29b‑3p. In conclusion, the results of the present study indicated that lncRNA H19/miR‑29b‑3p/STAT3 signaling was involved in the development of lung adenocarcinoma, which may be critical for developing effective diagnostic and treatment strategies for lung adenocarcinoma.

Wang Y, Wang L, Sui M
Long non-coding RNA H19 promotes proliferation of Hodgkin's lymphoma via AKT pathway.
J BUON. 2018 Nov-Dec; 23(6):1825-1831 [PubMed] Related Publications
PURPOSE: To explore whether lncRNA (Long non-coding RNA) H19 could promote the development of Hodgkin's lymphoma (HL) by regulating cell proliferation via AKT pathway.
METHODS: H19 expressions in 60 HL tissues, 40 RH (reactive hyperplasia of lymph nodes) tissues, L428, A20 and Ly1 cell lines were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). H19 siRNA and pcDNA-H19 were constructed. Cell viability after altering H19 expression was detected by EdU and cell counting kit-8 (CCK-8) assay. The mRNA level of AKT in HL tissues and RH tissues was detected by qRT-PCR. The relationship between AKT and H19 was further detected by Western blot.
RESULTS: H19 was overexpressed in HL tissues and cell lines compared with those of controls. HL patients with huge lump and in Ann Arbor stage III-IV presented higher expression of H19. Besides, H19 expression was negatively correlated to overall survival (OS) of HL patients. In vitro experiments suggested that H19 downregulation decreased proliferation and viability of HL cells. AKT expression was upregulated in HL tissues compared with RH tissues, and was positively regulated by H19. Western blot results also indicated that H19 overexpression upregulated protein expression of AKT in HL cells.
CONCLUSIONS: Overexpressed lncRNA H19 promotes HL development by stimulating proliferation of HL cells via AKT pathway.

Gyvyte U, Kupcinskas J, Juzenas S, et al.
Identification of long intergenic non-coding RNAs (lincRNAs) deregulated in gastrointestinal stromal tumors (GISTs).
PLoS One. 2018; 13(12):e0209342 [PubMed] Article available free on PMC after 19/07/2020 Related Publications
Long intergenic non-coding RNAs (lincRNAs) are >200 nucleotides long non-coding RNAs, which have been shown to be implicated in carcinogenic processes by interacting with cancer associated genes or other non-coding RNAs. However, their role in development of rare gastrointestinal stromal tumors (GISTs) is barely investigated. Therefore, the aim of this study was to define lincRNAs deregulated in GIST and find new GIST-lincRNA associations. Next-generation sequencing data of paired GIST and adjacent tissue samples from 15 patients were subjected to a web-based lincRNA analysis. Three deregulated lincRNAs (MALAT1, H19 and FENDRR; adjusted p-value < 0.05) were selected for expression validation in a larger group of patients (n = 22) by RT-qPCR method. However, only H19 and FENDRR showed significant upregulation in the validation cohort (adjusted p < 0.05). Further, we performed correlation analyses between expression levels of deregulated lincRNAs and GIST-associated oncogenes or GIST deregulated microRNAs. We found high positive correlations between expression of H19 and known GIST related oncogene ETV1, and between H19 and miR-455-3p. These findings expand the knowledge on lincRNAs deregulated in GIST and may be an important resource for the future studies investigating lincRNAs functionally relevant to GIST carcinogenesis.

Qi D, Wang M, Yu F
Knockdown of lncRNA-H19 inhibits cell viability, migration and invasion while promotes apoptosis via microRNA-143/RUNX2 axis in retinoblastoma.
Biomed Pharmacother. 2019; 109:798-805 [PubMed] Related Publications
BACKGROUND: Even though the role of long non-coding RNA H19 (lncRNA-H19) in diverse cancer types has been studied, exact effect of lncRNA-H19 as well as the underlying mechanism in retinoblastoma (RB) is poorly reported. We aimed to explore the possible functions of lncRNA-H19 in human RB Y79 cells.
METHODS: LncRNA-H19 in Y79 cells was silenced, and effects of lncRNA-H19 silence on cell viability, migration and invasion, and apoptosis were analyzed by using trypan blue exclusion, Transwell assay, and flow cytometry assay/Western blot analysis, respectively. Then, miR-143 expression in cells with lncRNA-H19 silence was determined by RT-qPCR, and effects of miR-143 inhibition on lncRNA-H19-suppressing cells were assessed. Whether RUNX2 was a target of miR-143 and the involved signaling pathways in the modulation of miR-143 were also studied.
RESULTS: LncRNA-H19 knockdown repressed cell viability, migration and invasion while promoted apoptosis in Y79 cells. miR-143 was a downstream factor of lncRNA-H19, and its inhibition reversed the effects of lncRNA-H19 silence on Y79 cells. RUNX2 was a target gene of miR-143, and miR-143 was found to affect Y79 cells via down-regulation of RUNX2. Phosphorylation of key kinases related in the PI3K/AKT/mTOR pathways was reduced by miR-143 via regulation of RUNX2.
CONCLUSION: Knockdown of lncRNA-H19 acted a tumor suppressive role in Y79 cells through up-regulating miR-143. Moreover, miR-143 exerted tumor suppressive effects on Y79 cells by targeting RUNX2, along with inhibition of the PI3K/AKT/mTOR pathways.

Lei Y, Guo W, Chen B, et al.
Tumor‑released lncRNA H19 promotes gefitinib resistance via packaging into exosomes in non‑small cell lung cancer.
Oncol Rep. 2018; 40(6):3438-3446 [PubMed] Article available free on PMC after 19/07/2020 Related Publications
Currently, resistance to tyrosine kinase inhibitors, such as gefitinib, has become one major obstacle for improving the clinical outcome of patients with metastatic and advanced‑stage non‑small cell lung cancer (NSCLC). While cell behavior can be modulated by long non‑coding RNAs (lncRNAs), the contributions of lncRNAs within extracellular vesicles (exosomes) are largely unknown. To this end, the involvement and regulatory functions of lncRNA H19 wrapped by exosomes during formation of gefitinib resistance in human NSCLC were investigated. Gefitinib‑resistant cell lines were built by continuously grafting HCC827 and HCC4006 cells into gefitinib‑contained culture medium. RT‑qPCR assays indicated that H19 was increased in gefitinib‑resistant cells when compared to sensitive parent cells. Functional experiments revealed that silencing of H19 potently promoted gefitinib‑induced cell cytotoxicity. H19 was secreted by packaging into exosomes and this packaging process was specifically mediated by hnRNPA2B1. H19 wrapped in exosomes could be transferred to non‑resistant cells, thus inducing gefitinib resistance. Moreover, treatment‑sensitive cells with exosomes highly‑expressing H19 induced gefitinib resistance, while knockdown of H19 abrogated this effect. In conclusion, H19 promoted gefitinib resistance of NSCLC cells by packaging into exosomes. Therefore, exosomal H19 may be a promising therapeutic target for EGFR+ NSCLC patients.

Hidaka H, Higashimoto K, Aoki S, et al.
Comprehensive methylation analysis of imprinting-associated differentially methylated regions in colorectal cancer.
Clin Epigenetics. 2018; 10(1):150 [PubMed] Article available free on PMC after 19/07/2020 Related Publications
BACKGROUND: Imprinted genes are regulated by DNA methylation at imprinting-associated differentially methylated regions (iDMRs). Abnormal expression of imprinted genes is implicated in imprinting disorders and tumors. In colorectal cancer (CRC), methylation and imprinting status of the IGF2/H19 domain have been studied. However, no comprehensive methylation analysis of iDMRs in CRC has been reported. Furthermore, the relationship between iDMR methylation status and other methylation-related issues, such as CpG island methylator phenotype (CIMP) and long interspersed element-1 (LINE-1) methylation, remains unclear.
RESULTS: We analyzed the methylation status of 38 iDMRs in 106 CRC patients. We also investigated CIMP, LINE-1 methylation, KRAS and BRAF gene mutations, and loss of imprinting (LOI) of IGF2. We further examined the relationship between these factors and clinicopathological factors. The overall trend in iDMR methylation was towards hypermethylation, and iDMRs could be grouped into three categories: susceptible, resistant, and intermediate-to-aberrant methylation. The susceptible and resistant iDMRs consisted of all types of iDMR (gametic and somatic, maternally and paternally methylated). Hypermethylation of multiple iDMRs (HyMiD)-positive status was statistically associated with CIMP-positive status, but not associated with mutations in the BRAF and KRAS genes. HyMiD-positive status was inversely associated with LINE-1 methylation. Among four iDMRs within the IGF2/H19 domain, IGF2-DMR0 hypomethylation occurred most frequently, but was not associated with IGF2 LOI. Finally, we statistically calculated predictive prognostic scores based on aberrant methylation status of three iDMRs.
CONCLUSION: In CRC tissues, some iDMRs were susceptible to hypermethylation independent of the type of iDMR and genomic sequence. Although HyMiD-positive status was associated with CIMP-positive status, this was independent of the BRAF and KRAS pathways, which are responsible for CIMP. Since IGF2-DMR0 hypomethylation and aberrant methylation of other iDMRs within the IGF2/H19 domain were not associated with IGF2 LOI, dysfunction of any of the molecular components related to imprinting regulation may be involved in IGF2 LOI. The prognostic score calculated based on aberrant methylation of three iDMRs has potential clinical applications as a prognostic predictor in patients. Further study is required to understand the biological significance of, and mechanisms behind, aberrant methylation of iDMRs and IGF2 LOI in CRCs.

Basak P, Chatterjee S, Bhat V, et al.
Long Non-Coding RNA H19 Acts as an Estrogen Receptor Modulator that is Required for Endocrine Therapy Resistance in ER+ Breast Cancer Cells.
Cell Physiol Biochem. 2018; 51(4):1518-1532 [PubMed] Related Publications
BACKGROUND/AIMS: Blocking estrogen signaling with endocrine therapies (Tamoxifen or Fulverstrant) is an effective treatment for Estrogen Receptor-α positive (ER+) breast cancer tumours. Unfortunately, development of endocrine therapy resistance (ETR) is a frequent event resulting in disease relapse and decreased overall patient survival. The long noncoding RNA, H19, was previously shown to play a significant role in estrogen-induced proliferation of both normal and malignant ER+ breast epithelial cells. We hypothesized that H19 expression is also important for the proliferation and survival of ETR cells.
METHODS: Here we utilized established ETR cell models; the Tamoxifen (Tam)-resistant LCC2 and the Fulvestrant and Tam cross-resistant LCC9 cells. Gain and loss of H19 function were achieved through lentiviral transduction as well as pharmacological inhibitors of the Notch and c-Met receptor signaling pathways. The effects of altered H19 expression on cell viability and ETR were assessed using three-dimensional (3D) organoid cultures and 2D co-cultures with low passage tumour-associated fbroblasts (TAFs).
RESULTS: Here we report that treating ETR cells with Tam or Fulvestrant increases H19 expression and that it's decreased expression overcomes resistance to Tam and Fulvestrant in these cells. Interestingly, H19 expression is regulated by Notch and HGF signaling in the ETR cells and pharmacological inhibitors of Notch and c-MET signaling together significantly reverse resistance to Tam and Fulvestrant in an H19-dependent manner in these cells. Lastly, we demonstrate that H19 regulates ERα expression at the transcript and protein levels in the ETR cells and that H19 protects ERα against Fulvestrant-mediated downregulation of ERα protein. We also observed that blocking Notch and the c-MET receptor signaling also overcomes Fulvestrant and Tam resistance in 3D organoid cultures by decreasing ERα and H19 expression in the ETR cells.
CONCLUSION: In endocrine therapy resistant breast cancer cells Fulvestrant is ineffective in decreasing ERα levels. Our data suggest that in the ETR cells, H19 expression acts as an ER modulator and that its levels and subsequently ERα levels can be substantially decreased by blocking Notch and c-MET receptor signaling. Consequently, treating ETR cells with these pharmacological inhibitors helps overcome resistance to Fulvestrant and Tamoxifen.

Abdollahzadeh S, Ghorbian S
Association of the study between LncRNA-H19 gene polymorphisms with the risk of breast cancer.
J Clin Lab Anal. 2019; 33(3):e22826 [PubMed] Related Publications
BACKGROUND: The H19 is a maternally expressed imprinted gene transcribing a long noncoding RNA (lncRNA), which has previously been reported to be involved in tumorigenesis and cancer progression. The aim of this study was to evaluate the associations between two lncRNA-H19 (rs3741219 T>C and rs217727 C>T) gene polymorphisms with the risk of breast cancer (BC).
METHODS: In a case-control investigation, we evaluated 150 BC patients and 100 cancer-free subjects in East Azerbaijan Province of Iran. To assess two gene polymorphisms, the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used.
RESULTS: The genotype frequencies of two lncRNA-H19 (rs217727 C>T and rs3741219 T>C) gene polymorphisms TT + TC/CC and CC + CT/TT have not shown a statistically significant association with the risk of BC (P = 0.065; OR = 0.967; 95% CI, 0.938-0.996) and (P = 0.510; OR = 1.583; 95% CI, 0.399-6.726), respectively. In addition, our findings revealed a significant differences in allele frequencies in lncRNA-H19 rs217727 C>T polymorphism between groups (P = 0.033; OR = 1.985; 95% CI, 1.048-3.761).
CONCLUSION: Our findings suggested that rs217727 C>T polymorphism may be involved in the pathogenesis of BC, whereas rs3741219 T>C variation may not be involved in the genetic background of BC in Iranian.

Zheng X, Zhou Y, Chen W, et al.
Ginsenoside 20(S)-Rg3 Prevents PKM2-Targeting miR-324-5p from H19 Sponging to Antagonize the Warburg Effect in Ovarian Cancer Cells.
Cell Physiol Biochem. 2018; 51(3):1340-1353 [PubMed] Related Publications
BACKGROUND/AIMS: The Warburg effect is one of the main metabolic features for cancers, with long non-coding RNA (lncRNA) being involved as a class of crucial regulators. Our previous studies have shown that ginsenoside 20(S)-Rg3, an active saponin monomer extracted from red ginseng, inhibits the Warburg effect in ovarian cancer cells. However, the detailed lncRNA regulatory network modulated by 20(S)-Rg3 to prevent the Warburg effect in ovarian cancer cells has not been explored.
METHODS: High-throughput sequencing was used to screen out the differentially expressed lncRNAs between 20(S)-Rg3-treated and non-treated SKOV3 cells. The levels of lncRNA H19 and miR-324-5p were manipulated in SKOV3 and A2780, and the glucose consumption, lactate production and PKM2 protein level were detected. Dual-luciferase reporter assay and RIP were utilized to verify the direct binding of H19 to miR-324-5p and miR-324-5p to PKM2. Cell proliferation was examined by CCK8 and colony formation assay. Nude mice subcutaneous xenograft tumor models were established to evaluate the impact of miR-324-5p on tumor growth in vivo.
RESULTS: 20(S)-Rg3 downregulated 67 lncRNAs, and H19 was one of the most decreased lncRNAs. Suppression of H19 by siRNA transfection reduced glucose consumption, lactate production and PKM2 expression in ovarian cancer cells, while H19 overexpression in 20(S)-Rg3-treated ovarian cancer cells enhanced glucose consumption, lactate production and PKM2 expression. Dual-luciferase reporter assay and RIP results showed that H19 directly bound to miR-324-5p. Dual-luciferase reporter assay showed that miR-324-5p directly targeted PKM2, and miR-324-5p negatively regulated glucose consumption and lactate production in ovarian cancer cells. miR-324-5p overexpression inhibited cell proliferation in vitro and in vivo.
CONCLUSION: Our study revealed that 20(S)-Rg3 blocked the competitive inhibition of H19 on miR-324-5p, which enhanced the suppression of miR-324-5p on PKM2 and therefore inhibited the Warburg effect and repressed tumorigenesis. In a word, 20(S)-Rg3 inhibited the Warburg effect in ovarian cancer cells via H19/miR-324-5p/PKM2 pathway.

Wang F, Liang R, Tandon N, et al.
H19X-encoded miR-424(322)/-503 cluster: emerging roles in cell differentiation, proliferation, plasticity and metabolism.
Cell Mol Life Sci. 2019; 76(5):903-920 [PubMed] Article available free on PMC after 19/07/2020 Related Publications
miR-424(322)/-503 are mammal-specific members of the extended miR-15/107 microRNA family. They form a co-expression network with the imprinted lncRNA H19 in tetrapods. miR-424(322)/-503 regulate fundamental cellular processes including cell cycle, epithelial-to-mesenchymal transition, hypoxia and other stress response. They control tissue differentiation (cardiomyocyte, skeletal muscle, monocyte) and remodeling (mammary gland involution), and paradoxically participate in tumor initiation and progression. Expression of miR-424(322)/-503 is governed by unique mechanisms involving sex hormones. Here, we summarize current literature and provide a primer for future endeavors.

Aalijahan H, Ghorbian S
Long non-coding RNAs and cervical cancer.
Exp Mol Pathol. 2019; 106:7-16 [PubMed] Related Publications
Cervical cancer is determined as the second highest number of deaths factor in female cancers. Here is a need to find new biomarkers for detection and preliminary prognosis, metastasis. To find new treatment to enhance the survival of cervical cancer patients, pivotal actions are necessitated to be implemented. Long non-coding RNAs (lncRNAs) appear to be the crucial modulators in various processes and critically influence the oncogenesis. The commencement and general review actions of the following lncRNAs HOTAIR, H19, XIST, CCHE1, EBIC, MALAT1, ANRIL, LET, NEAT1, BLACAT1, UFC1, SNHG16 and SNHG20 are focused in this review article. Roles of the lncRNAs in cervical cancer in terms of prognosis and tumor progression, invasion and metastasis, apoptosis, and radio-resistance are pointed out. In this review the utilization of lncRNAs as biomarkers in cervical cancer prognosis for metastasis is discussed. An overview of this review will be useful for selection of biomarkers in diagnosis, prognosis, and targeted therapy of cervical cancer in the future.

Ghaedi H, Mozaffari MAN, Salehi Z, et al.
Co-expression profiling of plasma miRNAs and long noncoding RNAs in gastric cancer patients.
Gene. 2019; 687:135-142 [PubMed] Related Publications
PURPOSE: The recent researches indicate that differential non-coding RNAs expression signatures could be associated with the pathogenesis of gastric cancer (GC). However, there are few studies focused on lncRNA-miRNAs co-expression profiling in GC patients. Therefore, in the present study the expression of H19 and MEG3 and their related miRNAs including miR-148a-3p, miR-181a-5p, miR-675-5p and miR-141-3p were determined in the plasma samples of GC patients and controls.
MATERIALS AND METHODS: This case-control study included 62 GC patients and 40 age- sex matched controls. The non-coding RNA levels were assessed by real-time PCR. Further, using in silico analysis, we identified shared targets of studied miRNAs and performed GC-associated pathway enrichment analysis.
RESULTS: Our results showed that the H19 level was significantly (P = 0.008) elevated and MEG3 expression was significantly (P = 0.002) down-regulated in GC patients compared to healthy participants. Furthermore, it was revealed that the miR-675-5p level was increased, while miR-141-3p plasma levels were significantly reduced in GC patients (P < 0.05). We did not observe a significant difference for miR-148a-3p (P = 0.682) and miR-181a-5p (P = 0.098) expression between groups. In addition, the expression levels of H19, MEG3 and miR-148a-3p were associated with some clinicopathological features of patients (P < 0.05). ROC analysis revealed that a combination of H19, MEG3 and miR-675-5p levels able to discriminate controls and GC subjects with 88.87% sensitivity and 85% specificity (AUC, 0.927; 0.85-0.96 CI, P < 0.0001).
CONCLUSION: The results of current study demonstrated that combination of H19, MEG3 and miR-675-5p expression levels could provide a potential diagnostic panel for GC.

Bruno C, Blagoskonov O, Barberet J, et al.
Sperm imprinting integrity in seminoma patients?
Clin Epigenetics. 2018; 10(1):125 [PubMed] Article available free on PMC after 19/07/2020 Related Publications
BACKGROUND: Testicular germ cell tumor such as seminoma is strongly associated with male reproductive problems commonly associated with the alteration of sperm parameters as described in testicular dysgenesis syndrome. Interestingly, numerous studies have reported that the precursor of germ cell cancer, germ cell neoplasia in situ (GCNIS), present similarities to fetal gonocytes, specifically characterized by global DNA hypomethylation particularly on imprinting sequences. These disorders may have a common origin derived from perturbations of embryonal programming during fetal development. Presently, there is no available information concerning the sperm DNA methylation patterns of testicular cancer patients. For the first time, we evaluated the sperm imprinting of seminoma patients. A total of 92 cryopreserved sperm samples were included, 31 before seminoma treatment (S): 23 normozoospermic (SN) and 8 oligozoospermic (SO) and 61 sperm controls samples: 31 normozoospermic (N) and 30 oligozoospermic (O). DNA methylation levels of seven differentially methylated regions (DMRs) of imprinted genes [H19/IGF2: IG-DMR (CTCF3 and CTCF6 of H19 gene); IGF2-DMRs (DMR0 and DMR2); MEG3/DLK1:IG-DMR; SNURF:TSS-DMR; KCNQ1OT1:TSS-DMR] were assessed by pyrosequencing. All comparative analyses were adjusted for age.
RESULTS: Comparisons of sperm DNA methylation levels between seminoma (S) and normozoospermic (N) samples showed a significant difference for the SNURF sequence (p = 0.017), but after taking into account the sperm parameters, no difference was observed. However, we confirmed a significant association between oligozoospermia (O) and imprinting defects for H19/IGF2-CTCF6 (p = 0.001), MEG3/DLK1 (p = 0.017), IGF2-DMR2 (p = 0.022), and SNURF (p = 0.032) in comparison with control groups (N).
CONCLUSIONS: This study highlights the high risk of sperm imprinting defects in cases of oligozoospermia and shows for the first time that seminoma patients with normal spermatogenesis present sperm imprinting integrity. These data suggest a low probability of the involvement of a common imprinting defect in fetal cells leading to both TGCT and subfertility.

Han BW, Ye H, Wei PP, et al.
Global identification and characterization of lncRNAs that control inflammation in malignant cholangiocytes.
BMC Genomics. 2018; 19(1):735 [PubMed] Article available free on PMC after 19/07/2020 Related Publications
BACKGROUND: Long noncoding RNAs (lncRNAs) are known to play important roles in different cell contexts, including cancers. However, little is known about lncRNAs in cholangiocarcinoma (CCA), a cholangiocyte malignancy with poor prognosis, and associated with chronic inflammation and damage to the biliary epithelium. This study determined whether lncRNAs were dysregulated and participated in disease diagnosis or pivotal inflammation pathways through a genome-wide lncRNA screening and functional analysis.
RESULTS: We firstly identified a large number of lncRNAs abnormally expressed between 9 pairs of cancerous and adjacent tissues of CCA, and between intra-hepatic CCA and extra-hepatic CCA through a genome-wide profiling. A set of aberrant differentially expressed lncRNAs were further validated in a training set (16 pairs) and a test set (11 pairs) of CCA patient samples. Following assessment of the diagnostic value of the 7 differentially expressed lncRNAs, we confirmed the optimal combination of H19, C3P1, AC005550.3, PVT1, and LPAL2 with area under the curve of 0.8828 [95% CI: 0.7441-1.021, P < 0.001], with 93.75% sensitivity and 81.25% specificity, at the cutoff point of - 0.2884 to distinguish the CCA tissue from the normal ones, suggesting that specific lncRNAs may have potential for detecting CCA. More importantly, the genome-wide locus and lncRNA/mRNA co-expression analyses revealed a set of lncRNAs that participated in inflammation and oxidative stress response pathways by regulating genes in cis or in trans. Finally, APOC1P1, PVT1, and LPAL2 were validated to regulate the migration and some pivotal inflammation genes under the CCA pathogenesis.
CONCLUSIONS: Our findings are the first to show that lncRNAs may not only be potential biomarkers of CCA progression but also respond to inflammation in CCA.

Li CF, Li YC, Wang Y, Sun LB
The Effect of LncRNA H19/miR-194-5p Axis on the Epithelial-Mesenchymal Transition of Colorectal Adenocarcinoma.
Cell Physiol Biochem. 2018; 50(1):196-213 [PubMed] Related Publications
BACKGROUND/AIMS: Since the combined actions of lncRNAs and miRNAs have been considered to be involved in the occurrence and development of various neoplasms, the main purpose of this study was to discover whether and how lncRNA H19 and miR-194 influenced the epithelial-mesenchymal transition (EMT) process of colorectal adenocarcinoma (CRA).
METHODS: Totally 214 pairs of CRA and adjacent normal tissues were collected, and 5 human CRA cell lines (i.e. HCT116, HT-29, RKO SW280 and Lovo) were purchased. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was adopted to quantify the H19 and miR-194-5p expressions in cells and tissues. The expressions of FoxM1, E-cadherin, vimentin, N-cadherin were determined using western blot. On the side, si-H19, si-NC, miR-194-5p mimic, miR-194-5p inhibitor and negative control (NC) were transfected into CRA cell lines. Meanwhile, the invasive, migratory and proliferative conditions of the cells were assessed through transwell, wound healing and colony-forming experiments, with final verification of the relationship between H19 and miR-194-5p employing dual-luciferase reporter gene assay.
RESULTS: Highly-expressed H19, lowly-expressed miR-194-5p, low-grade differentiation and lymph node metastasis appeared as the independent predictors of unfavorable prognosis in CRA patients' (all P< 0.05). It indicated that FoxM1 expression displayed positive correlations with H19 expression, yet negative associations with miR-194-5p expression within CRA tissues (P< 0.05). In addition, transfection of H19-siRNA and miR-145-5p mimic triggered a conspicuous increase in E-cadherin expression, as well as an evidently down-regulation in vimentin and N-cadherin expressions within HT29 and RKO cells (P< 0.05). On the other hand, the invasive and migratory capacities of CRA cells were significantly hindered (P< 0.05). Moreover, the luciferase reporter gene assay confirmed that H19 modified miR-194-5p expression through directly targeting at it (P< 0.05). Ultimately, FoxM1 could reverse the role of miR-194-5p in inhibiting invasion, migration and EMT of CRA cells (P< 0.05).
CONCLUSION: LncRNA H19/miR-194/FoxM1 axis could serve as a profound target for the diagnosis and treatment of CRA.

Han J, Han B, Wu X, et al.
Knockdown of lncRNA H19 restores chemo-sensitivity in paclitaxel-resistant triple-negative breast cancer through triggering apoptosis and regulating Akt signaling pathway.
Toxicol Appl Pharmacol. 2018; 359:55-61 [PubMed] Related Publications
Triple negative breast cancer (TNBC) is associated with poor prognosis and systemic chemotherapy is the only treatment for TNBC. However, development of chemo-resistance remains a major obstacle for TNBC treatment. Paclitaxel-resistance is mainly related to the activation of the Akt signaling pathway and deregulation of apoptotic regulatory proteins. LncRNAs are frequently dysregulated in various malignancies, including breast cancer, facilitating cell proliferation, metastasis and drug resistance. LncRNA H19 is overexpressed in approximately 70% of breast cancer patients, and has been reported to confer chemo-resistance in breast cancer. In the present study, we investigated the expression level of lncRNA H19 in paclitaxel-resistant and paclitaxel-sensitive cell lines. The results showed that the level of lncRNA H19 expression in paclitaxel-resistant cells was significantly higher than that in paclitaxel-sensitive cells, and knockdown of lncRNA H19 might restore chemo-sensitivity in paclitaxel-resistant TNBC by mediating the AKT signaling pathway. Thus, lncRNA H19 might be an efficient therapeutic target in paclitaxel-resistant TNBC treatment.

Yin Z, Cui Z, Li H, et al.
Polymorphisms in the H19 gene and the risk of lung Cancer among female never smokers in Shenyang, China.
BMC Cancer. 2018; 18(1):893 [PubMed] Article available free on PMC after 19/07/2020 Related Publications
BACKGROUND: Long non-coding RNA (lncRNA) H19 is a hot spot in tumor development, progression and metastasis. This study assessed the association between H19 genetic polymorphisms and the susceptibility of lung cancer.
METHODS: The case-control study was conducted to evaluate the association between four selected single nucleotide polymorphisms (rs217727, rs2107425, rs2735469 and rs17658052) in H19 gene and the risk of lung cancer. There were 556 female never smoking lung cancer patients and 395 cancer-free controls. Unconditional logistic regression analysis was used to analyze the associations between four SNPs and lung cancer risks by calculating the odds ratios and their 95% confidence intervals. The gene-environment interactions were assessed on both additive and multiplicative scales.
RESULTS: Compared with carriers carrying homozygous CC genotype, there was a statistically significant increased risk of lung cancer for carriers of the rs2107425 TT genotype (odds ratio = 1.599, 95%CI = 1.106-2.313, P = 0.013). In both dominant and recessive models, significant associations were found between rs2107425 and lung cancer risk, and the corresponding odds ratios were 1.346 (1.022-1.774) and 1.400 (1.011-1.937), with P values 0.035 and 0.043, respectively. There was no significant correlation between lung cancer risk and rs2735469, rs217727 and rs17658052. Interaction analysis showed that their combined effects had a greater impact on lung cancer than individual effects of polymorphism and cooking smoke exposure. However, further analysis showed that the both additive model and the multiplicative model were not statistically significant.
CONCLUSION: The polymorphism rs2107425 in H19 gene was associated with the risk of lung cancer among female who never smokes in Shenyang, China.

Ren J, Ding L, Zhang D, et al.
Carcinoma-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer by transferring exosomal lncRNA H19.
Theranostics. 2018; 8(14):3932-3948 [PubMed] Article available free on PMC after 19/07/2020 Related Publications
Long non-coding RNAs (lncRNAs) are involved in the pathology of various tumors, including colorectal cancer (CRC). The crosstalk between carcinoma- associated fibroblasts (CAFs) and cancer cells in the tumor microenvironment promotes tumor development and confers chemoresistance. In this study, we further investigated the underlying tumor-promoting roles of CAFs and the molecular mediators involved in these processes.

Ibrahim T, Saer-Ghorra C, Trak-Smayra V, et al.
Molecular characteristics of colorectal cancer in a Middle Eastern population in a single institution.
Ann Saudi Med. 2018 Jul-Aug; 38(4):251-259 [PubMed] Article available free on PMC after 19/07/2020 Related Publications
BACKGROUND: The few studies of the molecular biology of colorectal cancer (CRC) in Middle Eastern populations have included only small samples of patients.
OBJECTIVE: Evaluate the frequency and prognostic effect of RAS, BRAF, PIK3CA, PTEN, and EGFR somatic mutations as well as mismatch repair (MMR) deficiency in Lebanese Middle Eastern patients.
DESIGN: Retrospective single-center descriptive study.
SETTING: Lebanese Middle Eastern patients in a tertiary medical cen.ter.
METHODS: We included all patients diagnosed with CRC between January 2010 and December 2015, in whom RAS mutational status and the expression of MLH1 and MSH2 proteins were available.
MAIN OUTCOME MEASURES: Genetic mutations detected by direct sequencing while MMR protein expression was evaluated by immunohistochemistry.
SAMPLE SIZE: 645 patients.
RESULTS: RAS, BRAF, EGFR, PI3KCA, and PTEN mutation rates were 38.5%,12.9%, 0%, 11.1% and 0% respectively. The MMR deficiency rate was 20.6%. No factor was associated with RAS mutation whereas MMR-deficient tumors were less likely to be metastatic at diagnosis. Among patients with wild-type RAS females fared better than males (median overall survival [OS]=1734 vs 1079 days respectively, P=.015) even after adjustment for confounding factors by Cox regression analy.sis. This finding was not reproduced in the RAS-mutated group. The median OS of patients with MMR-deficient tumors was not reached, while the median OS was 2475 days in patients who had maintained expression of both MLH1 and MSH2.
CONCLUSION: The RAS mutation rate was similar to Western and East Asian countries, but not for the BRAF mutation and MMR deficiency. We also found a prognostic effect for sex in the RAS wild-type group, a finding worthy of further exploration.
LIMITATIONS: Retrospective, single center and small sample size. Expression of MSH6 and PMS2 not analyzed.

Eldar-Geva T, Gross-Tsur V, Hirsch HJ, et al.
Incomplete methylation of a germ cell tumor (Seminoma) in a Prader-Willi male.
Mol Genet Genomic Med. 2018; 6(5):811-818 [PubMed] Article available free on PMC after 19/07/2020 Related Publications
BACKGROUND: Prader-Willi syndrome (PWS) is a multisystem genetic disorder characterized by lack of satiety leading to morbid obesity, variable degrees of mental retardation, behavior disorders, short stature, and hypogonadism. The underlying genetic cause for PWS is an imprinting defect resulting from a lack of expression of several paternally inherited genes embedded within the 15q11.2-q13 region. Although the clinical expression of hypogonadism in PWS is variable, there are no known cases of fertility in PWS men. In this paper, we described a pure, nearly diploid seminoma in an apparently 32 year-old infertile man with PWS due to maternal uniparental disomy (UPD) on chromosome 15. The development of a germ cell tumor in this subject was an unanticipated result. The aim of this study was to explore the origin of the germ cell tumor in this PWS male patient.
METHODS: To explain the origin of the germ cell tumor (seminoma) in our PWS patient we have characterized the tumor for cell morphology and tumor type by pathological examination (H&E and immuno-stainings), evaluated its karyotype by chromosomal microarray analysis and confirmed its UPD origin by haplotype analysis. In addition, DNA methylation status of the PWS- and H19- imprinting centers in wild-type and affected fibroblasts, patient derived induced pluripotent stem cells (iPSCs), and PWS seminoma were determined by bisulfite DNA colony sequencing.
RESULTS: To explain the apparent contradiction between the existence of a germ cell tumor and hypogonadism we first confirmed the germ cell origin of the tumor. Next, we determined the tumor chromosomal composition, and validated the presence of a maternal UPD in all examined cell types from this patient. Finally, we characterized the maternal imprints in the PWS and H19 imprinting centers in the tumor and compared them with patient's fibroblasts and iPSCs derived from them. Unpredictably, methylation was reduced to 50% in the tumor, while preserved in the other cell types.
CONCLUSION: We infer from this assay that the loss of methylation in the PWS-IC specifically in the tumor of our patient is most likely a locus-specific event resulting from imprint relaxation rather than from general resetting of the imprints throughout the genome during germ line specification.

Sellers ZP, Schneider G, Maj M, Ratajczak MZ
Analysis of the Paternally-Imprinted DLK1-MEG3 and IGF2-H19 Tandem Gene Loci in NT2 Embryonal Carcinoma Cells Identifies DLK1 as a Potential Therapeutic Target.
Stem Cell Rev Rep. 2018; 14(6):823-836 [PubMed] Related Publications
The paternally-imprinted genes insulin-like growth factor 2 (IGF2), H19, delta-like homologue 1 (DLK1), and maternally-expressed gene 3 (MEG3) are expressed from the tandem gene loci IGF2-H19 and DLK1-MEG3, which play crucial roles in initiating embryogenesis and development. The erasure of imprinting (EOI) at differentially methylated regions (DMRs) which regulate the expression of these genes maintains the developmental quiescence of primordial germ cells (PGCs) migrating through the embryo proper during embryogenesis and prevents them from forming teratomas. To address the potential involvement of the IGF2-H19 and DLK1-MEG3 loci in the pathogenesis of embryonal carcinoma (EC), we investigated their genomic imprinting at DMRs in the human PGC-derived EC cell line NTera-2 (NT2). We observed EOI at the IGF2-H19 locus and, somewhat to our surprise, a loss of imprinting (LOI) at the DLK1-MEG3 locus. As a result, NT2 cells express imprinted gene ratios from these loci such that there are i) low levels of the proliferation-promoting IGF2 relative to ii) high levels of the proliferation-inhibiting long noncoding RNA (lncRNA) H19 and iii) high levels of proliferation-promoting DLK1 relative to iv) low levels of the proliferation-inhibiting lncRNA MEG3. Consistent with this pattern of expression, the knockdown of DLK1 mRNA by shRNA resulted in decreased in vitro cell proliferation and in vivo tumor growth as well as decreased in vivo organ seeding by NT2 cells. Furthermore, treatment of NT2 cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-azaD) inhibited their proliferation. This inhibition was accompanied by changes in expression of both tandem gene sets: a decrease in the expression of DLK1 and upregulation of the proliferation-inhibiting lncRNA MEG3, and at the same time upregulation of IGF2 and downregulation of the lncRNA H19. These results suggest that the DLK1-MEG3 locus, and not the IGF2-H19 locus, drives the tumorigenicity of NT2 cells. Based on these results, we identified DLK1 as a novel treatment target for EC that could be downregulated by 5-azaD.

Luo J, Li Q, Pan J, et al.
Expression level of long noncoding RNA H19 in plasma of patients with nonsmall cell lung cancer and its clinical significance.
J Cancer Res Ther. 2018; 14(4):860-863 [PubMed] Related Publications
Objective: This study was aimed to explore the expression level of long noncoding RNA H19 in the plasma of patients with nonsmall cell lung cancer (NSCLC) and its clinical significance.
Methods: A total of 66 NSCLC patients (case group) and 31 patients with benign lung disease (control group) admitted from February 2015 to February 2017 were included in this study. Real-time polymerase chain reaction assay was applied to examine the relative expression level of long noncoding RNA H19 in the plasma of the two groups. The relationship between H19 expression and clinical, pathological features was explored. Receiver-operating characteristic (ROC) curve was applied to evaluate the clinical value of plasma H19 as a tumor marker in the auxiliary diagnosis of NSCLC.
Results: The relative expression levels of plasma H19 inpatients from NSCLC group and benign lung disease group were 5.62 ± 2.02 (ΔCt) and 7.74 ± 2.75 (ΔCt), respectively. The NSCLC group presented with significantly higher levels than that of the benign disease group (P < 0.05). According to the median of relative expression level of 5.54, the plasma H19 of NSCLC patients was classified into low expression group ≥5.54 (n = 34) and high expression group <5.52 (n = 32). The relationship between the patients' clinical, pathological features, and the expression level of H19 was analyzed. The expression of H19 was not significantly correlated with the gender, age, clinical staging, tumor diameter, and pathological type of the patients (P
Conclusion: Plasma level of H19 in NSCLC patients was significantly increased, which could be applied as a serological marker for the auxiliary diagnosis of NSCLC.

Kim SC, Shin YK, Kim YA, et al.
Identification of genes inducing resistance to ionizing radiation in human rectal cancer cell lines: re-sensitization of radio-resistant rectal cancer cells through down regulating NDRG1.
BMC Cancer. 2018; 18(1):594 [PubMed] Article available free on PMC after 19/07/2020 Related Publications
BACKGROUND: Resistance to preoperative radiotherapy is a major clinical problem in the treatment for locally advanced rectal cancer. The role of NDRG1 in resistance to ionizing radiation in rectal cancer has not been fully elucidated. This study aimed to investigate the effect of the reduced intracellular NDRG1 expression on radio-sensitivity of human rectal cancer cells for exploring novel approaches for treatment of rectal cancer.
METHODS: Three radio-resistant human rectal cancer cell lines (SNU-61R80Gy, SNU-283R80Gy, and SNU-503R80Gy) were established from human rectal cancer cell lines (SNU-61, SNU-283, and SNU-503) using total 80 Gy of fractionated irradiation. Microarray analysis was performed to identify differently expressed genes in newly established radio-resistant human rectal cancer cells compared to parental rectal cancer cells.
RESULTS: A microarray analysis indicated the RNA expression of five genes (NDRG1, ERRFI1, H19, MPZL3, and UCA1) was highly increased in radio-resistant rectal cancer cell lines. Short hairpin RNA-mediated silencing of NDRG1 sensitized rectal cancer cell lines to clinically relevant doses of radiation by causing more DNA double strand breakages to rectal cancer cells when exposed to radiation.
CONCLUSIONS: Targeting NDRG1 represents a promising strategy to increase response to radiotherapy in human rectal cancer.

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