The expression of the H19 gene and its function in human bladder carcinoma cell lines

Ohana, Patricia; Kopf, Eliezer; Bibi, O.; Ayesh, Suhail; Schneider, Tamar; Tykocinski, Mark L.; Groot, Nathan de; Hochberg, Abraham

doi:10.1016/s0014-5793(99)00780-2

Cited by 19 publications

(11 citation statements)

References 14 publications

(20 reference statements)

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“…The H19-Luc plasmid which contains the luciferase gene under the control of the human H19 promoter region from nucleotide -818 to + 14 was prepared as described [28]. The H19-Luc plasmid was digested with XbaI and NcoI, and the insert of the luciferase gene (luc) was replaced by the Diphtheria toxin A chain (DTA) coding region to yield the H19-DTA construct.…”

Section: Methodsmentioning

confidence: 99%

Development of targeted therapy for bladder cancer mediated by a double promoter plasmid expressing diphtheria toxin under the control of H19 and IGF2-P4 regulatory sequences

2010

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BackgroundThe human IGF2-P4 and H19 promoters are highly active in a variety of human cancers (including bladder cancer), while existing at a nearly undetectable level in the surrounding normal tissue.Single promoter vectors expressing diphtheria toxin A-fragment (DTA) under the control regulation of IGF2-P4 or H19 regulatory sequences (IGF2-P4-DTA and H19-DTA) were previously successfully used in cell lines, animal models and recently in human patients with superficial cell carcinoma of the bladder (treated with H19-DTA). However this targeted medicine approach could be limited, as not all cancer patients express high levels of H19. Hence, a double promoter DTA-expressing vector was created, carrying on a single construct two separate genes expressing the diphtheria toxin A-fragment (DTA), from two different regulatory sequences, selected from the cancer-specific promoters H19 and IGF2-P4.MethodsH19 and IGF2-P4 gene expression was tested in samples of Transitional Cell Carcinoma (TCC) of the bladder by in-situ hybridization (ISH) and by quantitative Real-Time PCR (qRT-PCR). The therapeutic potential of the double promoter toxin vector H19-DTA-IGF2-P4-DTA was tested in TCC cell lines and in heterotopic and orthotopic animal models of bladder cancer.ResultsNearly 100% of TCC patients highly expressed IGF2-P4 and H19, as determined by ISH and by qRT-PCR. The double promoter vector exhibited superior tumor growth inhibition activity compared to the single promoter expression vectors, in cell lines and in heterotopic and orthotopic bladder tumors.ConclusionsOur findings show that bladder tumors may be successfully treated by intravesical instillation of the double promoter vector H19-DTA-P4-DTA.Overall, the double promoter vector exhibited enhanced anti-cancer activity relative to single promoter expression vectors carrying either gene alone.

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Section: Methodsmentioning

confidence: 99%

Development of targeted therapy for bladder cancer mediated by a double promoter plasmid expressing diphtheria toxin under the control of H19 and IGF2-P4 regulatory sequences

2010

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“…All the luciferase gene reporter constructs were built from the pGL3 basic (Luc‐1) vector (Promega), which lacks both promoter and enhancer sequences. The construct Luc‐PBH19, which contains the reporter gene under the control of the human H19 promoter region from nucleotides −818 to +14, was prepared as described 6…”

Section: Methodsmentioning

confidence: 99%

“…We have previously reported that transcription of the human H19 gene is under the control of regulatory sequences downstream to the coding sequence 6. We demonstrated that luciferase activity could be selectively expressed in cells transfected with a plasmid carrying the luc gene linked to the 814 bp 5′‐flanking region of the H19 gene 6. Our results showed that elements responsible for basal promoter activity are contained within the 85 bp upstream region and that cell specificity is mainly conferred by the 814 bp upstream sequences 7…”

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confidence: 99%

Use of H19 regulatory sequences for targeted gene therapy in cancer

Ohana

Bibi

Matouk

et al. 2002

Intl Journal of Cancer

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Key words: H19 gene; regulatory sequences; gene therapy; bladder cancer; DT-A gene; HVS-tk geneOne of the most serious problems in cancer therapy is the obvious necessity to limit the action of the drug(s) used in the therapy to tumor cells only, in order to prevent damage to healthy tissue. The approach used in our work on cancer therapy is based on the use of regulatory sequences of genes that are differentially expressed between normal and cancer cells, to drive the expression of a toxin gene in tumor cells only.The H19 gene is highly expressed in embryonic tissues, expressed at low levels (or not at all) in normal adult tissues and expressed in tumors derived from tissues (such as bladder) that exhibited the gene during embryonic development. 1-3 H19 RNA is not present in normal adult bladder tissue but can be detected in bladder cancer cells in over 75% of bladder tumors; however, the relative number of H19-expressing cells is reduced during tumor differentiation. 4 The change in H19 RNA level may be caused by a change either in the level of H19 transcription or in H19 RNA stability or both. 5 We have previously reported that transcription of the human H19 gene is under the control of regulatory sequences downstream to the coding sequence. 6 We demonstrated that luciferase activity could be selectively expressed in cells transfected with a plasmid carrying the luc gene linked to the 814 bp 5Ј-flanking region of the H19 gene. 6 Our results showed that elements responsible for basal promoter activity are contained within the 85 bp upstream region and that cell specificity is mainly conferred by the 814 bp upstream sequences. 7 .We established a murine in vivo model for bladder carcinoma in which the dynamics of H19 expression and tumor progression could be correlated. 8 . Mice develop solid invasive bladder cancer after 20 -30 weeks of N-butyl-N(4-hydroxybutyl)nitrosamine (BBN) treatment after hyperplasia and dysplasia of the urothelium. 8 We showed that H19 is expressed in the preneoplastic phase during BBN-induced tumor evolution. 8 Moreover, when tumor formation is inhibited by the anticancer drug halofuginone, H19 expression is extinguished. 9 Halofuginone also exerts anticancer effects on tumors formed by subcutaneous transplantation of MBT2-t50 murine bladder carcinoma cells (H19-positive cells) into syngeneic mice. 9 Tumor cell-specific gene therapy might be accomplished with a construct carrying H19 regulatory sequences that determine the tissue-specific expression of a toxin or suicide enzyme gene. We therefore constructed expression vectors containing "therapeutic genes" such as the gene for the A fragment of diphtheria toxin (DT-A) or herpes simplex virus thymidine kinase (HSV-tk), under the control of a 814 bp 5Ј-flanking region of the H19 gene.Here we present evidence that the constructs expressing either the toxin or the suicide gene driven by the H19 regulatory sequence could selectively exert their cytotoxic effects in H19-positive cells. The cell killing activity of these constructs was in ac...

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“…The lncRNA H19 is located on chromosome 11p15.5 and is 2.3 kb in length [ 13 ]. The H19 gene, which is a paternally imprinted onco-fetal gene, is typically down-regulated in adult tissues, but can be expressed in cancer tissues at levels similar to those observed in fetal life [ 14 ]. Many studies have confirmed that H19 is re-expressed in many types of solid tumors, such as breast cancer, gastric cancer, and esophageal cancer, and H19 expression is closely related to tumor invasion, metastasis, recurrence and poor prognosis [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Significant association between lncRNA H19 polymorphisms and cancer susceptibility: a meta-analysis

Yin

Cai

et al. 2017

Oncotarget

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Previous epidemiological research suggests polymorphisms in long non-coding RNA (lncRNA) H19 are associated with an increased risk of cancer, but the results are inconsistent. We therefore conducted a meta-analysis to more accurately determine the association between lncRNA H19 polymorphisms and cancer risk. The PubMed, Embase, and Science Citation Index online databases were searched and 11 relevant studies involving a total of 33,209 participants were identified. Odds ratios (ORs) and corresponding 95% confidence interval (CIs) from these studies were used to detect associations between H19 polymorphisms and cancer risk using five genetic models. The pooled result suggested that the rs2839698 G>A polymorphism was associated with digestive cancer risk in all five models. Moreover, a protective effect against cancer development was observed for the T allele variant of the rs2107425 C>T polymorphism, especially in Caucasian patient populations. No significant associations were found between lncRNA H19 rs217727 G>A polymorphism and cancer risk. In summary, the rs2839698 G>A and rs2107425 C>T polymorphisms in lncRNA H19 may therefore play opposing roles during cancer development, and their effects may vary depending on cancer type and patient ethnicity.

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The expression of the H19 gene and its function in human bladder carcinoma cell lines

Cited by 19 publications

References 14 publications

Development of targeted therapy for bladder cancer mediated by a double promoter plasmid expressing diphtheria toxin under the control of H19 and IGF2-P4 regulatory sequences

Development of targeted therapy for bladder cancer mediated by a double promoter plasmid expressing diphtheria toxin under the control of H19 and IGF2-P4 regulatory sequences

Use of H19 regulatory sequences for targeted gene therapy in cancer

Significant association between lncRNA H19 polymorphisms and cancer susceptibility: a meta-analysis

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