Regression of upper gastric cancer in mice by FHIT gene delivery

Ishii, Hideshi; Zanesi, Nicola; Vecchione, Andrea; Trapasso, Francesco; Yendamuri, Sai; Sarti, Manuela; Baffa, Raffaele; During, Matthew J.; Huebner, Kay; Fong, Louise Y.Y.; Croce, Carlo M.

doi:10.1096/fj.03-0241fje

Cited by 51 publications

(44 citation statements)

References 10 publications

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“…Interestingly, whereas the involvement of components of the DNA damage checkpoint pathway at G 1 -S phase of the cell cycle in the reduction of expression level in the fragile site genes was shown, the experiment of adenoviral FHIT suggests that the proapoptotic Fhit protein might function in cells predominantly at the S phase. The results are compatible with the previous observation that FHIT inhibited or prevented the development of carcinogen-induced cancer through a mechanism involving apoptosis (37,38).…”

Section: Uv-induced Cell Death and Gene Expressionsupporting

confidence: 92%

Components of DNA Damage Checkpoint Pathway Regulate UV Exposure–Dependent Alterations of Gene Expression of FHIT and WWOX at Chromosome Fragile Sites

Ishii

Mimori

Inageta

et al. 2005

Molecular Cancer Research

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Common chromosome fragile sites are highly recombinogenic and susceptible to deletions during the development of environmental carcinogen -induced epithelial tumors. Previous studies showed that not only genetic but also epigenetic alterations in cancerous cells are involved in inactivation of the genes FHIT and WWOX at chromosome fragile sites, reported to be potential tumor suppressor genes. Here we investigated the effect of UV light on the gene expression. After exposure to UV, the mRNA and protein of the two genes in murine embryonic fibroblasts (MEF) were unstable, apparently at the G 1 -S phase of the cell cycle, which was consistent with nuclear run-on assay. A study of MEFs synchronized via a double thymidine block indicated that, after the exposure, the expression of Fhit and Wwox was reduced in E2f-1 -deficient cells and markedly in wild-type cells, whereas the reduction was partially inhibited in Trp53-deficient cells; cells at the S phase seemed to be sensitive to exogenous FHIT, suggesting a role of the checkpoint at the G 1 -S phase in the stability of gene expression and a possible involvement of FHIT function at the S phase. The transfection experiment showed that the UV-induced decrease in expression was partially inhibited by transfection of kinase-dead Atr (ataxia telangiectasia mutated and Rad3 related), which is a sensor of UV-induced damage. Taken together, the present study showed that UV-induced alterations of the fragile site gene expression are involved at least partially in the checkpoint function, suggesting the role in the process of carcinogenesis after exposure to UV. (Mol Cancer Res 2005;3(3):130 -8)

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Section: Uv-induced Cell Death and Gene Expressionsupporting

confidence: 92%

Components of DNA Damage Checkpoint Pathway Regulate UV Exposure–Dependent Alterations of Gene Expression of FHIT and WWOX at Chromosome Fragile Sites

Ishii

Mimori

Inageta

et al. 2005

Molecular Cancer Research

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“…12,[14][15][16][17]27 Very recently, it was shown that Fhit2/2Vhl1/2 mice are more susceptible to lung carcinogenesis than either parental recombinant mouse strain, suggesting that Fhit deficiency combined with haploinsufficiency for the VHL gene, a locus that is frequently hemizygous in lung cancers, creates a permissive environment for lung cancer development; this permissive environment is created in many lung cancer victims by exposure to carcinogens in tobacco smoke or other environmental exposures. 28 These and other studies have suggested that replacement of an FHIT induction in H1299D1, following treatment with PonA, either in vitro or in vivo, resulted in a significant decrease in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…11-13 Reexpression of Fhit in many Fhit-deficient cancer cells suppresses tumorigenicity and FHIT-viral gene therapy prevents and reverses carcinogen-induced gastric cancers in Fhit-deficient mice. 12,[14][15][16][17] Studies confirming the role of FHIT as a suppressor gene have used cancer cells infected with adenoviral-FHIT or stably transfected with FHIT-expressing plasmids, both of which cause high levels of constitutively expressed Fhit protein.Because of anatomical barriers associated with lung cancer and the need for high multiplicities of adeno or other virus for effective delivery, the therapeutic potential of FHIT gene therapy in lung cancer has not been fully examined in preclinical models. To further investigate this potential, we used hormone-inducible FHIT-expressing lung cancer cells in a nude mouse xenograft model to investigate the effect of differing Fhit expression levels on tumorigenesis and the potential for pharmacologically directed gene therapy.…”

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confidence: 99%

“…[11][12][13] Reexpression of Fhit in many Fhit-deficient cancer cells suppresses tumorigenicity and FHIT-viral gene therapy prevents and reverses carcinogen-induced gastric cancers in Fhit-deficient mice. 12,[14][15][16][17] Studies confirming the role of FHIT as a suppressor gene have used cancer cells infected with adenoviral-FHIT or stably transfected with FHIT-expressing plasmids, both of which cause high levels of constitutively expressed Fhit protein.…”

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confidence: 99%

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Epigenetic modulation of endogenous tumor suppressor expression in lung cancer xenografts suppresses tumorigenicity

Cantor

Iliopoulos

Rao

et al. 2006

Intl Journal of Cancer

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Epigenetic changes involved in cancer development, unlike genetic changes, are reversible. DNA methyltransferase and histone deacetylase inhibitors show antiproliferative effects in vitro, through tumor suppressor reactivation and induction of apoptosis. Such inhibitors have shown activity in the treatment of hematologic disorders but there is little data concerning their effectiveness in treatment of solid tumors. FHIT, WWOX and other tumor suppressor genes are frequently epigenetically inactivated in lung cancers. Lung cancer cell clones carrying conditional FHIT or WWOX transgenes showed significant suppression of xenograft tumor growth after induction of expression of the FHIT or WWOX transgene, suggesting that treatments to restore endogenous Fhit and Wwox expression in lung cancers would result in decreased tumorigenicity. H1299 lung cancer cells, lacking Fhit, Wwox, p16 INK4a and Rassf1a expression due to epigenetic modifications, were used to assess efficacy of epigenetically targeted protocols in suppressing growth of lung tumors, by injection of 5-aza-2-deoxycytidine (AZA) and trichostatin A (TSA) in nude mice with established H1299 tumors. High doses of intraperitoneal AZA/TSA suppressed growth of small tumors but did not affect large tumors (200 mm 3 ); lower AZA doses, administered intraperitoneally or intratumorally, suppressed growth of small tumors without apparent toxicity. Responding tumors showed restoration of Fhit, Wwox, p16 INKa , Rassf1a expression, low mitotic activity, high apoptotic fraction and activation of caspase 3. These preclinical studies show the therapeutic potential of restoration of tumor suppressor expression through epigenetic modulation and the promise of re-expressed tumor suppressors as markers and effectors of the responses. ' 2006 Wiley-Liss, Inc.Key words: DNA methylation; tumor suppressor genes; 5-aza-2-deoxycytidine Lung cancer is the leading cause of cancer death in the western hemisphere for men and women, eclipsing the combined mortalities from breast, colon and prostate cancers. Genomic aberrations involving chromosome 3p are the most frequent and earliest genetic events in lung carcinogenesis. 1,2 In particular, the FHIT gene, spanning the human common fragile site, FRA3B, at chromosome 3p14.2, and the RASSF1A gene at 3p21 are frequently silenced in lung cancer and show hallmarks of tumor suppressor genes. 3 FHIT is altered in many other types of cancers, including breast, head and neck, cervical, bladder, esophageal, gastric, pancreatic and renal cancer and alterations occur in very early stages of preneoplasia in some organs. Fhit loss is associated with progression and outcome in cancers of various organs. 4 Similarly, the WWOX gene at FRA16D is frequently silenced in lung cancers, and has recently been shown to suppress growth of lung cancer cells in nude mice. [5][6][7] The RASSF1A promoter region is hypermethylated in a large fraction of lung and other cancers 8,9 and methylation of the RASSF1A regulatory region has been proposed as a biomarker of lung ca...

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“…It has been reported that genes encoding these growth factors have an ulcer healing effect in vivo [2,[32][33][34]. Moreover, gene therapy has been tried for gastric cancer in vitro and in vivo with various therapeutic genes, namely p53 [35], FHIT [36], NK4 [37,38] and the Fas ligand [39]. In addition, adenovirus-mediated suicide gene therapy by E. coli cytosine deaminase/5-fluorocytosine [30] or E. coli uracil phosphoribosyltransferase/5-fluorouracil have been reported [31].…”

Section: Resultsmentioning

confidence: 99%

Improved stomach selectivity of gene expression following microinstillation of plasmid DNA onto the gastric serosal surface in mice

Nishi

Fumoto

Ishii

et al. 2008

European Journal of Pharmaceutics and Biopharmaceutics

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Stomach-selective gene transfer is a promising approach as a therapeutic strategy for refractory gastric diseases. In this study, we improved the stomach selectivity of gene expression following microinstillation of naked plasmid DNA (pDNA) onto the gastric serosal surface in mice. pDNA encoding firefly luciferase was used as a reporter gene. It was confirmed that the gene expression level in the stomach 6 h after gastric serosal surface microinstillation of pDNA was significantly higher than after intragastric, intraperitoneal and intravenous administration. Regarding selectivity of gene expression, the gene expression level in the stomach after gastric serosal surface microinstillation of 1 µg/1 µL (dose/volume) pDNA was 5.7 times higher than that in the spleen. In our previous study (30 µg/30 µL), the expression level in the stomach was 2.7 times higher than that in the spleen; therefore, the selectivity was 2.1 times higher in this study. When we investigated gene expression at various pDNA solution concentrations, the ratio of the gene expression level in the stomach to that in the spleen was the highest as 1 µg/1 µL of pDNA, which was considered the optimal concentration. Information in this study is useful for further development of target organ-selective gene delivery systems.

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Regression of upper gastric cancer in mice by FHIT gene delivery

Cited by 51 publications

References 10 publications

Components of DNA Damage Checkpoint Pathway Regulate UV Exposure–Dependent Alterations of Gene Expression of FHIT and WWOX at Chromosome Fragile Sites

Components of DNA Damage Checkpoint Pathway Regulate UV Exposure–Dependent Alterations of Gene Expression of FHIT and WWOX at Chromosome Fragile Sites

Epigenetic modulation of endogenous tumor suppressor expression in lung cancer xenografts suppresses tumorigenicity

Improved stomach selectivity of gene expression following microinstillation of plasmid DNA onto the gastric serosal surface in mice

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