Durable Expression of Minicircle DNA-Liposome-Delivered Androgen Receptor cDNA in Mice with Hepatocellular Carcinoma

Chang, Tian; Chung, Chin Ying; Chuang, Wei Min; Li, Long Yuan; Jeng, Long Bin; Lung, Wen

doi:10.1155/2014/156356

Cited by 4 publications

(2 citation statements)

References 48 publications

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“…In general, the histological studies were performed as described in previous studies, with slight modification [40, 41]. For general histologic inspection, we treated tissue sections (2 μM) with hematoxylin and eosin, or stained sections with antibodies specific for AR and CD90 with an ABC kit (Vector Laboratories) to enhance the staining signals.…”

Section: Methodsmentioning

confidence: 99%

Androgen receptor mitigates postoperative disease progression of hepatocellular carcinoma by suppressing CD90+ populations and cell migration and by promoting anoikis in circulating tumor cells

et al. 2016

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PurposeAlthough hepatectomy and liver transplantation surgery for hepatocellular carcinoma (HCC) are effective treatment modalities, the risk of recurrence remains high, particularly in patients with a high number of circulating tumor cells (CTCs) expressing cancer stem/progenitor cell markers. Androgen receptor (AR) signaling has been shown to suppress HCC metastasis in rodent models of HCC. In this study, we investigated whether AR is associated with postoperative HCC recurrence.Experimental DesignCTCs were obtained from patients with HCC who had undergone hepatectomy to investigate whether they are associated with disease outcome. AR knockout was introduced in two mouse models of spontaneous HCC (carcinogen- and hepatitis B virus-related HCC) to delineate the role that AR plays in HCC recurrence. Biological systems analysis was used to investigate the cellular and molecular mechanisms.ResultsWe found that the expression of AR in CTCs was negatively associated with HCC recurrence/progression after hepatectomy. Our results suggest that AR-mediated suppression of HCC recurrence/progression is governed by a three-pronged mechanism. First, AR suppresses the expression of CD90 in CTCs by upregulating Histone 3H2A. Second, AR suppresses cell migration at the transcriptome level. Third, AR promotes anoikis of CTCs via dysregulation of cytoskeletal adsorption.ConclusionsThe results indicate that AR expression may be the gatekeeper of postoperative HCC recurrence. Therefore, targeting AR in presurgical down-staging procedures may serve as a secondary prevention measure against HCC recurrence in the future.

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Section: Methodsmentioning

confidence: 99%

Androgen receptor mitigates postoperative disease progression of hepatocellular carcinoma by suppressing CD90+ populations and cell migration and by promoting anoikis in circulating tumor cells

et al. 2016

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“…The assay was performed as previously described [36,37]. Briefly, CYP2B6-ERE-SNP-luciferase and pRL-TK (thymidine kinase promoterdriven renilla luciferase plasmid) were co-transfected into cells using liposomes [38]. Cells were then treated, lysed (Promega, WI, USA) and subjected to a Dual-luminescence reader (Promega).…”

Section: Transfection and Dual Luciferase Assaymentioning

confidence: 99%

Reduced dosing and liability in methadone maintenance treatment by targeting oestrogen signal for morphine addiction

Chiang

Wang

Huang

et al. 2017

J Cellular Molecular Medi

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Methadone maintenance treatment (MMT) is the major tapering therapy for morphine addictive patients. There have gender differences reported in response to MMT. This study discovered that the estrogen‐response element single nucleotide polymorphism (ERE‐SNP; rs16974799, C/T) of cytochrome 2B6 gene (cyp2b6; methadone catabolic enzyme) responded differently to MMT dosing. Oestradiol was associated with high MMT dosing, high enantiomer (R‐ or S‐) of 2‐ethylidene‐1,5‐dimethyl‐3,3‐dipheny‐pyrrolidine (EDDP; methadone metabolite) to methadone ratio and increased drug‐seeking behaviour, implicating oestradiol‐CYP‐EDDP/methadone axis decreasing MMT efficacy. In mouse model, oestrogen mitigates methadone antinociceptive response, facilitates methadone catabolism and up‐regulates methadone‐associated metabolizing enzymes. Oestrogen also ablates chronic methadone administration‐induced rewarding response. Mechanism dissection revealed the CC genotype of CYP2B6‐ERE‐SNP exerts higher ERE sequence alignment score, higher estrogenic response as compared to TT genotype. At last, preclinical study via targeting estrogen signal that tamoxifen (TMX; selective estrogen receptor modulator, SERM) could facilitate the tolerance phase rewarding response of methadone. Strikingly, TMX also reduces tapering/abstinence phases methadone liability in mice. In conclusion, this study demonstrates altering methadone metabolism through targeting estrogen signals might be able to free morphine addictive patients from the addiction of opioid replacement therapy. Therefore, the add‐on therapy clinical trial introducing SERM in MMT regimen is suggested.

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Sequence-Modified Antibiotic Resistance Genes Provide Sustained Plasmid-Mediated Transgene Expression in Mammals

Zhang

Fire

et al. 2017

Molecular Therapy

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Conventional plasmid vectors are incapable of achieving sustained levels of transgene expression in vivo even in quiescent mammalian tissues because the transgene expression cassette is silenced. Transcriptional silencing results from the presence of the bacterial plasmid backbone or virtually any DNA sequence of >1 kb in length placed outside of the expression cassette. Here, we show that transcriptional silencing can be substantially forestalled by increasing the An/Tn sequence composition in the plasmid bacterial backbone. Increasing numbers of An/Tn sequences increased sustained transcription of both backbone sequences and adjacent expression cassettes. In order to recapitulate these expression profiles in compact and portable plasmid DNA backbones, we engineered the standard kanamycin or ampicillin antibiotic resistance genes, optimizing the number of An/Tn sequence without altering the encoded amino acids. The resulting vector backbones yield sustained transgene expression from mouse liver, providing generic DNA vectors capable of sustained transgene expression without additional genes or mammalian regulatory elements.

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Durable Expression of Minicircle DNA-Liposome-Delivered Androgen Receptor cDNA in Mice with Hepatocellular Carcinoma

Cited by 4 publications

References 48 publications

Androgen receptor mitigates postoperative disease progression of hepatocellular carcinoma by suppressing CD90+ populations and cell migration and by promoting anoikis in circulating tumor cells

Androgen receptor mitigates postoperative disease progression of hepatocellular carcinoma by suppressing CD90+ populations and cell migration and by promoting anoikis in circulating tumor cells

Reduced dosing and liability in methadone maintenance treatment by targeting oestrogen signal for morphine addiction

Sequence-Modified Antibiotic Resistance Genes Provide Sustained Plasmid-Mediated Transgene Expression in Mammals

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