A double suicide gene system driven by vascular endothelial growth factor promoter selectively kills human hepatocellular carcinoma cells

Wu, Kai; Lü, Yang; Huang, Zong-hai; Zhao, Haijun; Wang, Jianjun; Xu, Shiwen

doi:10.3892/ol.2016.4360

Cited by 7 publications

(6 citation statements)

References 37 publications

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“…It is tempting to assume that a promoter of a well-known tissue-specific gene can drive tissue-specific expression when cloned upstream of a transgene [54]. For example, gene therapy strategies targeting vascular endothelial cells frequently utilize a promoter of vascular endothelial growth factor [89]. The problem is that the activity of the proximal promoter might be modified by the genomic context, nearby enhancers, epigenetic modifications, miRNA-binding sites, the 3 0 untranslated region (UTR), etc.…”

Section: Box 4 a Practical Application: A Systematic Approach To Conmentioning

confidence: 99%

Can We Predict Gene Expression by Understanding Proximal Promoter Architecture?

Huminiecki

Horbańczuk

2017

Trends in Biotechnology

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We review computational predictions of expression from the promoter architecture - the set of transcription factors that can bind the proximal promoter. We focus on spatial expression patterns in animals with complex body plans and many distinct tissue types. This field is ripe for change as functional genomics datasets accumulate for both expression and protein-DNA interactions. While there has been some success in predicting the breadth of expression (i.e., the fraction of tissue types a gene is expressed in), predicting tissue specificity remains challenging. We discuss how progress can be achieved through either machine learning or complementary combinatorial data mining. The likely impact of single-cell expression data is considered. Finally, we discuss the design of artificial promoters as a practical application.

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Section: Box 4 a Practical Application: A Systematic Approach To Conmentioning

confidence: 99%

Can We Predict Gene Expression by Understanding Proximal Promoter Architecture?

Huminiecki

Horbańczuk

2017

Trends in Biotechnology

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“…The main obstacle is that these cancer stem cells are often in a state of dormancy which impairs the treatment effects of chemotherapeutic drugs (9). Some recent studies have shown that the herpes simplex virus thymidine kinase (HSVtk) gene and the complementary treatment with ganciclovir (GCV) exert marked antitumor effects against HCC by promoting apoptosis and inhibiting angiogenesis (10,11). However, it is still difficult to prevent the recurrence of liver tumors (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

“…It is well known that normal gap junction intercellular communication (GJIC) between tumor cells is crucial for HSVtk/GCV to exert its therapeutic effects (10). However, there are few studies on the structure and function of GJIC between liver cancer stem cells, although some studies have reported that their GJIC is obviously defective in liver tumors (13).…”

Section: Introductionmentioning

confidence: 99%

Connexin 43 SUMOylation improves gap junction functions between liver cancer stem cells and enhances their sensitivity to HSVtk/GCV

Shen

et al. 2018

Int J Oncol

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Connexin 43 (Cx43) can be modified and regulated by small ubiquitin-like modifier (SUMO)1; however, its role in liver cancer stem cells is poorly understood. In this study, we found a significant difference in the expression of Cx43 and SUMO1 between cancer stem cells and non-cancer stem cells in liver cancer. In liver cancer stem cells, Cx43 was almost absent, although the level of SUMO1 was significantly higher than that in non-cancer stem cells. Further experiments confirmed that the conjugated site of Cx43 by SUMO1 was located in Lys-144 and Lys-237, both of which are highly conserved among species. By the co-expression of Cx43 and SUMO1 in cancer stem cells, the gap junction intercellular communication (GJIC) of liver cancer stem cells was obviously improved. Using this feature, we verified whether it could effectively increase the sensitivity of cancer stem cells to the herpes simplex virus 1 thymidine kinase (HSVtk) gene in combination with ganciclovir (GCV), a conventional chemotherapeutic drug, in vitro and in vivo. As expected, increasing the expression of Cx43 SUMOylation in liver cancer stem cells effectively enhanced their sensitivity to HSVtk/GCV. On the whole, this study revealed a novel method which may be used to effectively restore GJIC in cancer stem cells in liver cancer, which enhances their sensitivity to conventional chemotherapeutic drugs.

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“…Recently, gene therapy has proven to be an emerging and efficient means of cancer treatment [14, 15] and has entered clinical trials. A phase III clinical trial of suicide gene therapy using retrovirus-mediated transduction in glioblastoma failed to show improvements in survival outcomes by systemic viral administration owing to a failure to achieve a therapeutic dose of transgene expression at the site of disease [8, 16]. Free flaps may provide an alternative approach to systemic viral administration.…”

Section: Discussionmentioning

confidence: 99%

Lentivirus-mediated CDglyTK gene-modified free flaps by intra-artery perfusion show targeted therapeutic efficacy in rat model of breast cancer

et al. 2019

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Background Free flap-mediated gene therapy in the tumor bed following surgical resection is a promising approach in cancer targeted treatment of residual disease. We investigated the selective killing efficacy of a lentivirus-mediated cytosine deaminase-thymidine kinase (CDglyTK) gene in transplanted breast cancer delivered into a free flap by intra-artery perfusion. Methods Proliferation, apoptosis, and cell cycle of rat SHZ-88 breast cancer cells transfected with a lentivirus-mediated CD/TK gene were measured following treatment with ganciclovir and 5-flucytosine in vitro. A model of residual disease of breast cancer in a rat superficial inferior epigastric artery (SIEA) flap model was used to study the therapeutic potential of a double suicide CD/TK and prodrug system in vivo. Results Killing efficacy of the double suicide CD/TK and prodrug system on SHZ-88 cells was mediated by increased apoptosis and cell cycle arrest at the G1 phase with significant bystander effect. Following recombinant lentivirus transfection of rat SIEA flap by intra-artery perfusion, CD/TK gene expression was limited to the flap, and the volume and weight of transplanted tumors were significantly reduced without observable toxicity. Conclusions SIEA flaps transfected with a lentivirus-mediated CDglyTK gene by intra-artery perfusion effectively suppress transplanted breast tumor growth without obvious systemic toxic effects in rats.

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A double suicide gene system driven by vascular endothelial growth factor promoter selectively kills human hepatocellular carcinoma cells

Cited by 7 publications

References 37 publications

Can We Predict Gene Expression by Understanding Proximal Promoter Architecture?

Can We Predict Gene Expression by Understanding Proximal Promoter Architecture?

Connexin 43 SUMOylation improves gap junction functions between liver cancer stem cells and enhances their sensitivity to HSVtk/GCV

Lentivirus-mediated CDglyTK gene-modified free flaps by intra-artery perfusion show targeted therapeutic efficacy in rat model of breast cancer

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