Jiakai Lin

Institute of Bioengineering and Nanotechnology

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Ying Zhao

Xi'an Jiaotong University

S Wang

National University of Singapore

Dang Hoang Lam

Institute of Bioengineering and Nanotechnology

Shu Wang

Qiqihar Medical University

Jieming Zeng

Institute of Bioengineering and Nanotechnology

Chunxiao Wu

Soochow University

Poonam Balani

Institute of Bioengineering and Nanotechnology

Wai Hoe Ng

National Neuroscience Institute

Chee Kian Tham

National Cancer Centre Singapore

Jianbo Yang

Rice Research Institute

Cooperative Institutions

National University of Singapore

Institute of Bioengineering and Nanotechnology

Duke-NUS Medical School

University of Manchester

Huashan Hospital

Fudan University

Singapore General Hospital

Rice Research Institute

Anhui Academy of Agricultural Sciences

Sichuan University of Science and Engineering

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MicroRNA-10b pleiotropically regulates invasion, angiogenicity and apoptosis of tumor cells resembling mesenchymal subtype of glioblastoma multiforme

Cell Death and Disease (2012)

Jiakai Lin Siew Hoon Teo Dang Hoang Lam Kandiah Jeyaseelan S Wang

Glioblastoma multiforme (GBM) is a heterogeneous disease despite its seemingly uniform pathology. Deconvolution of The Cancer Genome Atlas's GBM gene expression data has unveiled the existence of distinct gene expression signature underlying discrete GBM subtypes. Recent conflicting findings proposed that microRNA (miRNA)-10b exclusively regulates glioma growth or invasion but not both. We showed that silencing of miRNA-10b by baculoviral decoy vectors in a glioma cell line resembling the mesenchymal subtype of GBM reduces its growth, invasion and angiogenesis while promoting apoptosis in vitro. In an orthotopic human glioma mouse model, inhibition of miRNA-10b diminishes the invasiveness, angiogenicity and growth of the mesenchymal subtype-like glioma cells in the brain and significantly prolonged survival of glioma-bearing mice. We demonstrated that the pleiotropic nature of miRNA-10b was due to its suppression of multiple tumor suppressors, including TP53, FOXO3, CYLD, PAX6, PTCH1, HOXD10 and NOTCH1. In particular, siRNA-mediated knockdown experiments identified TP53, PAX6, NOTCH1 and HOXD10 as invasion regulatory genes in our mesenchymal subtype-like glioma cells. By interrogating the REMBRANDT, we noted that dysregulation of many direct targets of miRNA-10b was associated with significantly poorer patient survival. Thus, our study uncovers a novel role for miRNA-10b in regulating angiogenesis and suggests that miRNA-10b may be a pleiotropic regulator of gliomagenesis.

Oncomir

10.1038/cddis.2012.134

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Delivery of Micro RNA Sponges for Interrogation of Micro RNA Function In Vitro and In Vivo

Jiakai Lin Shu Wang

Promoters are regulatory elements that provide precise control of magnitude, specificity and duration of shRNA expression and gene silencing. The selection of a suitable promoter is therefore critical in the design of a shRNA expression system. We discuss the use of different promoters for shRNA expression, including constitutive promoters, inducible promoters, and tissue/tumor specific promoters. Recently, miRNA-based shRNAs have received increasing attention as a promising RNAi approach. We have therefore also summarized the use of miRNA backbone to enhance gene silencing and to reduce toxicities. The application of miRNA-shRNA for combinatorial gene therapy is also discussed.

Interrogation

Sponge

10.1002/9781118610749.ch20

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Retraction Note: Targeted suicide gene therapy for glioma using human embryonic stem cell-derived neural stem cells genetically modified by baculoviral vectors

Gene Therapy (2020)

Ying Zhao Dang Hoang Lam Jialiang Yang Jiakai Lin Chee Kian Tham

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Suicide gene

10.1038/s41434-020-0135-y

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High-efficiency Transient Transduction of Human Embryonic Stem Cell–derived Neurons With Baculoviral Vectors

Molecular Therapy (2009)

Jieming Zeng Juan Du Jiakai Lin Xiao Ying Bak Chunxiao Wu

Transient genetic manipulation of human neurons without chromosomal integration of the transgene would be valuable but has been challenging due to the quiescent nature of these postmitotic cells. In this study, we developed a set of baculoviral vectors for transient transduction in nondividing neurons derived from human embryonic stem cells (hESCs). Using a baculoviral vector equipped with the woodchuck hepatitis virus posttranscriptional regulatory element (WPRE), we observed a quick onset of transgene expression as early as day 1 after baculoviral transduction and a high efficiency of up to 80%. Strong transgene expression in the cultured human neurons was observed for more than 1 month and the signal was easily detectable even after 3 months. Using two baculoviral vectors carrying different transgenes, we found that co-transduction at a single neuron level was possible. After transplantation into the brain of nude mice, the baculovirus-transduced human neurons were integrated into the mouse brain and maintained transgene expression for at least 4 weeks, portending the usefulness of this technique in assisting neural transplantation. Therefore, by mediating efficient transient gene expression, baculoviral vectors can provide useful tools for both basic gene function studies in human neurons and therapeutic applications of these cells.

Transduction (biophysics)

Transient (computer programming)

10.1038/mt.2009.124

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RETRACTED ARTICLE: Targeted suicide gene therapy for glioma using human embryonic stem cell-derived neural stem cells genetically modified by baculoviral vectors

Gene Therapy (2011)

Ying Zhao Dang Hoang Lam Jianbo Yang Jiakai Lin Chee Kian Tham

Suicide gene

10.1038/gt.2011.82

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High Mobility Group Box2 Promoter-controlled Suicide Gene Expression Enables Targeted Glioblastoma Treatment

Molecular Therapy (2009)

Poonam Balani Jérôme Boulaire Ying Zhao Jieming Zeng Jiakai Lin

Achievement of specific tumor cell targeting remains a challenge for glioma gene therapy. We observed that the human high mobility group box2 (HMGB2) gene had a low level of expression in normal human brain tissues, but was significantly upregulated in glioblastoma tissues. With progressive truncation of a 5′-upstream sequence of the HMGB2 gene, we identified a 0.5-kb fragment displaying a high transcriptional activity in glioblastoma cells, but a low activity in normal brain cells. To test the feasibility of using the HMGB2 promoter sequence in targeted cancer therapy, we constructed a baculoviral vector expressing the herpes simplex virus thymidine kinase (HSVtk) gene driven by the HMGB2 promoter. Transduction with the viral vector induced cell death in glioblastoma cell lines in the presence of ganciclovir (GCV), but did not affect the survival of human astrocytes and neurons. In a mouse xenograft model, intratumor injection of the baculoviral vector suppressed the growth of human glioblastoma cells and prolonged the survival of tumor-bearing mice. Our results suggest that the novel 5′ sequence of HMGB2 gene has a potential to be used as an efficient, tumor-selective promoter in targeted vectors for glioblastoma gene therapy. Achievement of specific tumor cell targeting remains a challenge for glioma gene therapy. We observed that the human high mobility group box2 (HMGB2) gene had a low level of expression in normal human brain tissues, but was significantly upregulated in glioblastoma tissues. With progressive truncation of a 5′-upstream sequence of the HMGB2 gene, we identified a 0.5-kb fragment displaying a high transcriptional activity in glioblastoma cells, but a low activity in normal brain cells. To test the feasibility of using the HMGB2 promoter sequence in targeted cancer therapy, we constructed a baculoviral vector expressing the herpes simplex virus thymidine kinase (HSVtk) gene driven by the HMGB2 promoter. Transduction with the viral vector induced cell death in glioblastoma cell lines in the presence of ganciclovir (GCV), but did not affect the survival of human astrocytes and neurons. In a mouse xenograft model, intratumor injection of the baculoviral vector suppressed the growth of human glioblastoma cells and prolonged the survival of tumor-bearing mice. Our results suggest that the novel 5′ sequence of HMGB2 gene has a potential to be used as an efficient, tumor-selective promoter in targeted vectors for glioblastoma gene therapy.

Suicide gene

U87

10.1038/mt.2009.22

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Combinatorial Control of Suicide Gene Expression by Tissue-specific Promoter and microRNA Regulation for Cancer Therapy

Molecular Therapy (2009)

Chunxiao Wu Jiakai Lin Michelle Hong Yukti Choudhury Poonam Balani

Transcriptional targeting using a tissue-specific cellular promoter is proving to be a powerful means for restricting transgene expression in targeted tissues. In the context of cancer suicide gene therapy, this approach may lead to cytotoxic effects in both cancer and nontarget normal cells. Considering microRNA (miRNA) function in post-transcriptional regulation of gene expression, we have developed a viral vector platform combining cellular promoter-based transcriptional targeting with miRNA regulation for a glioma suicide gene therapy in the mouse brain. The therapy employed, in a single baculoviral vector, a glial fibrillary acidic protein (GFAP) gene promoter and the repeated target sequences of three miRNAs that are enriched in astrocytes but downregulated in glioblastoma cells to control the expression of the herpes simplex virus thymidine kinase (HSVtk) gene. This resulted in significantly improved in vivo selectivity over the use of a control vector without miRNA regulation, enabling effective elimination of human glioma xenografts while producing negligible toxic effects on normal astrocytes. Thus, incorporating miRNA regulation into a transcriptional targeting vector adds an extra layer of security to prevent off-target transgene expression and should be useful for the development of gene delivery vectors with high targeting specificity for cancer therapy.

Suicide gene

10.1038/mt.2009.225

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Citations (70)