Combinatorial Control of Transgene Expression by Hypoxia-Responsive Promoter and MicroRNA Regulation for Neural Stem Cell-Based Cancer Therapy

Owing to their strong migratory capacity, tumor tropism, and tumor inhibitory effect, neural stem cells (NSCs) have recently emerged as one of the most attractive gene delivery vectors for cancer therapy. However, further animal studies found that proportional NSC vectors were distributed to nontarget organs after intravenous injection and the nonspecific transgene expression led to significant cytotoxic effects in these organs. Hence, an expression cassette that controls the transgene expression within NSC vectors in a tumor site-specific manner is desired. Considering hypoxia as a hallmark of tumor microenvironment, we have developed a novel NSC vector platform coupling transcriptional targeting with microRNA (miRNA) regulation for tumor hypoxia targeting. This combinatorial vector employed a hypoxia-responsive promoter and repeated targeting sequences of an miRNA that is enriched in NSCs but downregulated upon hypoxia induction to control the transgene expression. This resulted in significantly improved hypoxic selectivity over the use of a control vector without miRNA regulation. 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 NSC vectors with high targeting specifcity for cancer therapy.

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Faculty Opinions recommendation of Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13839.544089 ◽

2007 ◽

Author(s):

Mark Kay

Keyword(s):

Gene Transfer ◽

Transgene Expression ◽

Stable Gene ◽

Microrna Regulation

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A light-controlled multi-step drug release nanosystem targeting tumor hypoxia for synergistic cancer therapy

Chemical Science ◽

10.1039/d1sc01888d ◽

2021 ◽

Author(s):

Bin Zhang ◽

Zichen Xu ◽

Wen Zhou ◽

Zhikun Liu ◽

Jian Zhao ◽

...

Keyword(s):

Cell Proliferation ◽

Cancer Therapy ◽

Drug Release ◽

Distant Metastasis ◽

Tumor Hypoxia ◽

Treatment Resistance ◽

Major Obstacle

Hypoxia is a major obstacle for cancer therapy due to its association with cell proliferation, tumor distant metastasis, and treatment resistance. In this study, a hypoxia-activated bifunctional prodrug (CC5) was...

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Tumor Hypoxia in Cancer Therapy

Methods in Enzymology - Oxygen Biology and Hypoxia ◽

10.1016/s0076-6879(07)35015-5 ◽

2007 ◽

pp. 295-321 ◽

Cited By ~ 69

Author(s):

J. Martin Brown

Keyword(s):

Cancer Therapy ◽

Tumor Hypoxia

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RGD peptide-based non-viral gene delivery vectors targeting integrin αvβ3 for cancer therapy

Journal of Drug Targeting ◽

10.1080/1061186x.2018.1455841 ◽

2018 ◽

Vol 27 (1) ◽

pp. 1-11 ◽

Cited By ~ 22

Author(s):

Shuang Fu ◽

Xiaodong Xu ◽

Yu Ma ◽

Shubiao Zhang ◽

Shufen Zhang

Keyword(s):

Cancer Therapy ◽

Gene Delivery ◽

Integrin Αvβ3 ◽

Rgd Peptide ◽

Viral Gene ◽

Gene Delivery Vectors ◽

Viral Gene Delivery

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MicroRNA Regulation of the Autotaxin-Lysophosphatidic Acid Signaling Axis

Cancers ◽

10.3390/cancers11091369 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1369 ◽

Cited By ~ 3

Author(s):

Mandi M. Murph

Keyword(s):

Lysophosphatidic Acid ◽

Current Status ◽

Mirna Regulation ◽

Exciting Field ◽

Microrna Regulation ◽

Normal Tissues ◽

Argonaute Proteins ◽

Signaling Axis ◽

Lysophosphatidic Acid Signaling ◽

Lysophosphatidic Acid Receptors

The revelation that microRNAs (miRNAs) exist within the human genome uncovered an underappreciated mechanism of gene expression. For cells to regulate expression of their genes, miRNA molecules and argonaute proteins bind to mRNAs and interfere with efficient translation of the RNA transcript. Although miRNAs have important roles in normal tissues, miRNAs may adopt aberrant functions in malignant cells depending on their classification as either a tumor suppressor or oncogenic miRNA. Within this review, the current status of miRNA regulation is described in the context of signaling through the lysophosphatidic acid receptors, including the lysophosphatidic acid-producing enzyme, autotaxin. Thus far, research has revealed miRNAs that increase in response to lysophosphatidic acid stimulation, such as miR-21, miR-30c-2-3p, and miR-122. Other miRNAs inhibit the translation of lysophosphatidic acid receptors, such as miR-15b, miR-23a, and miR200c, or proteins that are downstream of lysophosphatidic acid signaling, such as miR-146 and miR-21. With thousands of miRNAs still uncharacterized, it is anticipated that the complex regulation of lysophosphatidic acid signaling by miRNAs will continue to be elucidated. RNA-based therapeutics have entered the clinic with enormous potential in precision medicine. This exciting field is rapidly emerging and it will be fascinating to witness its expansion in scope.

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Ozone Therapy as Adjuvant for Cancer Treatment: Is Further Research Warranted?

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/7931849 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 11

Author(s):

Bernardino Clavo ◽

Norberto Santana-Rodríguez ◽

Pedro Llontop ◽

Dominga Gutiérrez ◽

Gerardo Suárez ◽

...

Keyword(s):

Cancer Treatment ◽

Immune Modulation ◽

Animal Studies ◽

Potential Role ◽

Randomized Clinical Trials ◽

Tumor Hypoxia ◽

Tumor Resection ◽

Ozone Therapy

Introduction. This article provides an overview of the potential use of ozone as an adjuvant during cancer treatment.Methods. We summarize the findings of the most relevant publications focused on this goal, and we include our related clinical experience.Results. Over several decades, prestigious journals have publishedin vitrostudies on the capacity of ozone to induce direct damage on tumor cells and, as well, to enhance the effects of radiotherapy and chemotherapy. Indirect effects have been demonstrated in animal models: immune modulation by ozone alone and sensitizing effect of radiotherapy by concurrent ozone administration. The effects of ozone in modifying hemoglobin dissociation curve, 2,3-diphosphoglycerate levels, locoregional blood flow, and tumor hypoxia provide additional support for potential beneficial effects during cancer treatment. Unfortunately, only a few clinical studies are available. Finally, we describe some works and our experience supporting the potential role of local ozone therapy in treating delayed healing after tumor resection, to avoid delays in commencing radiotherapy and chemotherapy.Conclusions.In vitroand animal studies, as well as isolated clinical reports, suggest the potential role of ozone as an adjuvant during radiotherapy and/or chemotherapy. However, further research, such as randomized clinical trials, is required to demonstrate its potential usefulness as an adjuvant therapeutic tool.

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Inhibition of endotoxin-induced lung inflammation by interleukin-10 gene transfer in mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2000.279.5.l872 ◽

2000 ◽

Vol 279 (5) ◽

pp. L872-L877 ◽

Cited By ~ 11

Author(s):

Sujatha Dokka ◽

Carl J. Malanga ◽

Xianglin Shi ◽

Fei Chen ◽

Vincent Castranova ◽

...

Keyword(s):

Gene Transfer ◽

Lung Inflammation ◽

Transgene Expression ◽

Tumor Necrosis ◽

Interleukin 10 ◽

Inhibitory Effect ◽

Biologically Active ◽

Tnf Α ◽

Anti Inflammatory Cytokine ◽

Necrosis Factor

Interleukin (IL)-10 is an anti-inflammatory cytokine that has great potential for use in the treatment of inflammatory and immune illnesses. In this study, gene transfer was used to induce IL-10 transgene expression in murine lungs for treatment of endotoxin-induced lung inflammation. Gene transfer was performed with a cytomegalovirus (CMV)-IL-10 plasmid with the aid of the liposomal agents LipofectAMINE and N-[1-(2,3-dioleoyl)propyl]- N, N, N-trimethylammonium methylsulfate (DOTAP). Administration of the endotoxin caused a marked increase in lung inflammation as indicated by increased tumor necrosis factor (TNF)-α release and neutrophil count. Pretreatment of the mice with IL-10 plasmid with and without LipofectAMINE had no inhibitory effect on lung inflammation and IL-10 transgene expression. LipofectAMINE by itself induced lung inflammation, an effect that was not observed with DOTAP. IL-10 plasmid when codelivered with DOTAP expressed biologically active IL-10 protein and caused a reduction in endotoxin-induced inflammation. Transgene expression was observed as early as 3 h after administration, peaked at 12 h, and declined thereafter. We conclude that IL-10 gene transfer is a feasible approach for the treatment of lung inflammation.

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