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CRISPR, Cancer, and p53
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CRISPR, Cancer, and p53

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (31 December 2019)

Special Issue Editor

Dr. Amin Hajitou

E-Mail Website
Guest Editor
Faculty of Medicine, Department of Brain Sciences, Imperial College London, London W12 0NN, UK
Interests: cancer targeted therapies; bacteriophage gene delivery; gene therapy; cancer immunotherapy; vaccine delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mutations of the tumor suppressor p53 gene are the most frequent abnormality identified in human tumors. Restoration of the natural function of p53 has been used as a therapeutic strategy against cancer. Gene delivery to transfer a wild-type copy of the p53 sequence to cancer has been tested as safe and efficient in clinical trials. However, the mutant p53 version still persists within malignant cells, which could interfere with its therapeutic efficacy. Additionally, mutations are distributed throughout the whole p53 gene. Therefore, replacing the entire p53 locus should increase therapeutic efficacy of targeting p53. In this context, a CRISPR-based gene editing system presents a viable approach for the stable recovery of p53 wild-type function via the full replacement of the mutant locus within the tumor genome with a normal p53 copy. Yet, the success of this strategy will depend on the ideal vector that can deliver a CRISPR functional cassette to tumors in an efficient and selective manner. The present Special Issue aims to introduce the potential applications of CRISPR in correcting the p53 function in cancer and the role of nucleic acid delivery technologies that could present a breakthrough in CRISPR-mediated targeted replacement of an abnormal p53 gene in cancer.

Dr. Amin Hajitou
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • p53
  • Tumor suppressor genes
  • Cancer
  • Metastases
  • CRISPR-based genome editing
  • Gene therapy
  • Nucleic acid delivery technologies
  • Targeted therapy

Published Papers (2 papers)

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Research

11 pages, 4133 KiB  
Article
Initial Steps for the Development of a Phage-Mediated Gene Replacement Therapy Using CRISPR-Cas9 Technology
by Jordi Yang Zhou, Keittisak Suwan and Amin Hajitou
J. Clin. Med. 2020, 9(5), 1498; https://doi.org/10.3390/jcm9051498 - 16 May 2020
Cited by 10 | Viewed by 4027
Abstract
p53 gene (TP53) replacement therapy has shown promising results in cancer gene therapy. However, it has been hampered, mostly because of the gene delivery vector of choice. CRISPR-Cas9 technology (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) can knock out the [...] Read more.
p53 gene (TP53) replacement therapy has shown promising results in cancer gene therapy. However, it has been hampered, mostly because of the gene delivery vector of choice. CRISPR-Cas9 technology (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) can knock out the mutated TP53 (mutTP53), but due to its large size, many viral vectors are not suitable or require implemented strategies that lower the therapeutic efficiency. Here, we introduced a bacteriophage or phage-based vector with the ability to target cancer cells and aimed to investigate the feasibility of using this vector to deliver CRISPR-Cas9 transgene in human lung adenocarcinoma cells. First, we produced a tumour-targeted bacteriophage carrying a CRISPR-Cas9 transgene cassette. Next, we investigated any negative impact on vector titers via quantitative polymerase chain reaction (qPCR) and colony-forming agar plate. Last, we combined Western blot analysis and immunofluorescence staining to prove cell transduction in vitro. We showed that the tumour-targeted bacteriophage can package a large-size vector genome, ~10 kb, containing the CRISPR-Cas9 sequence without any negative impact on the active or total number of bacteriophage particles. Then, we detected expression of the Cas9 in human lung adenocarcinoma cells in a targeted and efficient manner. Finally, we proved loss of p53 protein expression when a p53 gRNA was incorporated into the CRISPR-Cas9 phage DNA construct. These proof-of-concept findings support the use of engineered bacteriophage for TP53 replacement therapy in lung cancer. Full article
(This article belongs to the Special Issue CRISPR, Cancer, and p53)
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22 pages, 7463 KiB  
Article
p53 CRISPR Deletion Affects DNA Structure and Nuclear Architecture
by Aline Rangel-Pozzo, Samuel Booth, Pak Lok Ivan Yu, Madhurendra Singh, Galina Selivanova and Sabine Mai
J. Clin. Med. 2020, 9(2), 598; https://doi.org/10.3390/jcm9020598 - 22 Feb 2020
Cited by 4 | Viewed by 4062
Abstract
The TP53 gene is a key tumor suppressor. Although the tumor suppressor p53 was one of the first to be characterized as a transcription factor, with its main function potentiated by its interaction with DNA, there are still many unresolved questions about its [...] Read more.
The TP53 gene is a key tumor suppressor. Although the tumor suppressor p53 was one of the first to be characterized as a transcription factor, with its main function potentiated by its interaction with DNA, there are still many unresolved questions about its mechanism of action. Here, we demonstrate a novel role for p53 in the maintenance of nuclear architecture of cells. Using three-dimensional (3D) imaging and spectral karyotyping, as well as super resolution microscopy of DNA structure, we observe significant differences in 3D telomere signatures, DNA structure and DNA-poor spaces as well gains or losses of chromosomes, between normal and tumor cells with CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-deleted or wild-type TP53. Additionally, treatment with Nutlin-3 results in differences in nuclear architecture of telomeres in wild-type but not in p53 knockout MCF-7 (Michigan Cancer Foundation-7) cells. Nutlin-3 binds to the p53-binding pocket of mouse double minute 2 (MDM2) and blocks the p53-MDM2 interaction. Moreover, we demonstrate that another p53 stabilizing small molecule, RITA (reactivation of p53 and induction of tumor cell apoptosis), also induces changes in 3D DNA structure, apparently in a p53 independent manner. These results implicate p53 activity in regulating nuclear organization and, additionally, highlight the divergent effects of the p53 targeting compounds Nutlin-3 and RITA. Full article
(This article belongs to the Special Issue CRISPR, Cancer, and p53)
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