A new mouse model to study the role of ectopic Nanos3 expression in cancer

Autor: Joachim Taminau, Vanessa Andries, Geert Berx, Kelly Lemeire, Katrien Staes, Evi De Keuckelaere, Frans van Roy, Tino Hochepied, Philippe Birembaut
Přispěvatelé: Inflammation Research Center [Gand, Belgique] (IRC), Universiteit Gent = Ghent University [Belgium] (UGENT)-Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Department of Biomedical Molecular Biology [Ghent], Universiteit Gent = Ghent University [Belgium] (UGENT), Cancer Research Institute Ghent [Gand, Belgique] (CRIG), Department of Biopathology [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims)-Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported in part by the Belgian Federation for the Study Against Cancer (Stichting tegen Kanker) to Prof. Frans van Roy (Grant 2012–191) and Prof. Geert Berx (Grant B/13590), by the Research Foundation – Flanders (Fonds Wetenschappelijk Onderzoek - FWO-Vlaanderen – Grant G.0235.10 N) to Prof. Frans van Roy, by the Belgian Science Policy (Federaal Wetenschapsbeleid - Interuniversity Attraction Poles – Award IAP7/07) to Prof. Frans van Roy, and by Ghent University (Concerted Research Actions - Grant BOF08/GOA/019) to Prof. Frans van Roy. EDK has been a Ph.D. fellow of FWO-Vlaanderen., Universiteit Gent = Ghent University (UGENT)-Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Universiteit Gent = Ghent University (UGENT), Bodescot, Myriam
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
Cancer Research
Lung Neoplasms
INVASION
Kaplan-Meier Estimate
Ectopic Gene Expression
ACTIVATION
Mice
0302 clinical medicine
Carcinoma
Non-Small-Cell Lung
Medicine and Health Sciences
Tumor Cells
Cultured
Transgenes
INDUCTION
PUMILIO
RNA-Binding Proteins
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Allografts
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
NANOS3 Gene
Doxycycline
Female
Germ cell
Signal Transduction
Research Article
Genetically modified mouse
GENES
PROTEINS
Transgene
Cre recombinase
Mice
Nude
Mice
Transgenic
[SDV.CAN]Life Sciences [q-bio]/Cancer
Biology
Mouse embryogenesis
lcsh:RC254-282
03 medical and health sciences
LUNG-CANCER
[SDV.CAN] Life Sciences [q-bio]/Cancer
Genetics
medicine
[SDV.BBM] Life Sciences [q-bio]/Biochemistry
Molecular Biology
Animals
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
ROSA26 locus
COMPLEX
Integrases
Lung cancer model
Biology and Life Sciences
Cancer
ADENOCARCINOMA
Neoplasms
Experimental
medicine.disease
NANOS
Mice
Inbred C57BL
030104 developmental biology
CELLS
Cancer research
Cre-loxP
Ectopic expression
Cre-Lox recombination
Tumor Suppressor Protein p53
Zdroj: BMC Cancer
BMC Cancer, BioMed Central, 2019, 19 (1), pp.598. ⟨10.1186/s12885-019-5807-x⟩
BMC Cancer, 2019, 19 (1), pp.598. ⟨10.1186/s12885-019-5807-x⟩
BMC CANCER
BMC Cancer, Vol 19, Iss 1, Pp 1-17 (2019)
ISSN: 1471-2407
DOI: 10.1186/s12885-019-5807-x⟩
Popis: Background NANOS3 is a gene conserved throughout evolution. Despite the quite low conservation of Nanos sequences between different organisms and even between Nanos paralogs, their role in germ cell development is remarkably universal. Human Nanos3 expression is normally restricted to the gonads and the brain. However, ectopic activation of this gene has been detected in various human cancers. Until now, Nanos3 and other Nanos proteins have been studied almost exclusively in germ cell development. Methods Transgenic mice were generated by targeted insertion of a human Nanos3 cDNA into the ROSA26 locus. The transgene could be spatiotemporally induced by Cre recombinase activity removing an upstream floxed STOP cassette. A lung tumor model with ectopic Nanos3 expression was based on the lung-specific activation of the reverse tetracycline transactivator gene, in combination with a tetO-CMV promoter controlling Cre expression. When doxycycline was provided to the mice, Cre was activated leading to deletion of TP53 alleles and activation of both oncogenic KRasG12D and Nanos3. Appropriate controls were foreseen. Tumors and tumor-derived cell cultures were analyzed in various ways. Results We describe the successful generation of Nanos3LSL/− and Nanos3LSL/LSL mice in which an exogenous human NANOS3 gene can be activated in vivo upon Cre expression. These mice, in combination with different conditional and doxycycline-inducible Cre lines, allow the study of the role of ectopic Nanos3 expression in several cancer types. The Nanos3LSL mice were crossed with a non-small cell lung cancer (NSCLC) mouse model based on conditional expression of oncogenic KRas and homozygous loss of p53. This experiment demonstrated that ectopic expression of Nanos3 in the lungs has a significant negative effect on survival. Enhanced bronchiolar dysplasia was observed when Nanos3-expressing NSCLC mice were compared with control NSCLC mice. An allograft experiment, performed with cell cultures derived from primary lung tumors of control and Nanos3-expressing NSCLC mice, revealed lymph node metastasis in mice injected with Nanos3-expressing NSCLC cells. Conclusions A new mouse model was generated allowing examination of Nanos3-associated pathways and investigation of the influence of ectopic Nanos3 expression in various cancer types. This model might identify Nanos3 as an interesting target in cancer therapeutics. Electronic supplementary material The online version of this article (10.1186/s12885-019-5807-x) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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