A Transgenic Model Reveals the Role of Klotho in Pancreatic Cancer Development and Paves the Way for New Klotho-Based Therapy
Rubinstein, Tammi Arbel (Institute of Oncology, Tel Aviv Sourasky Medical Center)
Reuveni, Inbal (Institute of Oncology, Tel Aviv Sourasky Medical Center)
Hesin, Arkadi (Institute of Oncology, Tel Aviv Sourasky Medical Center)
Klein-Goldberg, Anat (Institute of Oncology, Tel Aviv Sourasky Medical Center)
Olauson, Hannes (Karolinska Institutet (Estocolm, Suècia))
Larsson, Tobias E. (Karolinska University Hospital and Karolinska Institutet (Suècia))
Abraham, Carmela R. (Boston University School of Medicine. Department of Biochemistry)
Zeldich, Ella (Boston University School of Medicine. Department of Biochemistry)
Bosch i Merino, Assumpció (Universitat Autònoma de Barcelona. Institut de Neurociències)
Chillón Rodríguez, Miguel (Universitat Autònoma de Barcelona. Institut de Neurociències)
Hollander, Kenneth Samuel (Institute of Oncology, Tel Aviv Sourasky Medical Center)
Shabtay-Orbach, Ayelet (Institute of Oncology, Tel Aviv Sourasky Medical Center)
Vainer, Gilad W. (Pathology Institute, Tel Aviv Sourasky Medical Center)
Wolf, Ido (Institute of Oncology, Tel Aviv Sourasky Medical Center)
Rubinek, Tami (Institute of Oncology, Tel Aviv Sourasky Medical Center)

Fecha:	2021
Descripción:	13 pàg.
Resumen:	Klotho is an anti-aging transmembrane protein, which can be shed and can function as a hormone. Accumulating data indicate that klotho is a tumor suppressor in a wide array of malignancies, and designate the subdomain KL1 as the active region of the protein towards this activity. We aimed to study the role of klotho as a tumor suppressor in pancreatic ductal adenocarcinoma (PDAC). Bioinformatics analyses of The Cancer Genome Atlas (TCGA) datasets revealed a correlation between the survival of PDAC patients, levels of klotho expression, and DNA methylation, and demonstrated a unique hypermethylation pattern of klotho in pancreatic tumors. The in vivo effects of klotho and KL1 were examined using three mouse models. Employing a novel genetic model, combining pancreatic klotho knockdown with a mutation in Kras, the lack of klotho contributed to PDAC generation and decreased mousece survival. In a xenograft model, administration of viral particles carrying sKL, a spliced klotho isoform containing the KL1 domain, inhibited pancreatic tumors. Lastly, treatment with soluble sKL prolonged survival of Pdx1-Cre; KrasG12D/+;Trp53R172H/+ (KPC) mice, a model known to recapitulate human PDAC. In conclusion, this study provides evidence that klotho is a tumor suppressor in PDAC. Furthermore, these data suggest that the levels of klotho expression and DNA methylation could have prognostic value in PDAC patients, and that administration of exogenous sKL may serve as a novel therapeutic strategy to treat PDAC.
Ayudas:	Agencia Estatal de Investigación PID2019-104034RB-I00
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Klotho ; KL1 ; Skl ; Tumor suppressor ; Pancreatic cancer ; PDAC ; SDG 3 - Good Health and Well-being
Publicado en:	Cancers, Vol. 13 Núm. 24 (2021) , p. 6297, ISSN 2072-6694

DOI: 10.3390/cancers13246297
PMID: 34944918

13 p, 2.3 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut de Neurociències (INc)
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