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RNA profiling of 6xAOM induced colon tumors from wt, miR-34a IEC deficient, p53 IEC deficient and miR-34a/p53 IEC deficient mice

ABSTRACT: P53 induced Mir34a is a tumor suppressor microRNA that plays important roles in cancer related processes such as proliferation, invasion and metastasis. Simultaneous loss of Mir34a and p53 is often observed in CRC. Here we show that, combined deletion of Mir34a and p53 has synergistic effects in suppressing tumor initiation, progression, invasion and metastasis in CRC by using mice lacking Mir34a and p53 in their intestinal epithelium. By in vivo inhibition of IL6R and SERPINE1, which we identified as up-regulated Mir34a targets in tumors of Mir34a/p53 deficient mice, we obtained preclinical evidence for their therapeutic value for treatment of sporadic CRC.

ORGANISM(S): Mus musculus

PROVIDER: GSE99452 | GEO | 2018/08/31

REPOSITORIES: GEO

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Project description:Endothelial defects significantly contribute to cardiovascular pathology in the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). Using an endothelium-specific progeria mouse model, we identify a novel, endothelium-specific microRNA (miR) signature linked to the p53-senescence pathway and a senescence-associated secretory phenotype (SASP). Progerin-expressing endothelial cells exert profound cell-non-autonomous effects initiating senescence in non-endothelial cell populations and causing immune cell infiltrates around blood vessels. Comparative miR expression analyses revealed unique upregulation of senescence-associated miR34a-5p in endothelial cells with strong accumulation at atheroprone aortic arch regions but also, in whole cardiac- and lung tissues as well as in the circulation of progeria mice. Mechanistically, miR34a-5p knockdown reduced not only p53 levels but also late-stage senescence regulator p16 with no effect on p21 levels, while p53 knockdown reduced miR34a-5p and partially rescued p21-mediated cell cycle inhibition with a moderate effect on SASP. These data demonstrate that miR34a-5p reinforces two separate senescence regulating branches in progerin-expressing endothelial cells, the p53- and p16-associated pathways, which synergistically maintain a senescence phenotype that contributes to cardiovascular pathology. Thus, the key function of circulatory miR34a-5p in endothelial dysfunction-linked cardiovascular pathology offers novel routes for diagnosis, prognosis and treatment for cardiovascular aging in HGPS and potentially geriatric patients. This research was supported by by the Austrian Science Fund grant [P 32595 /Grant DOI: 10.55776/P32595] to Selma Osmanagic-Myers, and (I 4694-B) to Roland Foisner, the latter under the frame of EJP RD, the European Joint Programme on Rare Diseases. In addition, this project has received funding from the European Union’s Horizon 2020 research and innovation programme under the EJP RD COFUND-EJP N 825575. https://www.doi.org/10.55776/P32595

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RNA profiling of 6xAOM induced colon tumors from wt, miR-34a IEC deficient, p53 IEC deficient and miR-34a/p53 IEC deficient mice

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