Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas
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Tartalom: http://clincancerres.aacrjournals.org/content/17/14/4650....
Archívum: MTA Könyvtár
Gyűjtemény: Status = Published

Type = Article
Cím:
Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas
Létrehozó:
Jacob, Karine
Quang-Khuong, Dongh-Anh
Jones, David T. W.
Witt, Hendrik
Lambert, Sally
Albrecht, Steffen
Witt, Olaf
Vezina, Catherine
Shirinian, Margret
Faury, Damien
Garami, Miklos
Hauser, Peter
Klekner, Almos
Bognar, Laszlo
Farmer, Jean-Pierre
Montes, Jose-Luis
Atkinson, Jeffrey
Hawkins, Cynthia
Korshunov, Andrey
Collins, V. Peter
Pfister, Stefan M.
Tabori, Uri
Jabado, Nada
Dátum:
2011-07-15
Téma:
RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia
Tartalmi leírás:
PURPOSE
Oncogenic BRAF/Ras or NF1 loss can potentially trigger oncogene-induced senescence (OIS) through activation of the mitogen-activated protein kinase (MAPK) pathway. Somatic genetic abnormalities affecting this pathway occur in the majority of pilocytic astrocytomas (PA), the most prevalent brain neoplasm in children. We investigated whether OIS is induced in PA.
EXPERIMENTAL DESIGN
We tested expression of established senescence markers in three independent cohorts of sporadic PA. We also assessed for OIS in vitro, using forced expression of wild-type and V600E-mutant BRAF in two astrocytic cell lines: human telomerase reverse transcriptase (hTERT)-immortalized astrocytes and fetal astrocytes.
RESULTS
Our results indicate that PAs are senescent as evidenced by marked senescence-associated acidic ?-galactosidase activity, low KI-67 index, and induction of p16(INK4a) but not p53 in the majority of 52 PA samples (46 of 52; 88.5%). Overexpression of a number of senescence-associated genes [CDKN2A (p16), CDKN1A (p21), CEBPB, GADD45A, and IGFBP7] was shown at the mRNA level in two independent PA tumor series. In vitro, sustained activation of wild-type or mutant BRAF induced OIS in both astrocytic cell lines. Loss of p16(INK4a) in immortalized astrocytes abrogated OIS, indicative of the role of this pathway in mediating this phenomenon in astrocytes. OIS is a mechanism of tumor suppression that restricts the progression of benign tumors. We show that it is triggered in PAs through p16(INK4a) pathway induction following aberrant MAPK activation.
CONCLUSIONS
OIS may account for the slow growth pattern in PA, the lack of progression to higher-grade astrocytomas, and the high overall survival of affected patients.
Típus:
Article
PeerReviewed
Formátum:
text
Azonosító:
Jacob, Karine and Quang-Khuong, Dongh-Anh and Jones, David T. W. and Witt, Hendrik and Lambert, Sally and Albrecht, Steffen and Witt, Olaf and Vezina, Catherine and Shirinian, Margret and Faury, Damien and Garami, Miklos and Hauser, Peter and Klekner, Almos and Bognar, Laszlo and Farmer, Jean-Pierre and Montes, Jose-Luis and Atkinson, Jeffrey and Hawkins, Cynthia and Korshunov, Andrey and Collins, V. Peter and Pfister, Stefan M. and Tabori, Uri and Jabado, Nada (2011) Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clinical Cancer Research, 17 (14). pp. 4650-60. ISSN 1078-0432
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