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Pirin inhibits cellular senescence in melanocytic cells.

ABSTRACT: Cellular senescence has been widely recognized as a tumor suppressing mechanism that acts as a barrier to cancer development after oncogenic stimuli. A prominent in vivo model of the senescence barrier is represented by nevi, which are composed of melanocytes that, after an initial phase of proliferation induced by activated oncogenes (most commonly BRAF), are blocked in a state of cellular senescence. Transformation to melanoma occurs when genes involved in controlling senescence are mutated or silenced and cells reacquire the capacity to proliferate. Pirin (PIR) is a highly conserved nuclear protein that likely functions as a transcriptional regulator whose expression levels are altered in different types of tumors. We analyzed the expression pattern of PIR in adult human tissues and found that it is expressed in melanocytes and has a complex pattern of regulation in nevi and melanoma: it is rarely detected in mature nevi, but is expressed at high levels in a subset of melanomas. Loss of function and overexpression experiments in normal and transformed melanocytic cells revealed that PIR is involved in the negative control of cellular senescence and that its expression is necessary to overcome the senescence barrier. Our results suggest that PIR may have a relevant role in melanoma progression.

SUBMITTER: Licciulli S

PROVIDER: S-EPMC3081152 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Pirin inhibits cellular senescence in melanocytic cells.

Licciulli Silvia S Luise Chiara C Scafetta Gaia G Capra Maria M Giardina Giuseppina G Nuciforo Paolo P Bosari Silvano S Viale Giuseppe G Mazzarol Giovanni G Tonelli Chiara C Lanfrancone Luisa L Alcalay Myriam M

The American journal of pathology 20110501 5

Cellular senescence has been widely recognized as a tumor suppressing mechanism that acts as a barrier to cancer development after oncogenic stimuli. A prominent in vivo model of the senescence barrier is represented by nevi, which are composed of melanocytes that, after an initial phase of proliferation induced by activated oncogenes (most commonly BRAF), are blocked in a state of cellular senescence. Transformation to melanoma occurs when genes involved in controlling senescence are mutated or ...[more]

PMID: 21514450

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Project description:BackgroundDoctors have always been overwhelmed by tumor drug resistance because it is a major challenge in the clinical treatment of tumors. Cellular senescence has a strong relationship with the development of tumor drug resistance. Herein, we aimed to explore new regulatory factors involved in the aging process of colorectal cancer (CRC) cells and assess the effect of cellular senescence on CRC drug resistance.MethodsGenes associated with cellular senescence for anticipating regulatory factors were first used, and the regulatory molecules of survival significance were then identified based on the results of public database analysis. The effects of E2F translation factor 1 (E2F1) on CRC cell viability, invasion, migration, and cellular senescence processes were assessed through 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT), 5-Ethynyl-2'-deoxyuridine (EdU), Transwell, scar repairining, β-galactosidase staining, and cell immunofluorescence assays, respectively. Overexpression or silencing plasmids were used for transfecting HCT116 or OXA-HCT116 to assess the effect of E2F1 on the senescence process and drug resistance in CRC cells.ResultsOn combining the database analysis results with those of our studies, we found that E2F1 was a critical regulator of cellular senescence in CRC. In the in vitro experiments, the E2F1 overexpression significantly stimulated the proliferation, invasion, and migration of CRC cells and even reduced oxaliplatin-induced senescence, further enhancing their resistance to oxaliplatin. Conversely, the tumorigenesis of colorectal cancer was repressed after the suppression of E2F1. Furthermore, CRC cells, which were otherwise resistant to oxaliplatin, also showed senescent phenotypes.ConclusionsOur results suggest that E2F1 suppresses the aging of CRC cells and tumor cells develop resistance to oxaliplatin through high E2F1 expression. Moreover, E2F1 may act as a possible target for oxaliplatin resistance studies.

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Pirin inhibits cellular senescence in melanocytic cells.

Publications

Pirin inhibits cellular senescence in melanocytic cells.

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