The Journal of pathology, 2019-01, Vol.247 (1), p.72-85
2019
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- Autor(en) / Beteiligte
- Titel
- Tumor suppressive function of E2F‐1 on PTEN‐induced serrated colorectal carcinogenesis
- Ist Teil von
- The Journal of pathology, 2019-01, Vol.247 (1), p.72-85
- Ort / Verlag
- Chichester, UK: John Wiley & Sons, Ltd
- Erscheinungsjahr
- 2019
- Quelle
- Access via Wiley Online Library
- Beschreibungen/Notizen
- Many human cancers present Phosphatase and tensin homolog (PTEN) deficiency and between 20 and 30% of colorectal tumors show PTEN loss. The transcription factor, E2 promoter binding factor 1 (E2F‐1), exhibits tumor promoter or suppressive functions depending on cellular type and tissue context, but its role in the progression and development of colorectal carcinogenesis was largely unknown. Here, using a tamoxifen‐inducible PTEN knockout mouse model, we have demonstrated that loss of PTEN leads to the development of colorectal tumorigenesis through the serrated pathway. Next, we studied PTEN loss‐driven colorectal lesions in the context of E2F‐1 deficiency in vivo. Our results revealed that monoallelic and biallelic absence of E2F‐1 led to an increased incidence and progression of serrated tumorigenesis induced by PTEN loss. Finally, we investigated the mechanisms by which double PTEN/E2F‐1 deficiency leads to enhanced tumorigenesis. We found that colorectal tumors from PTEN/E2F‐1 double knockout mice and the human colorectal carcinoma cell line HT29 with shRNA‐mediated downregulation of PTEN and E2F‐1 exhibit hyperactivation of the RAS‐MAPK pathway, accumulation of DNA damage and resistance to apoptosis. To date, this is the first preclinical study evaluating the effect of genetic deletion of E2F‐1 in colorectal malignancies driven by PTEN deficiency. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0022-3417eISSN: 1096-9896DOI: 10.1002/path.5168Titel-ID: cdi_proquest_journals_2157432300
- Format
- –
- Schlagworte
- Animals, Apoptosis, Carcinogenesis, Clonal deletion, Colorectal cancer, Colorectal carcinoma, Colorectal Neoplasms - enzymology, Colorectal Neoplasms - genetics, Colorectal Neoplasms - pathology, DNA Damage, E2F1 Transcription Factor - genetics, E2F1 Transcription Factor - metabolism, E2F‐1, Gene Expression Regulation, Neoplastic, Homology, HT29 Cells, Humans, Lesions, MAP kinase, Mice, Knockout, Mitogen-Activated Protein Kinases - metabolism, PTEN, PTEN Phosphohydrolase - genetics, PTEN Phosphohydrolase - metabolism, PTEN protein, ras Proteins - metabolism, serrated pathway, Signal Transduction, Tamoxifen, Tensin, Tumor Suppressor Proteins - genetics, Tumor Suppressor Proteins - metabolism, Tumorigenesis, Tumors