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Tumor suppressive function of E2F‐1 on PTEN‐induced serrated colorectal carcinogenesis
Author(s) -
Dosil Maria A,
Navaridas Raúl,
Mirantes Cristina,
Tarragona Jordi,
Eritja Núria,
Felip Isidre,
Urdanibia Izaskun,
Megino Cristina,
Domingo Mónica,
Santacana Maria,
Gatius Sònia,
Piñol Carme,
Barceló Carla,
Maiques Oscar,
Macià Anna,
Velasco Ana,
Vaquero Marta,
MatiasGuiu Xavier,
Dolcet Xavier
Publication year - 2019
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5168
Subject(s) - pten , tensin , cancer research , carcinogenesis , biology , colorectal cancer , medicine , pi3k/akt/mtor pathway , cancer , signal transduction , microbiology and biotechnology
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.