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Loss of Igf2 Gene Imprinting in Murine Prostate Promotes Widespread Neoplastic Growth.
- Source :
-
Cancer research [Cancer Res] 2017 Oct 01; Vol. 77 (19), pp. 5236-5247. Date of Electronic Publication: 2017 Aug 03. - Publication Year :
- 2017
-
Abstract
- Loss of imprinting (LOI) is an epigenetic event that relaxes an allele-specific restriction on gene expression. One gene that experiences LOI is the paracrine insulin-like growth factor IGF2 , which occurs commonly in human prostate tissues during aging and tumorigenesis. However, the relationship between IGF2 LOI and prostate tumorigenesis has not been established functionally. In this study, we created a mouse model with CTCF-binding site mutations at the Igf2-H19 imprint control region that abolishes CTCF insulator activity, resulting in biallelic Igf2 expression that mimics increased levels seen with aging-induced LOI. We found that Igf2 LOI increased the prevalence and severity of prostatic intraepithelial neoplasia (PIN), a premalignant lesion. Engineering Nkx3.1 deficiency into our model increased the frequency of PIN lesions in an additive fashion. Prostates harboring LOI displayed increased MAPK signaling and epithelial proliferation. In human prostate tissue arrays, we documented a positive correlation in benign tissues of IGF2 levels with phospho-ERK and phospho-AKT levels. Overall, our results establish that Igf2 LOI is sufficient on its own to increase rates of neoplastic development in the prostate by upregulating critical cancer-associated signaling pathways. Cancer Res; 77(19); 5236-47. ©2017 AACR .<br /> (©2017 American Association for Cancer Research.)
- Subjects :
- Animals
Apoptosis
Cell Proliferation
Epigenesis, Genetic
Female
Homeodomain Proteins physiology
Humans
Insulin-Like Growth Factor II metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Prostate metabolism
Prostatic Intraepithelial Neoplasia genetics
Prostatic Intraepithelial Neoplasia metabolism
Prostatic Neoplasms genetics
Prostatic Neoplasms metabolism
Transcription Factors physiology
Tumor Cells, Cultured
Gene Expression Regulation, Neoplastic
Genomic Imprinting genetics
Insulin-Like Growth Factor II genetics
Prostate pathology
Prostatic Intraepithelial Neoplasia pathology
Prostatic Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 77
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 28775169
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-16-3089