Jehnan Liu1, Harrison T Muturi2, Saja S Khuder1, Raghd Abu Helal3, Hilda E Ghadieh2, Sadeesh K Ramakrishnan1, Meenakshi K Kaw1, Sumona Ghosh Lester1, Ahmed Al-Khudhair4, Philip B Conran5, Khew-Voon Chin4, Cara Gatto-Weis6, Sonia M Najjar7. 1. Center for Diabetes and Endocrine Research, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA. 2. Center for Diabetes and Endocrine Research, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA. 3. Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA. 4. Center for Diabetes and Endocrine Research, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA. 5. Department of Pathology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA. 6. Center for Diabetes and Endocrine Research, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; Department of Pathology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA. 7. Center for Diabetes and Endocrine Research, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, 45701, USA. Electronic address: najjar@ohio.edu.
Abstract
OBJECTIVE: PTEN haploinsufficiency plays an important role in prostate cancer development in men. However, monoallelic deletion of Pten gene failed to induce high prostate intraepithelial neoplasia (PIN) until Pten+/- mice aged or fed a high-calorie diet. Because CEACAM1, a cell adhesion molecule with a potential tumor suppression activity, is induced in Pten+/- prostates, the study aimed at examining whether the rise of CEACAM1 limited neoplastic progression in Pten+/- prostates. METHODS: Pten+/- were crossbred with Cc1-/- mice harboring a null deletion of Ceacam1 gene to produce Pten+/-/Cc1-/- double mutants. Prostates from 7-month old male mice were analyzed histologically and biochemically for PIN progression. RESULTS: Deleting Ceacam1 in Pten+/- mice caused an early development of high-grade PIN in parallel to hyperactivation of PI3 kinase/Akt and Ras/MAP kinase pathways, with an increase in cell proliferation, epithelial-to-mesenchymal transition, angiogenesis and inflammation relative to Pten+/- and Cc1-/- individual mutants. It also caused a remarkable increase in lipogenesis in prostate despite maintaining insulin sensitivity. Concomitant Ceacam1 deletion with Pten+/- activated the IL-6/STAT3 signaling pathways to suppress Irf-8 transcription that in turn, led to a decrease in the expression level of promyelocytic leukemia gene, a well characterized tumor suppressor in prostate. CONCLUSIONS: Ceacam1 deletion accelerated high-grade prostate intraepithelial neoplasia in Pten haploinsufficient mice while preserving insulin sensitivity. This demonstrated that the combined loss of Ceacam1 and Pten advanced prostate cancer by increasing lipogenesis and modifying the STAT3-dependent inflammatory microenvironment of prostate.
OBJECTIVE:PTEN haploinsufficiency plays an important role in prostate cancer development in men. However, monoallelic deletion of Pten gene failed to induce high prostate intraepithelial neoplasia (PIN) until Pten+/- mice aged or fed a high-calorie diet. Because CEACAM1, a cell adhesion molecule with a potential tumor suppression activity, is induced in Pten+/- prostates, the study aimed at examining whether the rise of CEACAM1 limited neoplastic progression in Pten+/- prostates. METHODS:Pten+/- were crossbred with Cc1-/- mice harboring a null deletion of Ceacam1 gene to produce Pten+/-/Cc1-/- double mutants. Prostates from 7-month old male mice were analyzed histologically and biochemically for PIN progression. RESULTS: Deleting Ceacam1 in Pten+/- mice caused an early development of high-grade PIN in parallel to hyperactivation of PI3 kinase/Akt and Ras/MAP kinase pathways, with an increase in cell proliferation, epithelial-to-mesenchymal transition, angiogenesis and inflammation relative to Pten+/- and Cc1-/- individual mutants. It also caused a remarkable increase in lipogenesis in prostate despite maintaining insulin sensitivity. Concomitant Ceacam1 deletion with Pten+/- activated the IL-6/STAT3 signaling pathways to suppress Irf-8 transcription that in turn, led to a decrease in the expression level of promyelocytic leukemia gene, a well characterized tumor suppressor in prostate. CONCLUSIONS:Ceacam1 deletion accelerated high-grade prostate intraepithelial neoplasia in Pten haploinsufficientmice while preserving insulin sensitivity. This demonstrated that the combined loss of Ceacam1 and Pten advanced prostate cancer by increasing lipogenesis and modifying the STAT3-dependent inflammatory microenvironment of prostate.
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