Transgenic Overexpression of NanogP8 in the Mouse Prostate is Insufficient to Initiate Tumorigenesis but Weakly Promotes Tumor Development in the Hi-Myc Mouse Model
Oncotarget(2017)
Abstract
This project was undertaken to address a critical cancer biology question: Is overexpression of the pluripotency molecule Nanog sufficient to initiate tumor development in a somatic tissue? Nanog1 is critical for the self-renewal and pluripotency of ES cells, and its retrotransposed homolog, NanogP8 is preferentially expressed in somatic cancer cells. Our work has shown that shRNA-mediated knockdown of NanogP8 in prostate, breast, and colon cancer cells inhibits tumor regeneration whereas inducible overexpression of NanogP8 promotes cancer stem cell phenotypes and properties. To address the key unanswered question whether tissue-specific overexpression of NanogP8 is sufficient to promote tumor development in vivo, we generated a NanogP8 transgenic mouse model, in which the ARR(2)PB promoter was used to drive NanogP8 cDNA. Surprisingly, the ARR(2)PB-NanogP8 transgenic mice were viable, developed normally, and did not form spontaneous tumors in >2 years. Also, both wild type and ARR(2)PB-NanogP8 transgenic mice responded similarly to castration and regeneration and castrated ARR(2)PB-NanogP8 transgenic mice also did not develop tumors. By crossing the ARR(2)PB-NanogP8 transgenic mice with ARR(2)PB-Myc (i.e., Hi-Myc) mice, we found that the double transgenic (i.e., ARR(2)PB-NanogP8; Hi-Myc) mice showed similar tumor incidence and histology to the Hi-Myc mice. Interestingly, however, we observed white dots in the ventral lobes of the double transgenic prostates, which were characterized as overgrown ductules/buds featured by crowded atypical Nanog-expressing luminal cells. Taken together, our present work demonstrates that transgenic overexpression of NanogP8 in the mouse prostate is insufficient to initiate tumorigenesis but weakly promotes tumor development in the Hi-Myc mouse model.
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Key words
NanogP8,Nanog,prostate,prostate cancer,stem cells
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