KLF4 as a rheostat of osteolysis and osteogenesis in prostate tumors in the bone
| Autor: | Ana Sastre-Perona, Lei Bu, Jonathan Melamed, Evelyne Tassone, Alireza Khodadadi-Jamayran, Vivian Bradaschia-Correa, Philipp Leucht, Elaine L. Wilson, Markus Schober, Xiaozhong Xiong, Anne M Josephson, Liliana Ossowski, David J. Kahler |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Cancer Research Osteolysis Kruppel-Like Transcription Factors Bone Neoplasms Biology bone Article osteogenesis Cohort Studies 03 medical and health sciences Prostate cancer Kruppel-Like Factor 4 Mice 0302 clinical medicine stomatognathic system Prostate Cell Line Tumor Genetics medicine Null cell Animals Humans Molecular Biology Cell Proliferation KLF4 prostate tumors bone fungi Prostatic Neoplasms medicine.disease prostate cancer prostate tumors KLF4 030104 developmental biology medicine.anatomical_structure Cell culture 030220 oncology & carcinogenesis Cancer cell embryonic structures Cancer research Heterografts sense organs Stem cell biological phenomena cell phenomena and immunity transcriptional program |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 |
| Popis: | We previously showed that KLF4, a gene highly expressed in murine prostate stem cells, blocks the progression of indolent intraepithelial prostatic lesions into aggressive and rapidly growing tumors. Here, we show that the anti-tumorigenic effect of KLF4 extends to PC3 human prostate cancer cells growing in the bone. We compared KLF4 null cells with cells transduced with a DOX-inducible KLF4 expression system, and find KLF4 function inhibits PC3 growth in monolayer and soft agar cultures. Furthermore, KLF4 null cells proliferate rapidly, forming large, invasive, and osteolytic tumors when injected into mouse femurs, whereas KLF4 re-expression immediately after their intra-femoral inoculation blocks tumor development and preserves a normal bone architecture. KLF4 re-expression in established KLF4 null bone tumors inhibits their osteolytic effects, preventing bone fractures and inducing an osteogenic response with new bone formation. In addition to these profound biological changes, KLF4 also induces a transcriptional shift from an osteolytic program in KLF4 null cells to an osteogenic program. Importantly, bioinformatic analysis shows that genes regulated by KLF4 overlap significantly with those expressed in metastatic prostate cancer patients and in three individual cohorts with bone metastases, strengthening the clinical relevance of the findings in our xenograft model. |
| Databáze: | OpenAIRE |
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