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1.
Oncogene ; 38(29): 5766-5777, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31239516

RESUMO

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.


Assuntos
Neoplasias Ósseas/secundário , Fatores de Transcrição Kruppel-Like/fisiologia , Osteólise/fisiopatologia , Neoplasias da Próstata/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Estudos de Coortes , Xenoenxertos , Humanos , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Camundongos , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo
2.
Cell Rep ; 25(11): 3006-3020.e7, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30540935

RESUMO

There is a considerable need to identify those individuals with prostate cancer who have indolent disease. We propose that genes that control adult stem cell homeostasis in organs with slow turnover, such as the prostate, control cancer fate. One such gene, KLF4, overexpressed in murine prostate stem cells, regulates their homeostasis, blocks malignant transformation, and controls the self-renewal of tumor-initiating cells. KLF4 loss induces the molecular features of aggressive cancer and converts PIN lesions to invasive sarcomatoid carcinomas; its re-expression in vivo reverses this process. Bioinformatic analysis links these changes to human cancer. KLF4 and its downstream targets make up a gene signature that identifies indolent tumors and predicts recurrence-free survival. This approach may improve prognosis and identify therapeutic targets for advanced cancer.


Assuntos
Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Homeostase , Fatores de Transcrição Kruppel-Like/genética , Células-Tronco Neoplásicas/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Autorrenovação Celular/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Transição Epitelial-Mesenquimal/genética , Humanos , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Células-Tronco Neoplásicas/metabolismo , Fenótipo , Prognóstico
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