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1.
Cancer Sci ; 112(10): 4176-4186, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34327778

RESUMO

As a POU homeodomain transcription factor, POU4F2 has been implicated in regulating tumorigenic processes in various cancers. However, the role of POU4F2 in colorectal cancer (CRC) remains unclear. Here, we revealed that POU4F2 functions as a tumor promotor in CRC. Bioinformatics analysis in specimens from CRC patients and expression analysis in CRC cell lines showed that POU4F2 was upregulated at the mRNA and protein levels in CRC. Depletion of POU4F2 suppressed the metastatic phenotypes of CRC cells, including cell migration, invasion, and the expression of epithelial-mesenchymal transition (EMT) markers. Moreover, depletion of POU4F2 decreased the number of lung metastatic nodes in nude mice. Mechanistically, POU4F2 positively regulated the Hedgehog signaling pathway, as inferred from the downregulation of the expression of sonic Hedgehog homolog, patched 1, Smoothened, and GLI family zinc finger 1 in vitro and vivo following silencing of POU4F2. Furthermore, the SMO agonist SAG reversed the effects of POU4F2 knockdown in CRC. Functionally, POU4F2 contributed to the Hedgehog signaling-regulated activation of the EMT process and promotion of CRC cell migration and invasion. Collectively, these findings elucidated the role of POU4F2 as a tumor promotor in CRC through the regulation of Hedgehog signaling-mediated EMT and suggested that POU4F2 suppression might be a promising therapeutic target in inhibiting CRC metastasis.


Assuntos
Movimento Celular , Neoplasias Colorretais/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Proteínas Hedgehog/metabolismo , Invasividade Neoplásica , Fator de Transcrição Brn-3B/fisiologia , Animais , Linhagem Celular Tumoral , Colo/metabolismo , Colo/patologia , Neoplasias Colorretais/patologia , Cicloexilaminas/farmacologia , Regulação para Baixo , Inativação Gênica , Humanos , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia de Alvo Molecular , Receptor Patched-1/metabolismo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Receptor Smoothened/agonistas , Receptor Smoothened/metabolismo , Tiofenos/farmacologia , Fator de Transcrição Brn-3B/antagonistas & inibidores , Fator de Transcrição Brn-3B/genética , Fator de Transcrição Brn-3B/metabolismo , Regulação para Cima , Dedos de Zinco
2.
J Cell Biochem ; 102(1): 1-12, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17668438

RESUMO

Osteoclastic bone resorption is a central mechanism in skeletal development, remodeling and pathology. RANKL is a mandatory factor controlling osteoclastogenesis; however, the underlying signaling pathways are only partially characterized. Using a screening array for the investigation of differential transcription factor activation, we identified activation of the Brn3 transcription factor family as a downstream event of RANKL signaling during terminal osteoclastogenesis. RANKL stimulation induces expression of Brn3a and b and maximal transcriptional activity of Brn3 family members concurrent with osteoclastic giant cell formation. Immunohistochemical analysis revealed both nuclear and cytoplasmic localization of Brn3a and b in mature osteoclasts. Functional inhibition of Brn3 transcription factors resulted in inhibition of pre-osteoclast fusion and reduction in bone resorbing activity of mature osteoclasts. Furthermore, we identified synaptotagmin-1, a regulator of membrane and vesicular fusion, as downstream target of Brn3 with a role in osteoclast function. We conclude that Brn-3 represents a novel molecular differentiation factor that controls osteoclast maturation and function, suggesting an important role in bone metabolism.


Assuntos
Proteínas de Homeodomínio/fisiologia , Osteoclastos/fisiologia , Fator de Transcrição Brn-3A/fisiologia , Fator de Transcrição Brn-3B/fisiologia , Animais , Sequência de Bases , Reabsorção Óssea , Diferenciação Celular , Células Cultivadas , Sequência Consenso , Proteínas de Homeodomínio/antagonistas & inibidores , Proteínas de Homeodomínio/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Oligonucleotídeos/química , Osteoclastos/citologia , Osteoclastos/metabolismo , Sinaptotagmina I/fisiologia , Fator de Transcrição Brn-3A/antagonistas & inibidores , Fator de Transcrição Brn-3A/metabolismo , Fator de Transcrição Brn-3B/antagonistas & inibidores , Fator de Transcrição Brn-3B/metabolismo , Ativação Transcricional
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