RESUMO
Osteosarcoma, considered as the primary cause of malignant bone tumors in children, necessitates novel therapeutic strategies to enhance overall survival rates. KAT7, a histone acetyltransferase, exerts pivotal functions in gene transcription and immune modulation. In light of this, our study identified a significant upregulation of KAT7 in the mRNA and protein levels in human osteosarcoma, boosting cell proliferation in vivo and in vitro. In addition, KAT7-mediated H3K14ac activation induced MMP14 transcription, leading to increased expression and facilitation of osteosarcoma cell metastasis. Subsequent bioinformatics analyses highlighted a correlation between KAT7 and adaptive immune responses, indicating CCL3 as a downstream target of KAT7. Mechanistically, STAT1 was found to transcriptionally upregulate CCL3 expression. Furthermore, overexpression of KAT7 suppressed CCL3 secretions, whereas knockdown of KAT7 enhanced its release. Overall, these findings underscore the oncogenic role of KAT7 in regulating immune responses for osteosarcoma treatment.
Assuntos
Neoplasias Ósseas , Quimiocina CCL3 , Regulação Neoplásica da Expressão Gênica , Histona Acetiltransferases , Osteossarcoma , Fator de Transcrição STAT1 , Transdução de Sinais , Animais , Humanos , Camundongos , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Quimiocina CCL3/metabolismo , Quimiocina CCL3/genética , Histona Acetiltransferases/metabolismo , Histona Acetiltransferases/genética , Camundongos Nus , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/genéticaRESUMO
BACKGROUND: Tumor necrosis factor α (TNFα) antagonists, namely, golimumab, adalimumab, infliximab, etanercept and certolizumab have been prescribed to alleviate and treat ankylosing spondylitis (AS). However, the lack of comparative evidence does not enable us to make constructive recommendations particularly for AS patient populations. METHODS: Eligible controlled trials regarding the above 5 anti-TNFα therapies were searched electronically through PubMed, Embase and Cochrane until April 1, 2015. Odds ratios (ORs) were estimated and compared for efficacy (ASAS20, ASAS40, ASAS5/6 responses and ASAS partial remission) and acceptability (serious adverse effects (SAE)) among the anti-TNFα reagents. RESULTS: Totally, 25 trials with 2989 participants were incorporated in this mixed treatment comparison. All the 5 TNFα blockers achieved better ASAS20, ASAS40, ASAS5/6 and ASAS-PR responses than the placebo. Furthermore, there was no significant distinction existed among inter-drug comparisons, except that unfavorable effects induced by certolizumab seemed to be less severe than those by etanercept (OR = 0.22, 95% CI: 0.05-0.93). Apart from that, etanercept was estimated to arrive at the most favorable ASAS20 response (90.6%) and SAE (83.6%), while infliximab seemed to accomplish the best ASAS40 (83.6%) and ASAS-PR responses (77.3%). In addition, adalimumab was estimated to rank the highest ASAS5/6 response (75.0%). CONCLUSIONS: Etanercept, infliximab and adalimumab might be prioritized among the commonly recognized 5 anti-TNFα therapies specific for AS patients, though existing evidence did not suffice to confirm significant superiority among the above 5 anti-TNFα reagent.
