RESUMO
Although cilia loss and cell transformation are frequently observed in the early stage of tumorigenesis, the roles of cilia in cell transformation are unknown. In this study, disrupted ciliogenesis was observed in cancer cells and pancreatic cancer tissues, which facilitated oncogene-induced transformation of normal pancreatic cells (HPDE6C7) and NIH3T3 cells through activating the mevalonate (MVA) pathway. Disruption of ciliogenesis up-regulated MVA enzymes through ß catenin-T cell factor (TCF) signaling, which synchronized with sterol regulatory element binding transcription factor 2 (SREBP2), and the regulation of MVA by ß-catenin-TCF signaling was recapitulated in a mouse model of pancreatic ductal adenocarcinoma (PDAC) and human PDAC samples. Moreover, disruption of ciliogenesis by depleting Tg737 dramatically promoted tumorigenesis in the PDAC mouse model, driven by KrasG12D , which was inhibited by statin, an inhibitor of the MVA pathway. Collectively, this study emphasizes the crucial roles of cilia in governing the early steps of the transformation by activating the MVA pathway, suggesting that statin has therapeutic potential for pancreatic cancer treatment.
Assuntos
Transformação Celular Neoplásica/metabolismo , Cílios/patologia , Redes e Vias Metabólicas , Ácido Mevalônico/metabolismo , Animais , Carcinoma Ductal Pancreático/etiologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Células NIH 3T3 , Oncogenes , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteína de Ligação a Elemento Regulador de Esterol 2 , Fatores de Transcrição TCF/metabolismo , Neoplasias PancreáticasRESUMO
<p><b>OBJECTIVE</b>To evaluate the plasma membrane integrity and morphology of fresh and frozen goat spermatozoa.</p><p><b>METHODS</b>The ejaculates of three male goats were obtained by the artificial vagina method of collection and the rates of sperm abnormality and acrosome integrity were detected after freezing-thawing processing. The plasma membrane integrity of the fresh and frozen-thawed goat spermatozoa was evaluated with a combination of fluorescent probes, carboxyfluorescein diacetate and propidium iodide.</p><p><b>RESULTS</b>The freezing-thawing process significantly influenced the viability and integrity of the spermatozoa ([74.43 +/- 13.78]% vs. [46.25 +/- 2.69]%; [64.26 +/- 7.03]% vs. [6.27 +/- 2.90]%, P < 0.01). The results showed differences in acrosome integrity rate between the fresh and frozen samples ([80.77 +/- 10.70]% vs. [58.42 +/- 18.05]% , P < 0.05).</p><p><b>CONCLUSION</b>The freezing-thawing process significantly reduces sperm viability and acrosome integrity and seriously damages the plasma membrane integrity.</p>
